Jean Sassard - Academia.edu (original) (raw)
Papers by Jean Sassard
American journal of physiology. Renal physiology, 2002
These experiments examined whether the conscious sinoaortic baroreceptor-denervated (SAD) rat, ow... more These experiments examined whether the conscious sinoaortic baroreceptor-denervated (SAD) rat, owing to its high spontaneous arterial pressure (AP) variability, might represent a model for renal blood flow (RBF) autoregulation studies. In eight SAD and six baroreceptor-intact rats, AP and RBF were recorded (1-h periods) before and after furosemide (10 mg/kg followed by 10 mg. kg(-1). h(-1) iv) administration. In control conditions, AP variability was markedly enhanced in SAD rats (coefficient of variation: 16.0 +/- 1.2 vs. 5.4 +/- 0.5% in intact rats), whereas RBF variability was only slightly increased (8.7 +/- 0.6 vs. 6.1 +/- 0.5% in intact rats), suggesting buffering by autoregulatory mechanisms. In SAD rats, but not in intact rats, the AP-RBF relationships could be modeled with a four-parameter sigmoid Weibull equation (r(2) = 0.24 +/- 0.07, 3,600 data pairs/rat), allowing for estimation of an autoregulatory plateau (10.1 +/- 0.7 ml/min) and a lower limit of RBF autoregulation (...
Journal of Lipid Research, 2002
In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the str... more In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the structure and composition of HDL in vivo, simian CETP was expressed in Fisher rat that spontaneously displays high plasma levels of HDL1. In the new CETPTg rat line, the production of active CETP by the liver induced a significant 48% decrease in plasma HDL cholesterol, resulting in a 34% decrease in total cholesterol level (P Ͻ 0.01 in both cases). Among the various plasma HDL subpopulations, the largest HDL were those mostly affected by CETP, with a 74% decrease in HDL1 versus a significantly weaker 38% decrease in smaller HDL2 (P Ͻ 0.0001). Apolipoprotein E (apoE)-containing HDL1 were selectively affected by CETP expression, whereas apoA content of HDL remained unmodified. The reduction in the apoE content of serum HDL observed in CETPTg rats compared to controls (53%, P Ͻ 0.02) suggests that apoE in HDL may constitute in vivo a major determinant of their ability to interact with CETP. These results bring new insight into the lack of HDL1 in plasma from CETP-deficient heterozygotes despite their substantial 50% decrease in CETP activity. In addition, they indicate that HDL1 constitute reliable and practicable sensors of very low plasma CETP activity in vivo.
Hypertension, 2004
The complex nature of hypertension makes identifying the pathophysiology and its genetic contribu... more The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes. We have performed a total genome scan in offspring of an F 2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome ide...
Hypertension, 1999
Adrenocorticosteroid activity in Lyon hypertensive (LH) and low blood pressure (LL) rat strains d... more Adrenocorticosteroid activity in Lyon hypertensive (LH) and low blood pressure (LL) rat strains differ in several respects. Abnormal activity of 11-hydroxysteroid dehydrogenase enzymes (11-HSD1 and 11-HSD2), which interconvert corticosterone and inactive 11-dehydrocorticosterone, might contribute to the LH phenotype by regulating corticosteroid hormone access to receptors. 11-HSD2 (expressed in kidney but not liver) prevents endogenous glucocorticoids from binding to mineralocorticoid receptors. 11-HSD1 (expressed in liver and kidney) favors active glucocorticoid formation from 11-dehydrocorticosterone. 11-HSD properties in LH and LL have been compared by several approaches: (1) 11HSD activities have been measured in vitro as corticosterone dehydrogenation and in vivo as interconversion of injected cortisol and cortisone; (2) the effects of cortisol and cortisone on urine electrolytes and volume have been measured; and (3) 11-HSD mRNA expression has been measured by in situ hybridization. 11-HSD2 enzyme activities in LH and LL rats were similar and urinary cortisone:cortisol ratios were not different after cortisol injection. Cortisol caused a natriuresis and kaliuresis in both strains, with a slightly reduced response in LH rats. Renal 11-HSD2 mRNA expression was slightly lower in LH rats. 11-HSD1 was less active in LH than LL rats: enzyme activities were lower in tissue extracts; urinary cortisone:cortisol was lower in LL rats after cortisone injections; cortisone increased urine volume in LL but not LH rats; and mRNA levels tended to be lower in LH tissues. We conclude that 11-HSD1 is impaired in LH rats. The LH phenotype of heavier adrenals, raised corticosterone, and reduced thymus weight is similar to that described for 11-HSD1 knockout mice.
Hypertension, 1991
Young, genetically hypertensive Lyon (LH) rats exhibited an increased renal in vivo turnover of n... more Young, genetically hypertensive Lyon (LH) rats exhibited an increased renal in vivo turnover of norepinephrine and an elevated urinary excretion of thromboxane B 2 when compared with nonnotensive (LN) and low blood pressure (LL) controls. Therefore, the effects of norepinephrine (1.2 xlO" 8 to 9.6 xlO" 7 M) and of phenylephrine (5xlO~8 to 1.9x10"' M) on renal function and the urinary excretion of prostanoids were assessed in isolated perfused kidneys of 8-week-old LH, LN, and LL rats. In addition, the effects of norepinephrine were assessed before and during thromboxane A 2 /prostaglandin H 2 receptor blockade by AH23848 (4xlO~* M). Before drug infusion, LH kidneys differed from those of LN and LL controls by having an elevated renal vascular resistance and a decreased natriuresis and glomerular filtration rate; the urinary output of prostaglandin E 2 and F^, of 6-ketoprostaglandin F la , and of thromboxane B 2 was similar in the three strains. The constrictor effects of norepinephrine and phenylephrine were significantly increased in LH rat kidneys compared with LL but not with LN controls, and their pressure-natriuresis was markedly reduced. Norepinephrine and phenylephrine induced a 10-to 20-fold dose-dependent increase in the synthesis of the four prostanoids, which was more pronounced in LH than in LN and LL rats for thromboxane B 2 only. AH23848 infusion significantly reduced the vascular effects of norepinephrine and increased the natriuretic response of LH but not of LN and LL rat kidneys. In conclusion, isolated perfused kidneys from LH rats exhibit an increased production of thromboxane A 2 , which enhances the renal effects of norepinephrine and therefore could participate in the development of hypertension of the Lyon model. (Hypertension 1991;17:296-302) W e have previously observed that the urinary excretion of renal thromboxane (Tx) B2, used as an index of the renal synthesis of TxA^1-2 was increased in 5-and 9-week-old genetically hypertensive (LH) rats of the Lyon strain. 3 The same abnormality has also been described in vivo 4 and in vitro 5-6 in spontaneously hypertensive rats (SHR) of the Japanese strain. Because TxA 2 is a potent vasoconstrictor 7 and promotes platelet aggregation, 8 such an increase is likely to play a pathogenic role. This hypothesis is supported by the observation that TxA 2 synthesis inhibition or blockade of TxA 2 receptors delays the onset 9 or reduces 10 the severity of hypertension in SHR and in LH rats. 11 However,
Hypertension, 2001
It is not known whether renal blood flow (RBF) is still autoregulated when the kidney is exposed ... more It is not known whether renal blood flow (RBF) is still autoregulated when the kidney is exposed to large transient blood pressure (BP) fluctuations such as those occurring spontaneously in conscious sinoaortic baroreceptor-denervated (SAD) rats. In this study, BP and RBF were simultaneously recorded in 8 SAD rats (2 weeks before study) and 8 baroreceptor-intact rats during ≈3 hours of spontaneous activity. The kidney used for RBF recordings was denervated to prevent the interference of changes in renal sympathetic tone with autoregulatory mechanisms. In intact rats, RBF variability (coefficient of variation 9.1±0.8%) was larger ( P <0.02) than BP variability (5.9±0.2%). This was mainly because of slow changes in RBF that were unrelated to BP and also to a prominent oscillation of RBF of ≈0.25-Hz frequency. Autoregulatory patterns were identified at frequencies <0.1 Hz and provided a modest attenuation of BP fluctuations. In SAD rats, RBF variability (12.4±1.6%) was lower ( P ...
