Effect of endothelin blockade on pressure natriuresis in nitric oxide-deficient hypertensive rats (original) (raw)
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Journal of the American Society of Nephrology : JASN, 1998
Unopposed actions of vasoconstrictors, such as angiotensin, play an important role in the effects of chronic nitric oxide synthase (NOS) inhibition. In this study, it is hypothesized that endothelin (ET), another important vasoconstrictor, may also play a role in the development of hypertension and renal lesions during chronic NOS inhibition. The ET(A) receptor was blocked with A-127722 during chronic NOS inhibition with Nomega-nitro-L-arginine (L-NNA), a potent NOS inhibitor without antimuscarinic action. Male Sprague Dawley rats were treated for 3 wk with L-NNA (40 mg/kg per d), L-NNA (40 mg/kg per d) + A-127722 (30 mg/kg per d), or remained untreated (control). In preliminary experiments, L-NNA (40 mg/kg per d) had been found to cause the maximum increase of systolic BP and a 35% decrease in renal NOS activity. Three weeks of L-NNA treatment resulted in a marked rise in systolic BP (240+/-4 versus control 151+/-7 mmHg; P < 0.01), proteinuria (209+/-46 versus control 27+/-3 mg/...
In-vivo interaction of nitric oxide and endothelin
Objective and methods Endothelin-1 (ET-1) was initially characterized as a potent vasoconstrictor. However, the expected role of ET-1 as a major blood pressure controlling peptide could not be clearly established. Moreover, ET-1 transgenic mice are not hypertensive. We assume that counter-regulating mechanisms such as the nitric oxide (NO) system or an altered expression of endothelin receptors might cause this finding.
Renal Hemodynamic Control by Endothelin and Nitric Oxide Under Angiotensin II Blockade in Man
Hypertension, 2002
To investigate whether endothelin-A receptors and nitric oxide modulate renal hemodynamics in man under angiotensin II receptor-1 blockade, 6 healthy volunteers, on a 240 mmol Na diet, underwent 4 separate renal hemodynamic measurements, in 3 of which endothelin-A blocker BQ-123 0.2 nmol · kg · min −1 was infused for 90 minutes after pretreatment with either placebo, telmisartan 1 mg · kg · day −1 for 3 days, or telmisartan as well, but with co-infusion of both BQ-123 and N G -nitro- l -arginine methylester 0.5 μg · kg · min −1 . A fourth infusion was made with N G -nitro- l -arginine methylester alone. No change followed infusion of either N G -nitro- l -arginine methylester alone or BQ-123 alone. With BQ-123 after telmisartan, renal blood flow rose from 916±56 mL · min −1 · 1.73 m 2 to 1047±51.2 ( P <0.001), and renal vascular resistances fell from 89±7 mm Hg · min · L −1 to 74±4 ( P <0.001). These changes were fully abolished by the co-infused N G -nitro- l -arginine methyl...
Role of Endothelin in the Pathogenesis of Hypertension
Mayo Clinic Proceedings, 2005
In 1985, investigators characterized a potent vasoconstrictor of endothelial origin called endothelin (ET). Subsequently, 3 peptides were recognized that had a comparable molecular structure but different receptors that mediate potent vasoconstrictive and mild vasodilative effects. The renal effects are characterized by natriuresis despite renal vasoconstriction. This effect, along with the stimulation of ET by high sodium intake, suggests that ET may be responsible for maintaining sodium balance when the reninangiotensin system is depressed. Endothelin is activated in desoxycorticosterone acetate salt hypertension models and salt-sensitive hypertension. However, ET involvement with spontaneous hypertension models and renovascular hypertension in rats appears minimal. In humans, the role of ET appears similar to that in experimental animals; in both, ET regulates salt metabolism. Saltsensitive patients exhibit a blunted renal ET-1 response during sodium load. The role of ET in humans has been investigated using nonspecific ET receptor blockers that inhibit the vasoconstrictive and vasodilative components of ET. However, the effects of ET blockade should be investigated with ET subtype A receptor blockers that mediate vasoconstriction alone. Effects of ET blockade also should be evaluated with respect to stimulation of oxidative stress and tissue damage, important mechanisms responsible for tissue fibrosis. This review offers the clinician a balanced view on the hypertensive mechanisms involved with activation of ET and associated clinical implications.
Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension
Journal of The American Society of Nephrology, 2007
Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice that overexpress ET-1 exhibit normal BP. It was hypothesized that vascular effects of ET-1 may be antagonized by an increase of the endothelial counterpart of ET-1, nitric oxide (NO), which is produced by the endothelial NO synthase (eNOS). Therefore, cross-bred animals of ET transgenic mice (ET؉/؉) and eNOS knockout (eNOS؊/؊) mice and were generated, and BP and endothelial function were evaluated in these animals. Endothelium-dependent and-independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings. The tissue ET and NO system was determined in aortic rings by quantitative real-time PCR and Western blotting. Systolic BP was similar in ET؉/؉ and wild-type (WT) mice but was significantly elevated in eNOS؊/؊ mice (117 ؎ 4 mmHg versus 94 ؎ 6 mmHg in WT mice; P < 0.001) and even more elevated in ET؉/؉ eNOS؊/؊ cross-bred mice (130 ؎ 4 mmHg; P < 0.05 versus eNOS؊/؊). Maximum endothelium-dependent relaxation was enhanced in ET؉/؉ mice (103 ؎ 6 versus 87 ؎ 4% of preconstriction in WT littermates; P < 0.05) and was completely blunted in eNOS؊/؊ (؊3 ؎ 4%) and ET؉/؉ eNOS؊/؊ mice (؊4 ؎ 4%), respectively. Endothelium-independent relaxation was comparable among all groups. Quantitative real-time PCR as well as Western blotting revealed an upregulation of the aortic ET A and ET B receptors in ET؉/؉ eNOS؊/؊, whereas eNOS was absent in aortic rings of eNOS؊/؊ and ET؉/؉ eNOS؊/؊ mice. ET-1 aortic tissue concentrations were similar in WT mice and ET؉/؉ eNOS؊/؊ mice most probably as a result of an enhanced clearance of ET-1 by the upregulated ET B receptor. These data show for the first time that in transgenic mice that overexpress human ET-1, additional knockout of eNOS results in a further enhancement of BP as compared with eNOS؊/؊ mice. The human ET؉/؉ eNOS؊/؊ mice therefore represent a novel model of hypertension as a result of an imbalance between the vascular ET-1 and NO systems.
Circulation, 1999
Background-Although endothelin-1 is a potent vasoconstrictor peptide, stimulation of endothelin type B receptor (ETBR) causes bidirectional changes in vascular tone, ie, vasodilation and vasoconstriction. Roles of ETBR in pathological conditions are largely unknown. Methods and Results-We studied the effect of BQ-3020, a highly selective ETBR agonist, on renal vascular resistance and nitric oxide (NO) release in the isolated, perfused kidney of rats with hypertension, diabetes mellitus, and hypercholesterolemia. Immunohistochemistry of endothelial NO synthase and ETBR was also examined. Infusion of BQ-3020 at concentrations of Յ10 Ϫ10 mol/L reduced renal perfusion pressure in Dahl salt-resistant (R) rats but increased renal perfusion pressure in Dahl salt-sensitive (S) rats (10 Ϫ10 mol/L: Ϫ10.3Ϯ0.6% versus 11.2Ϯ1.5%, R versus S; PϽ0.01). BQ-3020 caused a dose-dependent release of NO in both R and S rats, although the level of NO release in S rats was lower, as detected by chemiluminescence (10 Ϫ10 mol/L: 10.7Ϯ0.7 versus 3.1Ϯ0.4 fmol/min per gram of kidney, R versus S; PϽ0.01). Similar effects of BQ-3020 were observed in streptozotocin-induced diabetic rats and diet-induced hypercholesterolemic rats. Expression of endothelial NO synthase decreased in S rats but not in diabetic or hypercholesterolemic rats. In contrast, expression of ETBR in the endothelium was decreased in all 3 disease models compared with that in the vascular smooth muscle cell. Conclusions-These results suggest that impaired NO release in response to stimulation of ETBR is due, at least in part, to a decrease in endothelial ETBR and may play a role in vascular dysfunction usually associated with arteriosclerosis-related diseases. (Circulation. 1999;99:1242-1248.)
Journal of the Renin-Angiotensin-Aldosterone System, 2001
In previous studies, we have observed that antagonism of angiotensin or endothelin receptors prevented the development of nephroangio-and glomerulo-sclerosis during hypertension by inhibiting collagen I gene synthesis, through a mechanism independent of systemic haemodynamics. The present study investigated whether treatment with angiotensin or endothelin receptor antagonists, given at doses that did not reduce blood pressure, could produce regression of renal sclerotic lesions and improve renal function during hypertension. Hypertension and renal vascular fibrosis were induced in rats by chronic inhibition of NO synthesis using N Gnitro-L-arginine methyl ester (L-NAME). Systolic blood pressure gradually increased following L-NAME administration, reaching a plateau of 170 mmHg after four weeks of treatment. At the same time, urinary protein excretion and plasma creatinine concentration were increased ten-and three-fold compared with controls, respectively (p<0.001). This increase was accompanied by the appearance of sclerotic lesions within renal vessels and glomeruli, as evidenced by Masson's trichromic staining (sclerotic index 2.34±0.29 vs. 0.10±0.01 in L-NAME four weeks and control, respectively, p<0.001). Thereafter, the L-NAME treatment was combined with either losartan (an AT 1receptor antagonist), bosentan (an ET A/B antagonist), co-treatment with both agents, or vehicle for an additional period of four weeks. Blockade of AT 1and/or ET A/B -receptors significantly reduced urinary protein excretion and plasma creatinine levels (p<0.01) and substantially improved renal vascular histology (sclerotic index 1.78±0.13, 1.57±0.22 and 1.85±0.15 respectively, p<0.01, vs. L-NAME eight week) without altering the L-NAME-induced increase of systolic pressure. These data indicate that angiotensin II and endothelin-1 participate in the mechanism(s) of renal vascular fibrosis by increasing extracellular matrix formation. Treatment with their respective receptor antagonists leads to the regression of renal vascular fibrosis and to the improvement of renal function by a common antifibrogenic mechanism that is independent of systemic haemodynamics.
