Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats (original) (raw)
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Hypertension, 2011
Novel AT(2)R ligands were designed by substituting individual β-amino acid in the sequence of the native ligand angiotensin II (Ang II). Relative ATR selectivity and functional vascular assays (in vitro AT(2)R-mediated vasorelaxation and in vivo vasodepressor action) were determined. In competition binding experiments using either AT(1)R- or AT(2)R- transfected HEK-293 cells, only β-Asp(1)-Ang II and Ang II fully displaced [(125)I]-Ang II from AT(1)R. In contrast, β-substitutions at each position of Ang II exhibited AT(2)R affinity, with β-Tyr(4)-Ang II and β-Ile(5)-Ang II exhibiting ≈ 1000-fold AT(2)R selectivity. In mouse aortic rings, β-Tyr(4)-Ang II and β-Ile(5)-Ang II evoked vasorelaxation that was sensitive to blockade by the AT(2)R antagonist PD123319 and the nitric oxide synthase inhibitor L-NAME. When tested with a low level of AT(1)R blockade, β-Ile(5)-Ang II (15 pmol/kg per minute IV for 4 hours) reduced blood pressure (BP) in conscious spontaneously hypertensive rats (β-...
Hypertension, 2008
In the kidney, angiotensin II (Ang II) is metabolized to angiotensin III (Ang III) by aminopeptidase A (APA). In turn, Ang III is metabolized to angiotensin IV by aminopeptidase N (APN). Renal interstitial (RI) infusion of Ang III, but not Ang II, results in angiotensin type-2 receptor (AT 2 R)-mediated natriuresis. This response is augmented by coinfusion of PC-18, a specific inhibitor of APN. The present study addresses the hypotheses that Ang II conversion to Ang III is critical for the natriuretic response. Sprague-Dawley rats received systemic angiotensin type-1 receptor (AT 1 R) blockade with candesartan (CAND; 0.01 mg/kg/min) for 24 hours before and during the experiment. After a control period, rats received either RI infusion of Ang II or Ang IIϩPC-18. The contralateral kidney received a RI infusion of vehicle in all rats. Mean arterial pressure (MAP) was monitored, and urinary sodium excretion rate (U Na V) was calculated separately from experimental and control kidneys for each period. In contrast to Ang II-infused kidneys, U Na V from Ang IIϩPC-18-infused kidneys increased from a baseline of 0.03Ϯ0.01 to 0.09Ϯ0.02 mol/min (PϽ0.05). MAP was unchanged by either infusion. RI addition of PD-123319, an AT 2 R antagonist, inhibited the natriuretic response. Furthermore, RI addition of EC-33, a selective APA inhibitor, abolished the natriuretic response to Ang IIϩPC-18. These data demonstrate that RI addition of PC-18 to Ang II enables natriuresis mediated by the AT 2 R, and that conversion of Ang II to Ang III is critical for this response. (Hypertension. 2008;51[part 2]:460-465.)
European Journal of Pharmacology, 1993
The purpose of this study was to investigate the renal actions of the new selective angiotensin AT 2 receptor ligands, CGP 42112B and PD 123319, in comparison to those of the AT~ receptor antagonist losartan, in the sodium-depleted, anesthetized rat. Losartan (1, 3 and 10 mg/kg i.v.) produced a dose-dependent decrease in blood pressure and renal vascular resistance that was statistically significant. Effective renal blood flow tended to increase in response to all doses of losartan while glomerular filtration rate either did not change or decreased, leading to a significant fall in filtration fraction. Losartan did not induce significant changes in urine volume, urinary sodium excretion, urinary potassium excretion or free water formation. The selective AT 2 receptor ligand CGP 42112B at infusion rates of 1-100 p~g/kg per min i.v. had no significant effect on blood pressure or any measured parameter of renal function. However, when infused at 1000/xg/kg per min i.v., CGP 42112B did not affect blood pressure, but significantly increased effective renal blood flow, glomerular filtration rate, urinary sodium excretion, urinary potassium excretion and free water formation, while significantly decreasing renal vascular resistance. The selective AT 2 receptor ligand PD 123319 at infusion rates between 1 and 100 p~g/kg per min i.v. also had no significant effect on blood pressure or on any measured parameter of renal function. However, at an infusion rate of 1000/xg/kg per min i.v., PD 123319 tended to increase renal vascular resistance, urinary sodium excretion, urinary potassium excretion and free water formation, and to decrease effective renal blood flow, although none of these changes reached a level of statistical significance. Based upon the published affinities of CGP 42112B and PD 123319 for AT 1 and AT 2 receptors, plasma levels of either compound after infusion at rates between 1 and 1000/xg/kg per rain would be compatible with an interaction with AT 2 receptors. However, at infusion rates of 1000 txg/kg per min, an interaction with AT 1 receptors could be expected. The data demonstrate that the new AT 2 receptor ligands PD 123319 and CGP 42112B either have little effect on renal function or, at high doses, have actions which might be indirect or explained by an interaction with AT a receptors. The results therefore support a role for AT 1 but not AT,_ receptors in the control of renal function in the sodium-depleted, anesthetized rat.