Genome Research, 2000
Models of human disease have long been used to understand the basic pathophysiology of disease an... more Models of human disease have long been used to understand the basic pathophysiology of disease and to facilitate the discovery of new therapeutics. However, as long as models have been used there have been debates about the utility of these models and their ability to mimic clinical disease at the phenotypic level. The application of genetic studies to both humans and model systems allows for a new paradigm, whereby a novel comparative genomics strategy combined with phenotypic correlates can be used to bridge between clinical relevance and model utility. This study presents a comparative genomic map for “candidate hypertension loci in humans” based on translating QTLs between rat and human, predicting 26 chromosomal regions in the human genome that are very likely to harbor hypertension genes. The predictive power appears robust, as several of these regions have also been implicated in mouse, suggesting that these regions represent primary targets for the development of SNPs for li...
Circulation Research, 2007
A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previ... more A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are 2 distinct BP quantitative trait loci, BP1 and BP2, in this region. Sisa1, a congenic substrain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of 2 new mutually exclusive congenic substrains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only 1 of the substrains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the 20 genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling o...
British Journal of Pharmacology, 1988
The acute cardiovascular effects of PY 108-068 and PN 200-110 were studied by means of a computer... more The acute cardiovascular effects of PY 108-068 and PN 200-110 were studied by means of a computerized analysis of the intra-aortic blood pressure (BP) recorded continuously for 26 h in conscious unrestrained spontaneously hypertensive rats. Both compounds were studied at three doses (50, 100 and 200 lgkg-') and each dose was administered intravenously 5 times (09hOOmin, 14 hOOmin, 19hOOmin, 24hOOmin and 09hOOmin). Baroreflex sensitivity was measured 1 h following the last injection. 2 The two compounds were found to induce rapid (3 min) and dose-dependent falls in BP. After the first administration, these decreases reached-20% and-35% for systolic BP (SBP) and diastolic BP (DBP) respectively with PY 108-068 (200pgkg-') and-25% and-45% for SBP and DBP respectively with PN 200-110 (200 pg kg-'). 3 The duration of the reduction in BP increased with the dose and was much longer for PN 200-110 (180 min for SBP) than for PY 108-068 (20 min for SBP). 4 A tachycardia was associated with the decrease in BP which did not differ at 200 pg kg-' between PY 108-068 (+ 108 beats min-') and PN 200-110 (+ 103 beats min'). Baroreflex sensitivity was not significantly increased by either drug. 5 The 5 repeated injections of PY 108-068 and PN 200-110 evoked similar responses. 6 In conclusion, both compounds exhibited marked hypotensive properties. PN 200-110 appeared to be more suitable for further development since its effects were found to be greater and much longer lasting than those of PY 108-068.
British Journal of Pharmacology, 1999
The present work examined the eects of the subtype 2 of angiotensin II (AT 2) receptors on the pr... more The present work examined the eects of the subtype 2 of angiotensin II (AT 2) receptors on the pressure-natriuresis using a new peptide agonist, and the possible involvement of cyclic guanosine 3', 5' monophosphate (cyclic GMP) in these eects. 2 In adult anaesthetized rats (Inactin, 100 mg kg 71 , i.p.) deprived of endogenous angiotensin II by angiotensin converting enzyme inhibition (quinapril, 10 mg kg 71 , i.v.), T 2-(Ang II 4-8) 2 (TA), a highly speci®c AT 2 receptor agonist (5, 10 and 30 mg kg 71 min 71 , i.v.) or its solvent was infused in four groups. Renal functions were studied at renal perfusion pressures (RPP) of 90, 110 and 130 mmHg and urinary cyclic GMP excretion when RPP was at 130 mmHg. The eects of TA (10 mg kg 71 min 71) were reassessed in animals pretreated with PD 123319 (PD, 50 mg kg 71 min 71 , i.v.), an AT 2 receptor antagonist and the action of the same dose of PD alone was also determined. 3 Increases in RPP from 90 to 130 mmHg did not change renal blood¯ow (RBF) but induced 8 and 15 fold increases in urinary¯ow and sodium excretion respectively. The 5 mg kg 71 min 71 dose of TA was devoid of action. The 10 and 30 mg kg 71 min 71 doses did not alter total RBF and glomerular ®ltration rate, but blunted pressure-diuresis and natriuresis relationships. These eects were abolished by PD. 4 TA decreased urinary cyclic GMP excretion. After pretreatment with PD, this decrease was reversed to an increase which was also observed in animals receiving PD alone. 5 In conclusion, renal AT 2 receptors oppose the sodium and water excretion induced by acute increases in blood pressure and this action cannot be directly explained by changes in cyclic GMP.