British Journal of Pharmacology, 1993
The objectives of the present experiments were to assess the role of endogenous nitric oxide (NO) in mediating and/or modulating the effects of endothelin-1 (ET-1) on blood pressure and microvascular permeability in conscious rats. 2 Intravenous administration of the NO synthesis inhibitors, NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME) at a dose (25 mg kg-' or 2 mg kg-', respectively) which evoked maximum increase in mean arterial blood pressure (MABP) significantly attenuated (by about 40%) the vasodepressor response and potentiated (by 100-180%) the pressor response to ET-1 (1 nmol kg-', i.v.) compared to the effects of ET-1 in animals where the peripheral vasoconstrictor effects of L-arginine analogues were mimicked by an infusion of noradrenaline (620-820 ng kg-1 min-'). Similar inhibition of the depressor and potentiation of the pressor actions of ET-1 were observed when the MABP which had been elevated by L-NMMA or L-NAME was titrated to normotensive levels with hydralazine or diazoxide before injection of ET-1. 3 L-NAME (2 mg kg-1) increased the vascular permeability of the large airways, stomach, duodenum, pancreas, liver, kidney and spleen (up to 280%) as measured by the extravasation of Evans blue dye. The permeability of pulmonary parenchyma, skeletal muscle and skin was not affected significantly by L-NAME treatment. Elevation of MABP by noradrenaline infusion did not evoke protein extravasation in the vascular beds studied with the exception of the lung. In the large airways, tissue Evans blue content was similar following noradrenaline infusion and L-NAME. 4 Both the pressor and permeability effects of L-NAME (2 mg kg-') were effectively reversed by L-arginine (300 mg kg-1) but not by D-arginine (300 mg kg-). The D-enantiomer of L-NAME, D-NAME (2 mg kg-1) had no effect on the parameters studied. 5 Protein extravasation was significantly enhanced by ET-1 (1 nmol kg-1) in the upper and lower bronchi, stomach, duodenum, kidney and spleen (up to 285%). This was potentiated by L-NAME (2 mg kg-'), resulting in marked increases in tissue Evans blue accumulation (up to 550%) in these tissues. The effects of L-NAME and ET-1 were additive in the trachea, duodenum, pancreas and liver. Combined administration of L-NAME plus ET-1 significantly increased protein extravasation in the pulmonary parenchyma, where neither L-NAME nor ET-1 alone caused significant increases. 6 Noradrenaline infusion (620-820 ng kg-' min ') potentiated the permeability action of ET-1 (1 nmol kg-') in the pulmonary circulation, whereas it did not modify ET-1-induced protein extravasation in the other vascular beds. 7 These results indicate that endogenous NO mediates, in part, the vasodepressor effect and attenuates the vasopressor action of ET-1 and modulates the effects of ET-1 on vascular permeability. These findings confirm the role of NO in the maintenance of blood pressure and suggest an important role for NO in the regulation of microvascular permeability.
The role of endothelin-1 and nitric oxide in the pathogenesis of hypertension in diabetic patients
Collegium antropologicum, 2008
The pathogenesis of renal hypertension has not yet been fully clarified. As the potential role of endothelin-1 (ET-1) and nitric oxide (NO) has been postulated, their concentrations were determined in plasma and urine of diabetic patients. The study included 30 diabetic patients (both IDDM and NIDDM) with initial or advanced diabetic nephropathy (decreased endogenous creatinine clearance, proteinuria) and 20 healthy control subjects. The correlation with blood pressure and other renal function parameters was monitored and compared with the control group. Also, the effect of ACE inhibitors (ACEI) on ET-1 and NO patterns was monitored in correlation with arterial hypertension. In diabetic patients that did not receive ACEI therapy, the increase in plasma ET-1 was associated with both systolic and diastolic blood pressure elevation, whereas in those administered ACEI the increase in plasma ET-1 was associated with a systolic blood pressure decline. In addition, the increase in plasma N...