Renal responses to AT1 receptor blockade
American Journal of Hypertension, 2000
Because of the importance of the renin-angiotensin system in the pathophysiology of hypertension and in mediating associated alterations in renal function, angiotensin II (Ang II) AT 1 receptor blockers provide a direct means of protecting against influences of excessive Ang II levels. The kidney is an important site of action of Ang II AT 1 receptor blockers because intrarenal Ang II not only vasoconstricts the renal vasculature but also reduces sodium excretion and suppresses the pressure natriuresis relationship. Even in normal conditions, intrarenal Ang II content is greater than can be explained on the basis of circulating Ang II and is compartmentalized with proximal tubule concentrations of Ang I and Ang II being several times higher than plasma concentrations.
Impact of AT2-receptor stimulation on vascular biology, kidney function, and blood pressure
Integrated Blood Pressure Control, 2013
The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors within the renin-angiotensin system, which mediate tissue-protective actions such as anti-inflammation, antifibrosis, and antiapoptosis. In recent years, several programs have been launched in order to develop drugs that act as agonists on the AT2R or MAS to take therapeutic advantage of the protective and regenerative properties of these receptors. This review article will focus on recent data obtained in preclinical animal and in vitro models with new AT2R-agonistic molecules (Compound 21 and β-amino acid substituted angiotensin II) and with relevance for blood pressure (BP) regulation or hypertensive end-organ damage. These data will include studies on vasodilation/vasoconstriction in isolated resistance arteries ex vivo, studies on kidney function, studies on vascular remodeling, and studies that measured the net effect of AT2R stimulation on BP in vivo. Current data indicate that although AT2R stimulation causes vasodilation ex vivo and promotes natriuresis, it does not alter BP levels in vivo acutely -at least as long as there is no additional low-dose blockade of AT1R. However, AT2R stimulation alone is able to attenuate hypertension-induced vascular remodeling and reduce arterial stiffening, which in more chronic settings and together with the natriuretic effect may result in modest lowering of BP. We conclude from these preclinical data that AT2R agonists are not suitable for antihypertensive monotherapy, but that this new future drug class may be beneficial in combination with established antihypertensives for the treatment of hypertension with improved protection from end-organ damage.
Unopposed stimulation of the angiotensin AT2 receptor in the kidney
Nephrology Dialysis Transplantation, 1998
Effects of angiotensin II in the kidney tor ligands/antagonists as for example PD123177, PD123319 and CGP42112, was the basis for the identi-Angiotensin II (ANG II), the major effector molecule fication and characterization of ANG II receptor of the renin-angiotensin system (RAS), exerts numersubtypes. Currently, two main angiotensin-receptor ous actions on kidney function and structure. Under subtypes, AT1 and AT2, have been cloned and pharmaphysiological conditions, ANG II modulates glomercologically characterized, which display a heterogenular filtration by constricting efferent and afferent eous distribution in peripheral tissues and in the brain arteriolar blood vessels and glomerular mesangial cells [overview: 2,5,6 ]. The existence of further subtypes to modify filtration coefficient, mechanisms which enable the kidney to autoregulate glomerular filtration such as the AT3-and AT4 receptor, is still controverrate in a broad range, when systemic blood pressure sial. In the human kidney, only a single gene encoding and/or renal perfusion pressure change [1]. ANG II for the AT1 receptor is expressed, which is localized also facilitates renal sodium retention through several on chromosome 3. In rodents, however, AT1a and mechanisms: via a decrease in medullary blood flow AT1b receptor isoforms exist, which are localized on and renal interstitial pressure, both leading to