In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the str... more In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the structure and composition of HDL in vivo, simian CETP was expressed in Fisher rat that spontaneously displays high plasma levels of HDL1. In the new CETPTg rat line, the production of active CETP by the liver induced a significant 48% decrease in plasma HDL cholesterol, resulting in a 34% decrease in total cholesterol level (P Ͻ 0.01 in both cases). Among the various plasma HDL subpopulations, the largest HDL were those mostly affected by CETP, with a 74% decrease in HDL1 versus a significantly weaker 38% decrease in smaller HDL2 (P Ͻ 0.0001). Apolipoprotein E (apoE)-containing HDL1 were selectively affected by CETP expression, whereas apoA content of HDL remained unmodified. The reduction in the apoE content of serum HDL observed in CETPTg rats compared to controls (53%, P Ͻ 0.02) suggests that apoE in HDL may constitute in vivo a major determinant of their ability to interact with CETP. These results bring new insight into the lack of HDL1 in plasma from CETP-deficient heterozygotes despite their substantial 50% decrease in CETP activity. In addition, they indicate that HDL1 constitute reliable and practicable sensors of very low plasma CETP activity in vivo.
Archives Des Maladies Du Coeur Et Des Vaisseaux, 2007
Le rat genetiquement hypertendu de souche lyonnaise (LH) presente une pression arterielle spontan... more Le rat genetiquement hypertendu de souche lyonnaise (LH) presente une pression arterielle spontanement elevee et sensible au sel, et des signes qui evoquent un syndrome metabolique : surcroit ponderal, hyperlipidemie et augmentation du rapport insuline/glucose. L'analyse de cosegregation effectuee sur les hybrides de seconde generation issus du croisement entre rats genetiquement hypertendus LH et normotendus LN a montre l'existence, sur le chromosome 17, de deux agregats de loci d'interet quantitatif (QTLs). Le premier de ces QTLs est associe a des parametres morphologiques alors que le second influence a la fois le niveau de pression arterielle et celui des lipides plasmatiques. Afin de determiner l'importance fonctionnelle de ces QTLs, nous avons genere une souche de rats LH chez lesquels le chromosome 17 est remplace par celui de rats normotendus Brown Norway (BN) : rats consomiques LH-17 BN . Le phenotypage des rats mâles LH, BN et LH-17 BN comprend l'enregi...
American Journal of Hypertension, 2000
Compared to the Lyon normotensive (LN) controls, adult Lyon hypertensive rats (LH) exhibit a reni... more Compared to the Lyon normotensive (LN) controls, adult Lyon hypertensive rats (LH) exhibit a reninangiotensin system (RAS) dependent hypertension despite a low renin secretion. This discrepancy could be explained by the elevated slow pressor response to angiotensin II (AII) found in LH rats compared to LN controls. To evaluate more precisely the pathophysiological importance of this increased response, the present work aimed at determining whether the characteristics of the RAS were identical in LN and low blood pressure (LL) rats, the other normotensive control strain simultaneously selected with LH rats. Plasma and kidney renin and prorenin were measured in 11-week-old LN and LL rats. Aortic blood pressure (BP) was recorded at 15 weeks of age in freely moving rats of both strains either untreated or having received an angiotensin converting enzyme inhibitor, perindopril (3 mg/kg/day orally) since the age of 3 weeks. Acute dose-response curves were constructed for AII and norepinephrine (NE). The long-term pressor effects of AII (200 ng/kg/ min) and NE (1000 ng/kg/min) were measured after chronic infusions in perindopril-treated LN and LL rats. LN and LL rats exhibited similar mean BP level before (114 ؎ ؎ 2 and 117 ؎ ؎ 2 mm Hg, respectively) and after perindopril treatment (91 ؎ ؎ 3 and 93 ؎ ؎ 1 mm Hg, respectively). Plasma and kidney renin and prorenin were decreased in LL rats. In acute conditions, LL rats exhibited an unspecific hypersensitivity to AII and NE. Chronically given AII exerted a greater pressor effect in LL than in LN rats after 4 weeks (113 ؎ ؎ 3 v 97 ؎ ؎ 5 mm Hg in LL and LN rats respectively, P < < .05) and, even more, after 8 weeks of infusion (144 ؎ ؎ 9 v 124 ؎ ؎ 4 mm Hg in LL and LN rats respectively, P < < .05). The NE was devoid of chronic pressor effects. In conclusion, 1) the increased slow pressor response to AII may not be a critical pathogenetic factor in the development of hypertension, as it also exists in normotensive LL rats; 2) LN and LL rats have the same normal BP despite marked differences in their RAS, thus suggesting that there could be several forms of normotension as known for hypertension; and 3) the simple comparison between one genetically hypertensive strain and one single normotensive control strain does not allow one to conclude that a phenotypic difference is of pathophysiological significance.
Physiological genomics, Jan 11, 2002
One or more quantitative trait locus (QTL) for blood pressure (BP) exists on rat chromosome 1, in... more One or more quantitative trait locus (QTL) for blood pressure (BP) exists on rat chromosome 1, in the vicinity of the Sa gene. The present work examined whether this QTL region: 1) alters pressure-natriuresis relationship and 2) affects the BP response to salt load. Male spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats, and rats from an SHR congenic strain that contains a WKY chromosome 1 segment spanning the BP QTL region (SHR. WKY-Sa) were used. In an acute study in anesthetized animals, renal function was measured at several levels of renal perfusion pressure. In a chronic study, BP was measured in freely moving rats using telemetry during normal and high sodium intake (2% NaCl as drinking water for 2 wk). WKY rats showed a significantly higher glomerular filtration rate and increased pressure-natriuresis compared with SHR. SHR.WKY-Sa also demonstrated an increased glomerular filtration rate and enhanced pressure-natriuresis, associated with a lower tubular sodium r...
American Journal of Hypertension, 2000
Compared with their two normotensive (LN and LL) controls, genetically hypertensive rats of the L... more Compared with their two normotensive (LN and LL) controls, genetically hypertensive rats of the Lyon strain (LH) exhibit increased renal vascular resistance and a blunted pressure natriuresis function as well as an increased urinary excretion of vasoconstrictor prostanoids. The aim of this study was to assess in the kidneys of these animals the synthesis of vasoconstrictor or sodiumretaining prostanoids. The relative abundance of the mRNAs of cyclooxygenases (COX) 1 and 2 and of thromboxane A 2 synthase (TXS), was measured by reverse-transcription polymerase chain reaction (RT-PCR) in renal cortex and medulla dissected in groups of male LH, LN, and LL rats either in baseline conditions or after 1 week of salt loading (1.5% NaCl in the drinking water). In basal conditions, at 3 and 11 weeks of age COX1 was expressed in the kidneys of all rats more markedly in medulla than in cortex. COX2 was poorly expressed in the whole kidney. TXS expression was usually too low to be quantified. No difference could be observed among LH, LN, and LL rats. After salt loading, the expression of COX1 was enhanced in the medulla and that of COX2 reduced in the cortex. LH rats differed from controls by a significantly more marked increase in medullary COX1 expression. The present work excludes any primary generalized increase in the renal expression of the genes that control the synthesis of vasoconstrictor prostanoids in LH rats, but suggests that medullary COX1 is upregulated by salt in these animals.
Physiological Genomics, 2008
The metabolic syndrome (involving obesity, hypertension, dyslipidemia, insulin resistance, and a ... more The metabolic syndrome (involving obesity, hypertension, dyslipidemia, insulin resistance, and a proinflammatory/prethrombotic state) is a major risk factor for cardiovascular disease. Its incidence continues to rise, in part because of the epidemic increase in obesity. The Lyon hypertensive (LH) rat is a model for hypertension and several other features of the metabolic syndrome, having high body weight, plasma cholesterol, and triglycerides, increased insulin-to-glucose ratio, and salt-sensitive hypertension. Previous genetic studies in LH/Mav rats and a normotensive control (LN/Mav) identified quantitative trait loci (QTLs) on rat chromosome (RNO)17 for multiple features of the metabolic syndrome. To further evaluate the role of RNO17 in the LH rat, we generated a consomic strain (LH-17BN) by substituting LH RNO17 with that of the sequenced Brown Norway (BN/NHsdMcwi) rat. Male LH and BN rats and LH-17BNrats were characterized for blood pressure and metabolic and morphological par...
Kidney International, 1988
Effects of DOCA-salt treatment on the urinary prostaglandins in Sabra rats. To determine whether ... more Effects of DOCA-salt treatment on the urinary prostaglandins in Sabra rats. To determine whether the increased renal synthesis of thromboxane (Tx)A2 found in genetically hypertensive rats also occurred in rats with a sodium-dependent form of hypertension, the urinary excretion of 6-keto-prostaglandin Fk. (6KPGF1) and of TxB2 was measured by a sensitive and specific radioimmunoassay in hypertension-prone (SBH),-resistant (SBN) and unselected (SB) female rats of the Sabra strains. Rats of the three strains were studied before (9 weeks of age) and after five weeks of deoxycorticosterone (DOCA)-salt treatment. Before treatment, the urinary 6KPGFI, did not differ among the three strains while a higher TxB2 excretion was seen in the SBN rats. After treatment, the urinary excretion of TxB2 increased significantly in SBH and SB but not in SBN rats, while the urinary 6KPGF1, remained unchanged in SBH, increased moderately in SB and markedly in SBN controls. Consequently, DOCA-salt-induced changes in blood pressure and in urinary 6KPGF observed in the three strains of rats were inversely related (r-0.78; P < 0.001). It is concluded that the high blood pressure developed after DOCA-salt treatment in SBH rats is more likely to depend upon a defect in the renal production of prostacyclin rather than upon an increased synthesis of thromboxane A2.
Journal of Clinical Investigation, 1997
In a backcross population (n ϭ 281) derived from a cross of the Lyon hypertensive rat with Lyon n... more In a backcross population (n ϭ 281) derived from a cross of the Lyon hypertensive rat with Lyon normotensive rat, we investigated whether genetic factors influence the acute cardiovascular responses to pharmacological modulation of the renin-angiotensin system, the sympathetic nervous system, and the voltage-sensitive L-type calcium channels. Using microsatellite markers, a quantitative trait locus was identified and mapped on rat chromosome 2 that specifically influences the systolic (peak LOD score 4.4) and diastolic (peak LOD score 4.1) blood pressure responses to administration of a dihydropyridine calcium antagonist, PY108-068. The locus accounted for 10.3 and 10.4% of the total variances in the systolic and diastolic responses to PY108-068, respectively. In marked contrast, the locus had no effect on either basal blood pressure or on the responses to acute administration of a ganglionic blocking agent, trimetaphan, or of an angiotensin II subtype 1 receptor antagonist, losartan. These findings provide strong direct support for the paradigm that genetic factors may influence the response to antihypertensive drugs and suggest that the heterogeneity seen in the responses to different antihypertensive agents in human essential hypertension may have a significant genetic determination.
Journal of Clinical Investigation, 1995
Angiotensin II recognizes two receptor subtypes, AT, and AT2, both of them having been recently c... more Angiotensin II recognizes two receptor subtypes, AT, and AT2, both of them having been recently cloned. Although AT2 receptors represent 5-10% of angiotensin II receptors in the kidneys of adult rats, their function remains unknown. In the present work, we examined the possible contribution of AT2 receptors to the regulation of pressurenatriuresis in anesthetized rats infused either with the specific AT2 antagonist PD 123319, or with CGP 42112B, an AT2 ligand with agonistic properties. The effects of PD 123319 were examined in a preparation with stable levels of angiotensin II, and in which AT1 receptors were blocked by the specific antagonist losartan. The effects of CGP 42112B were studied in rats deprived of endogenous angiotensin II. AT2 receptor blockade with PD 123319 did not change the renal blood flow while it increased the diuresis and natriuresis. These effects persisted even after full AT1 receptor blockade with losartan. CGP 42112B did not modify the renal blood flow, but dose-dependently decreased urine flow and natriuresis. These results show that, contrary to AT1 receptors, renal AT2 receptors have no effect on total renal blood flow, but blunt the pressure-natriuresis, thus demonstrating that this receptor subtype is involved in a function of importance for body fluid and blood pressure regulation.