a chromosome 17 and 2, respectively, and bear over 90% decrease in sodium excretion, via enhanced sodium identity. In humans, the gene for the AT2 receptor is reabsorption through an enhanced filtration fraction localized on the X-chromosome. Both, the AT1 and leading to augmentated peritubular capillary colloidthe AT2 receptor belong to the seven-transmembraneosmotic pressure [1], or via direct effects in the proxdomain superfamily of receptors, but the amino acid imal tubule as for example stimulation of the Na+/H+ sequence of the AT1 receptor is only 34% identical exchanger [overview: 2]. ANG II-induced aldosterone with the AT2 receptor sequence [overview: 6 ]. secretion from the adrenal gland also contributes to The distribution of the AT1 receptor isoforms within renal sodium retention [1]. Furthermore, ANG II has the kidney has not yet been extensively studied. In also been implicated in cellular growth and differrats, the AT1a receptor, expressed predominantly in entiation in the kidney, for example in angiogenesis vascular smooth muscle, is most abundant in the occurring during glomerular differentiation [3] and glomerular mesangial area, the vascular component of nephrosclerosis [4]. The role of ANG II as a growth the juxtaglomerular apparatus and the terminal portion factor has been demonstrated in a number of studies of the afferent arteriole [7-9]. In contrast, AT1b using fibroblasts, adrenal cortical-, vascular smooth mRNA levels seem to be much lower in the kidney, muscle-, or cardiac cells, and growth modulating effects and relatively high concentrations are only found of ANG II have also been shown in mesangial and within the lining of the papilla and the proximal tubular cells of the kidney [overview: 5]. portion of the ureter. Recent findings have demonstrated that in the rat kidney, AT1a mRNA is upregulated by dietary sodium whilst AT1b mRNA is Angiotensin II receptor subtypes in the kidney downregulated, indicating that these receptors are not only differentially regulated but might also mediate In an endeavour to block the RAS more specifically different renal functions. Compared to AT2 receptors, and, thereby, avoid unwarranted side effects of ACE AT1 receptors dominate by far the adult human [10] inhibitors, novel non-peptidergic ANG II receptor and rat [7] kidney, while AT2 receptors only represent antagonists have been developed. The development of 5-10% of the ANG II receptors, predominantly located highly specific and selective AT1-receptor antagonists in the renal capsule, larger vessels and to a lower such as losartan, valsartan, eprosartan, irbesartan,
Pharmacodynamics of Atrial Natriuretic Peptide in Isolated Perfused Dahl Rat Kidneys
Hypertension Research, 1995
Atrial natriuretic peptide (ANP) has been implicated in the development of hypertension in Dahl R and S rats. To test the responses of DR and DS kidneys in the absence of the influence of neural and humoral mechanisms, we investigated the pharmacokinetics and pharmacodynamics of ANP in isolated perfused DR and DS kidneys, obtained from rats given a high or low sodium diet, after a bolus injection of ANP (Lug) or after a bolus injection plus infusion of ANP to maintain the perfusate concentration at 1000 pg/ml. The elimination rate constant was not different between the groups (DR, 0.044 min-I Us. DS, 0.050 min-1). Clearance of ANP was 4 times greater than the glomerular filtration rate, indicating that a receptor-mediated peritubular clearance is probably the primary route of elimination. DS kidneys excreted 50% less sodium than DR kidneys. However, ANP caused a 5-fold increase in fractional sodium excretion in both DR and DS. ANP also increased sodium excretion, creatinine clearance, and urine flow. No alteration in ANP kinetics occurred to account for the reportedly increased circulating concentrations of ANP seen in DS rats. We conclude that isolated DR and DS kidneys respond differently to ANP after bolus ANP administration to concentrations of 10,000 pg/ml. This difference in response is due to the sodium excretory defect inherent in the DS kidney and not to an alteration in the DS kidney's ANP responsiveness.