Journal of Clinical Investigation, 1993
The role of the kidney in initiating hypertension has been much debated. Here we demonstrate that... more The role of the kidney in initiating hypertension has been much debated. Here we demonstrate that a recently identified gene of yet unknown function, termed SA, which is differentially expressed in the kidney of the spontaneously hypertensive rat, cosegregates with an increase in blood pressure in F2 rats derived from a cross of the spontaneously hypertensive rat with normotensive Wistar-Kyoto rats, accounting for 28 and 21% of the genetic variability in systolic and diastolic blood pressures, respectively. Further, the genotype at this locus appears to determine the level of expression of the gene in the kidney. The findings provide strong evidence for a primary genetic involvement of the kidney in hypertension. (
American journal of physiology. Renal physiology, 2002
These experiments examined whether the conscious sinoaortic baroreceptor-denervated (SAD) rat, ow... more These experiments examined whether the conscious sinoaortic baroreceptor-denervated (SAD) rat, owing to its high spontaneous arterial pressure (AP) variability, might represent a model for renal blood flow (RBF) autoregulation studies. In eight SAD and six baroreceptor-intact rats, AP and RBF were recorded (1-h periods) before and after furosemide (10 mg/kg followed by 10 mg. kg(-1). h(-1) iv) administration. In control conditions, AP variability was markedly enhanced in SAD rats (coefficient of variation: 16.0 +/- 1.2 vs. 5.4 +/- 0.5% in intact rats), whereas RBF variability was only slightly increased (8.7 +/- 0.6 vs. 6.1 +/- 0.5% in intact rats), suggesting buffering by autoregulatory mechanisms. In SAD rats, but not in intact rats, the AP-RBF relationships could be modeled with a four-parameter sigmoid Weibull equation (r(2) = 0.24 +/- 0.07, 3,600 data pairs/rat), allowing for estimation of an autoregulatory plateau (10.1 +/- 0.7 ml/min) and a lower limit of RBF autoregulation (...
Journal of Lipid Research, 2002
In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the str... more In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the structure and composition of HDL in vivo, simian CETP was expressed in Fisher rat that spontaneously displays high plasma levels of HDL1. In the new CETPTg rat line, the production of active CETP by the liver induced a significant 48% decrease in plasma HDL cholesterol, resulting in a 34% decrease in total cholesterol level (P Ͻ 0.01 in both cases). Among the various plasma HDL subpopulations, the largest HDL were those mostly affected by CETP, with a 74% decrease in HDL1 versus a significantly weaker 38% decrease in smaller HDL2 (P Ͻ 0.0001). Apolipoprotein E (apoE)-containing HDL1 were selectively affected by CETP expression, whereas apoA content of HDL remained unmodified. The reduction in the apoE content of serum HDL observed in CETPTg rats compared to controls (53%, P Ͻ 0.02) suggests that apoE in HDL may constitute in vivo a major determinant of their ability to interact with CETP. These results bring new insight into the lack of HDL1 in plasma from CETP-deficient heterozygotes despite their substantial 50% decrease in CETP activity. In addition, they indicate that HDL1 constitute reliable and practicable sensors of very low plasma CETP activity in vivo.
Hypertension, 2004
The complex nature of hypertension makes identifying the pathophysiology and its genetic contribu... more The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes. We have performed a total genome scan in offspring of an F 2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome ide...
Hypertension, 1999
Adrenocorticosteroid activity in Lyon hypertensive (LH) and low blood pressure (LL) rat strains d... more Adrenocorticosteroid activity in Lyon hypertensive (LH) and low blood pressure (LL) rat strains differ in several respects. Abnormal activity of 11-hydroxysteroid dehydrogenase enzymes (11-HSD1 and 11-HSD2), which interconvert corticosterone and inactive 11-dehydrocorticosterone, might contribute to the LH phenotype by regulating corticosteroid hormone access to receptors. 11-HSD2 (expressed in kidney but not liver) prevents endogenous glucocorticoids from binding to mineralocorticoid receptors. 11-HSD1 (expressed in liver and kidney) favors active glucocorticoid formation from 11-dehydrocorticosterone. 11-HSD properties in LH and LL have been compared by several approaches: (1) 11HSD activities have been measured in vitro as corticosterone dehydrogenation and in vivo as interconversion of injected cortisol and cortisone; (2) the effects of cortisol and cortisone on urine electrolytes and volume have been measured; and (3) 11-HSD mRNA expression has been measured by in situ hybridization. 11-HSD2 enzyme activities in LH and LL rats were similar and urinary cortisone:cortisol ratios were not different after cortisol injection. Cortisol caused a natriuresis and kaliuresis in both strains, with a slightly reduced response in LH rats. Renal 11-HSD2 mRNA expression was slightly lower in LH rats. 11-HSD1 was less active in LH than LL rats: enzyme activities were lower in tissue extracts; urinary cortisone:cortisol was lower in LL rats after cortisone injections; cortisone increased urine volume in LL but not LH rats; and mRNA levels tended to be lower in LH tissues. We conclude that 11-HSD1 is impaired in LH rats. The LH phenotype of heavier adrenals, raised corticosterone, and reduced thymus weight is similar to that described for 11-HSD1 knockout mice.
Hypertension, 1991
Young, genetically hypertensive Lyon (LH) rats exhibited an increased renal in vivo turnover of n... more Young, genetically hypertensive Lyon (LH) rats exhibited an increased renal in vivo turnover of norepinephrine and an elevated urinary excretion of thromboxane B 2 when compared with nonnotensive (LN) and low blood pressure (LL) controls. Therefore, the effects of norepinephrine (1.2 xlO" 8 to 9.6 xlO" 7 M) and of phenylephrine (5xlO~8 to 1.9x10"' M) on renal function and the urinary excretion of prostanoids were assessed in isolated perfused kidneys of 8-week-old LH, LN, and LL rats. In addition, the effects of norepinephrine were assessed before and during thromboxane A 2 /prostaglandin H 2 receptor blockade by AH23848 (4xlO~* M). Before drug infusion, LH kidneys differed from those of LN and LL controls by having an elevated renal vascular resistance and a decreased natriuresis and glomerular filtration rate; the urinary output of prostaglandin E 2 and F^, of 6-ketoprostaglandin F la , and of thromboxane B 2 was similar in the three strains. The constrictor effects of norepinephrine and phenylephrine were significantly increased in LH rat kidneys compared with LL but not with LN controls, and their pressure-natriuresis was markedly reduced. Norepinephrine and phenylephrine induced a 10-to 20-fold dose-dependent increase in the synthesis of the four prostanoids, which was more pronounced in LH than in LN and LL rats for thromboxane B 2 only. AH23848 infusion significantly reduced the vascular effects of norepinephrine and increased the natriuretic response of LH but not of LN and LL rat kidneys. In conclusion, isolated perfused kidneys from LH rats exhibit an increased production of thromboxane A 2 , which enhances the renal effects of norepinephrine and therefore could participate in the development of hypertension of the Lyon model. (Hypertension 1991;17:296-302) W e have previously observed that the urinary excretion of renal thromboxane (Tx) B2, used as an index of the renal synthesis of TxA^1-2 was increased in 5-and 9-week-old genetically hypertensive (LH) rats of the Lyon strain. 3 The same abnormality has also been described in vivo 4 and in vitro 5-6 in spontaneously hypertensive rats (SHR) of the Japanese strain. Because TxA 2 is a potent vasoconstrictor 7 and promotes platelet aggregation, 8 such an increase is likely to play a pathogenic role. This hypothesis is supported by the observation that TxA 2 synthesis inhibition or blockade of TxA 2 receptors delays the onset 9 or reduces 10 the severity of hypertension in SHR and in LH rats. 11 However,
Hypertension, 2001
It is not known whether renal blood flow (RBF) is still autoregulated when the kidney is exposed ... more It is not known whether renal blood flow (RBF) is still autoregulated when the kidney is exposed to large transient blood pressure (BP) fluctuations such as those occurring spontaneously in conscious sinoaortic baroreceptor-denervated (SAD) rats. In this study, BP and RBF were simultaneously recorded in 8 SAD rats (2 weeks before study) and 8 baroreceptor-intact rats during ≈3 hours of spontaneous activity. The kidney used for RBF recordings was denervated to prevent the interference of changes in renal sympathetic tone with autoregulatory mechanisms. In intact rats, RBF variability (coefficient of variation 9.1±0.8%) was larger ( P <0.02) than BP variability (5.9±0.2%). This was mainly because of slow changes in RBF that were unrelated to BP and also to a prominent oscillation of RBF of ≈0.25-Hz frequency. Autoregulatory patterns were identified at frequencies <0.1 Hz and provided a modest attenuation of BP fluctuations. In SAD rats, RBF variability (12.4±1.6%) was lower ( P ...
Genome Research, 2000
Models of human disease have long been used to understand the basic pathophysiology of disease an... more Models of human disease have long been used to understand the basic pathophysiology of disease and to facilitate the discovery of new therapeutics. However, as long as models have been used there have been debates about the utility of these models and their ability to mimic clinical disease at the phenotypic level. The application of genetic studies to both humans and model systems allows for a new paradigm, whereby a novel comparative genomics strategy combined with phenotypic correlates can be used to bridge between clinical relevance and model utility. This study presents a comparative genomic map for “candidate hypertension loci in humans” based on translating QTLs between rat and human, predicting 26 chromosomal regions in the human genome that are very likely to harbor hypertension genes. The predictive power appears robust, as several of these regions have also been implicated in mouse, suggesting that these regions represent primary targets for the development of SNPs for li...
Circulation Research, 2007
A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previ... more A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are 2 distinct BP quantitative trait loci, BP1 and BP2, in this region. Sisa1, a congenic substrain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of 2 new mutually exclusive congenic substrains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only 1 of the substrains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the 20 genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling o...
British Journal of Pharmacology, 1988
The acute cardiovascular effects of PY 108-068 and PN 200-110 were studied by means of a computer... more The acute cardiovascular effects of PY 108-068 and PN 200-110 were studied by means of a computerized analysis of the intra-aortic blood pressure (BP) recorded continuously for 26 h in conscious unrestrained spontaneously hypertensive rats. Both compounds were studied at three doses (50, 100 and 200 lgkg-') and each dose was administered intravenously 5 times (09hOOmin, 14 hOOmin, 19hOOmin, 24hOOmin and 09hOOmin). Baroreflex sensitivity was measured 1 h following the last injection. 2 The two compounds were found to induce rapid (3 min) and dose-dependent falls in BP. After the first administration, these decreases reached-20% and-35% for systolic BP (SBP) and diastolic BP (DBP) respectively with PY 108-068 (200pgkg-') and-25% and-45% for SBP and DBP respectively with PN 200-110 (200 pg kg-'). 3 The duration of the reduction in BP increased with the dose and was much longer for PN 200-110 (180 min for SBP) than for PY 108-068 (20 min for SBP). 4 A tachycardia was associated with the decrease in BP which did not differ at 200 pg kg-' between PY 108-068 (+ 108 beats min-') and PN 200-110 (+ 103 beats min'). Baroreflex sensitivity was not significantly increased by either drug. 5 The 5 repeated injections of PY 108-068 and PN 200-110 evoked similar responses. 6 In conclusion, both compounds exhibited marked hypotensive properties. PN 200-110 appeared to be more suitable for further development since its effects were found to be greater and much longer lasting than those of PY 108-068.
British Journal of Pharmacology, 1999
The present work examined the eects of the subtype 2 of angiotensin II (AT 2) receptors on the pr... more The present work examined the eects of the subtype 2 of angiotensin II (AT 2) receptors on the pressure-natriuresis using a new peptide agonist, and the possible involvement of cyclic guanosine 3', 5' monophosphate (cyclic GMP) in these eects. 2 In adult anaesthetized rats (Inactin, 100 mg kg 71 , i.p.) deprived of endogenous angiotensin II by angiotensin converting enzyme inhibition (quinapril, 10 mg kg 71 , i.v.), T 2-(Ang II 4-8) 2 (TA), a highly speci®c AT 2 receptor agonist (5, 10 and 30 mg kg 71 min 71 , i.v.) or its solvent was infused in four groups. Renal functions were studied at renal perfusion pressures (RPP) of 90, 110 and 130 mmHg and urinary cyclic GMP excretion when RPP was at 130 mmHg. The eects of TA (10 mg kg 71 min 71) were reassessed in animals pretreated with PD 123319 (PD, 50 mg kg 71 min 71 , i.v.), an AT 2 receptor antagonist and the action of the same dose of PD alone was also determined. 3 Increases in RPP from 90 to 130 mmHg did not change renal blood¯ow (RBF) but induced 8 and 15 fold increases in urinary¯ow and sodium excretion respectively. The 5 mg kg 71 min 71 dose of TA was devoid of action. The 10 and 30 mg kg 71 min 71 doses did not alter total RBF and glomerular ®ltration rate, but blunted pressure-diuresis and natriuresis relationships. These eects were abolished by PD. 4 TA decreased urinary cyclic GMP excretion. After pretreatment with PD, this decrease was reversed to an increase which was also observed in animals receiving PD alone. 5 In conclusion, renal AT 2 receptors oppose the sodium and water excretion induced by acute increases in blood pressure and this action cannot be directly explained by changes in cyclic GMP.