Hypertension, 2006
Whereas angiotensin (Ang) II is the major effector peptide of the renin-angiotensin system, its metabolite, des-aspartyl1-Ang II (Ang III), may also have biologic activity. We investigated the effects of renal interstitial (RI) administration of candesartan (CAND), a specific Ang II type 1 receptor (AT1) blocker, with and without coinfusion of PD-123319 (PD), a specific Ang II type 2 receptor (AT2) blocker, on Na+ excretion (UNaV) in uninephrectomized rats. We also studied the effects of unilateral RI infusion of Ang II or Ang III on UNaV with and without systemic infusion of CAND with the noninfused kidney as control. In rats receiving normal Na+ intake, RI CAND increased UNaV from 0.07+/-0.08 to 0.82+/-0.17 micromol/min (P<0.01); this response was abolished by PD. During Na+ restriction, CAND increased UNaV from 0.06+/-0.02 to 0.1+/-0.02 micromol/min (P<0.05); this response also was blocked by PD. In rats with both kidneys intact, in the absence of CAND, unilateral RI infusion of Ang III did not significantly alter UNaV. However, with systemic CAND infusion, RI Ang III increased U(Na)V from 0.08+/-0.01 micromol/min to 0.18+/-0.04 micromol/min (P<0.01) at 3.5 nmol/kg per minute, and UNaV remained elevated throughout the infusion; this response was abolished by PD. However, RI infusion of Ang II did not significantly alter UNaV at any infusion rate (3.5 to 80 nmol/kg per minute) with or without systemic CAND infusion. These results suggest that intrarenal AT1 receptor blockade engenders natriuresis by activation of AT2 receptors. AT2 receptor activation via Ang III, but not via Ang II, mediates the natriuretic response in the presence of systemic AT1 receptor blockade.
European Journal of Pharmacology, 1994
The purpose of this study was to investigate whether the selective angiotensin AT e receptor ligands, CGP 42112B (Nic-Tyr-(N~-benzoyloxycarbonyl-Arg)Lys-His-Pro-Ile-OH) and PD 123319 ((s)-l-[[4-(dimethylamino)-3-methyl-phenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]-pyridine-6-carboxylic acid) are agonists at angiotensin receptors influencing blood pressure and renal function in the enalaprilat-treated anesthetized rat. The agonist angiotensin II significantly increased blood pressure and renal vascular resistance. Glomerular filtration rate was unchanged by angiotensin II. Effective renal blood flow decreased significantly in response to angiotensin II leading to a significant increase in filtration fraction. Angiotensin II did not induce significant change in urinary potassium excretion or free water formation but significantly increased both urine volume and urinary sodium excretion. At doses up to 3 orders of magnitude greater than angiotensin II, CGP 42112B also significantly increased blood pressure, filtration fraction, glomerular filtration rate, urine volume and urinary sodium excretion, but did not significantly affect effective renal blood flow or renal vascular resistance. The selective angiotensin AT 2 receptor ligand PD 123319 had no significant effects on blood pressure nor any measured parameter of renal function. The changes in blood pressure and renal function produced by angiotensin II and CGP 42112B could be completely blocked by the angiotensin AT 1 receptor antagonist losartan. The results therefore only support a role for angiotensin AT 1 receptors and not angiotensin AT 2 receptors in the control of renal function in the rat and demonstrate that at high doses the angiotensin AT z selective ligand CGP 42112B behaves as an agonist at angiotensin AT 1 receptors.
Atrial natriuretic peptides: Reproducibility of renal effects and response of liver blood flow
European Journal of Clinical Pharmacology, 1986
To assess the variability of the response to exogenous atrial natriuretic peptide (ANP), it was infused at the rate of 1 tig/min for 2 h in 6 salt-loaded normal volunteers under controlled conditions on 2 occasions at an interval of I week. The effect on solute excretion and the haemodynamic and endocrine actions were highly reproducible. The constant ANP infusion caused a delayed and prolonged excretion of sodium, chloride and calcium, no change in potassium or phosphate excretion or in glomerular filtration rate but a marked decrease in renal plasma flow. Blood pressure, heart rate and the plasma levels of angiotensin II, aldosterone, arginine vasopressin and plasma renin activity were unaltered. The effect of a 2-h infusion of ANP 0.5 txg/min or its vehicle on apparent hepatic blood flow (HBF) was also studied in 14 normal volunteers by measuring the indocyanine green clearance. A 21% decrease in HBF was observed in subjects who received the ANP infusion (p < 0.01 vs vehicle). Thus, ANP infused at a dose that did not lower blood pressure decreased both renal and liver blood flow in normotensive volunteers. The renal and endocrine responses to ANP were reproducible over a 1-week interval.