In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the str... more In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the structure and composition of HDL in vivo, simian CETP was expressed in Fisher rat that spontaneously displays high plasma levels of HDL1. In the new CETPTg rat line, the production of active CETP by the liver induced a significant 48% decrease in plasma HDL cholesterol, resulting in a 34% decrease in total cholesterol level (P Ͻ 0.01 in both cases). Among the various plasma HDL subpopulations, the largest HDL were those mostly affected by CETP, with a 74% decrease in HDL1 versus a significantly weaker 38% decrease in smaller HDL2 (P Ͻ 0.0001). Apolipoprotein E (apoE)-containing HDL1 were selectively affected by CETP expression, whereas apoA content of HDL remained unmodified. The reduction in the apoE content of serum HDL observed in CETPTg rats compared to controls (53%, P Ͻ 0.02) suggests that apoE in HDL may constitute in vivo a major determinant of their ability to interact with CETP. These results bring new insight into the lack of HDL1 in plasma from CETP-deficient heterozygotes despite their substantial 50% decrease in CETP activity. In addition, they indicate that HDL1 constitute reliable and practicable sensors of very low plasma CETP activity in vivo.
Archives Des Maladies Du Coeur Et Des Vaisseaux, 2007
Le rat genetiquement hypertendu de souche lyonnaise (LH) presente une pression arterielle spontan... more Le rat genetiquement hypertendu de souche lyonnaise (LH) presente une pression arterielle spontanement elevee et sensible au sel, et des signes qui evoquent un syndrome metabolique : surcroit ponderal, hyperlipidemie et augmentation du rapport insuline/glucose. L'analyse de cosegregation effectuee sur les hybrides de seconde generation issus du croisement entre rats genetiquement hypertendus LH et normotendus LN a montre l'existence, sur le chromosome 17, de deux agregats de loci d'interet quantitatif (QTLs). Le premier de ces QTLs est associe a des parametres morphologiques alors que le second influence a la fois le niveau de pression arterielle et celui des lipides plasmatiques. Afin de determiner l'importance fonctionnelle de ces QTLs, nous avons genere une souche de rats LH chez lesquels le chromosome 17 est remplace par celui de rats normotendus Brown Norway (BN) : rats consomiques LH-17 BN . Le phenotypage des rats mâles LH, BN et LH-17 BN comprend l'enregi...
American Journal of Hypertension, 2000
Compared to the Lyon normotensive (LN) controls, adult Lyon hypertensive rats (LH) exhibit a reni... more Compared to the Lyon normotensive (LN) controls, adult Lyon hypertensive rats (LH) exhibit a reninangiotensin system (RAS) dependent hypertension despite a low renin secretion. This discrepancy could be explained by the elevated slow pressor response to angiotensin II (AII) found in LH rats compared to LN controls. To evaluate more precisely the pathophysiological importance of this increased response, the present work aimed at determining whether the characteristics of the RAS were identical in LN and low blood pressure (LL) rats, the other normotensive control strain simultaneously selected with LH rats. Plasma and kidney renin and prorenin were measured in 11-week-old LN and LL rats. Aortic blood pressure (BP) was recorded at 15 weeks of age in freely moving rats of both strains either untreated or having received an angiotensin converting enzyme inhibitor, perindopril (3 mg/kg/day orally) since the age of 3 weeks. Acute dose-response curves were constructed for AII and norepinephrine (NE). The long-term pressor effects of AII (200 ng/kg/ min) and NE (1000 ng/kg/min) were measured after chronic infusions in perindopril-treated LN and LL rats. LN and LL rats exhibited similar mean BP level before (114 ؎ ؎ 2 and 117 ؎ ؎ 2 mm Hg, respectively) and after perindopril treatment (91 ؎ ؎ 3 and 93 ؎ ؎ 1 mm Hg, respectively). Plasma and kidney renin and prorenin were decreased in LL rats. In acute conditions, LL rats exhibited an unspecific hypersensitivity to AII and NE. Chronically given AII exerted a greater pressor effect in LL than in LN rats after 4 weeks (113 ؎ ؎ 3 v 97 ؎ ؎ 5 mm Hg in LL and LN rats respectively, P < < .05) and, even more, after 8 weeks of infusion (144 ؎ ؎ 9 v 124 ؎ ؎ 4 mm Hg in LL and LN rats respectively, P < < .05). The NE was devoid of chronic pressor effects. In conclusion, 1) the increased slow pressor response to AII may not be a critical pathogenetic factor in the development of hypertension, as it also exists in normotensive LL rats; 2) LN and LL rats have the same normal BP despite marked differences in their RAS, thus suggesting that there could be several forms of normotension as known for hypertension; and 3) the simple comparison between one genetically hypertensive strain and one single normotensive control strain does not allow one to conclude that a phenotypic difference is of pathophysiological significance.
Physiological genomics, Jan 11, 2002
One or more quantitative trait locus (QTL) for blood pressure (BP) exists on rat chromosome 1, in... more One or more quantitative trait locus (QTL) for blood pressure (BP) exists on rat chromosome 1, in the vicinity of the Sa gene. The present work examined whether this QTL region: 1) alters pressure-natriuresis relationship and 2) affects the BP response to salt load. Male spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats, and rats from an SHR congenic strain that contains a WKY chromosome 1 segment spanning the BP QTL region (SHR. WKY-Sa) were used. In an acute study in anesthetized animals, renal function was measured at several levels of renal perfusion pressure. In a chronic study, BP was measured in freely moving rats using telemetry during normal and high sodium intake (2% NaCl as drinking water for 2 wk). WKY rats showed a significantly higher glomerular filtration rate and increased pressure-natriuresis compared with SHR. SHR.WKY-Sa also demonstrated an increased glomerular filtration rate and enhanced pressure-natriuresis, associated with a lower tubular sodium r...
American Journal of Hypertension, 2000
Compared with their two normotensive (LN and LL) controls, genetically hypertensive rats of the L... more Compared with their two normotensive (LN and LL) controls, genetically hypertensive rats of the Lyon strain (LH) exhibit increased renal vascular resistance and a blunted pressure natriuresis function as well as an increased urinary excretion of vasoconstrictor prostanoids. The aim of this study was to assess in the kidneys of these animals the synthesis of vasoconstrictor or sodiumretaining prostanoids. The relative abundance of the mRNAs of cyclooxygenases (COX) 1 and 2 and of thromboxane A 2 synthase (TXS), was measured by reverse-transcription polymerase chain reaction (RT-PCR) in renal cortex and medulla dissected in groups of male LH, LN, and LL rats either in baseline conditions or after 1 week of salt loading (1.5% NaCl in the drinking water). In basal conditions, at 3 and 11 weeks of age COX1 was expressed in the kidneys of all rats more markedly in medulla than in cortex. COX2 was poorly expressed in the whole kidney. TXS expression was usually too low to be quantified. No difference could be observed among LH, LN, and LL rats. After salt loading, the expression of COX1 was enhanced in the medulla and that of COX2 reduced in the cortex. LH rats differed from controls by a significantly more marked increase in medullary COX1 expression. The present work excludes any primary generalized increase in the renal expression of the genes that control the synthesis of vasoconstrictor prostanoids in LH rats, but suggests that medullary COX1 is upregulated by salt in these animals.
Physiological Genomics, 2008
The metabolic syndrome (involving obesity, hypertension, dyslipidemia, insulin resistance, and a ... more The metabolic syndrome (involving obesity, hypertension, dyslipidemia, insulin resistance, and a proinflammatory/prethrombotic state) is a major risk factor for cardiovascular disease. Its incidence continues to rise, in part because of the epidemic increase in obesity. The Lyon hypertensive (LH) rat is a model for hypertension and several other features of the metabolic syndrome, having high body weight, plasma cholesterol, and triglycerides, increased insulin-to-glucose ratio, and salt-sensitive hypertension. Previous genetic studies in LH/Mav rats and a normotensive control (LN/Mav) identified quantitative trait loci (QTLs) on rat chromosome (RNO)17 for multiple features of the metabolic syndrome. To further evaluate the role of RNO17 in the LH rat, we generated a consomic strain (LH-17BN) by substituting LH RNO17 with that of the sequenced Brown Norway (BN/NHsdMcwi) rat. Male LH and BN rats and LH-17BNrats were characterized for blood pressure and metabolic and morphological par...
Kidney International, 1988
Effects of DOCA-salt treatment on the urinary prostaglandins in Sabra rats. To determine whether ... more Effects of DOCA-salt treatment on the urinary prostaglandins in Sabra rats. To determine whether the increased renal synthesis of thromboxane (Tx)A2 found in genetically hypertensive rats also occurred in rats with a sodium-dependent form of hypertension, the urinary excretion of 6-keto-prostaglandin Fk. (6KPGF1) and of TxB2 was measured by a sensitive and specific radioimmunoassay in hypertension-prone (SBH),-resistant (SBN) and unselected (SB) female rats of the Sabra strains. Rats of the three strains were studied before (9 weeks of age) and after five weeks of deoxycorticosterone (DOCA)-salt treatment. Before treatment, the urinary 6KPGFI, did not differ among the three strains while a higher TxB2 excretion was seen in the SBN rats. After treatment, the urinary excretion of TxB2 increased significantly in SBH and SB but not in SBN rats, while the urinary 6KPGF1, remained unchanged in SBH, increased moderately in SB and markedly in SBN controls. Consequently, DOCA-salt-induced changes in blood pressure and in urinary 6KPGF observed in the three strains of rats were inversely related (r-0.78; P < 0.001). It is concluded that the high blood pressure developed after DOCA-salt treatment in SBH rats is more likely to depend upon a defect in the renal production of prostacyclin rather than upon an increased synthesis of thromboxane A2.
Journal of Clinical Investigation, 1997
In a backcross population (n ϭ 281) derived from a cross of the Lyon hypertensive rat with Lyon n... more In a backcross population (n ϭ 281) derived from a cross of the Lyon hypertensive rat with Lyon normotensive rat, we investigated whether genetic factors influence the acute cardiovascular responses to pharmacological modulation of the renin-angiotensin system, the sympathetic nervous system, and the voltage-sensitive L-type calcium channels. Using microsatellite markers, a quantitative trait locus was identified and mapped on rat chromosome 2 that specifically influences the systolic (peak LOD score 4.4) and diastolic (peak LOD score 4.1) blood pressure responses to administration of a dihydropyridine calcium antagonist, PY108-068. The locus accounted for 10.3 and 10.4% of the total variances in the systolic and diastolic responses to PY108-068, respectively. In marked contrast, the locus had no effect on either basal blood pressure or on the responses to acute administration of a ganglionic blocking agent, trimetaphan, or of an angiotensin II subtype 1 receptor antagonist, losartan. These findings provide strong direct support for the paradigm that genetic factors may influence the response to antihypertensive drugs and suggest that the heterogeneity seen in the responses to different antihypertensive agents in human essential hypertension may have a significant genetic determination.
Journal of Clinical Investigation, 1995
Angiotensin II recognizes two receptor subtypes, AT, and AT2, both of them having been recently c... more Angiotensin II recognizes two receptor subtypes, AT, and AT2, both of them having been recently cloned. Although AT2 receptors represent 5-10% of angiotensin II receptors in the kidneys of adult rats, their function remains unknown. In the present work, we examined the possible contribution of AT2 receptors to the regulation of pressurenatriuresis in anesthetized rats infused either with the specific AT2 antagonist PD 123319, or with CGP 42112B, an AT2 ligand with agonistic properties. The effects of PD 123319 were examined in a preparation with stable levels of angiotensin II, and in which AT1 receptors were blocked by the specific antagonist losartan. The effects of CGP 42112B were studied in rats deprived of endogenous angiotensin II. AT2 receptor blockade with PD 123319 did not change the renal blood flow while it increased the diuresis and natriuresis. These effects persisted even after full AT1 receptor blockade with losartan. CGP 42112B did not modify the renal blood flow, but dose-dependently decreased urine flow and natriuresis. These results show that, contrary to AT1 receptors, renal AT2 receptors have no effect on total renal blood flow, but blunt the pressure-natriuresis, thus demonstrating that this receptor subtype is involved in a function of importance for body fluid and blood pressure regulation.
Journal of Clinical Investigation, 1993
The role of the kidney in initiating hypertension has been much debated. Here we demonstrate that... more The role of the kidney in initiating hypertension has been much debated. Here we demonstrate that a recently identified gene of yet unknown function, termed SA, which is differentially expressed in the kidney of the spontaneously hypertensive rat, cosegregates with an increase in blood pressure in F2 rats derived from a cross of the spontaneously hypertensive rat with normotensive Wistar-Kyoto rats, accounting for 28 and 21% of the genetic variability in systolic and diastolic blood pressures, respectively. Further, the genotype at this locus appears to determine the level of expression of the gene in the kidney. The findings provide strong evidence for a primary genetic involvement of the kidney in hypertension. (