A new class of antihypertensive therapy: angiotensin II receptor antagonists

Despite the availability of safe and efficacious antihypertensive agents, hypertension continues to be a major source of morbidity and mortality in the United States. Losartan, the first of a new class of agents, the angiotensin II receptor antagonists, can be administered as monotherapy in the treatment of hypertension or to complement existing therapy. The angiotensin II receptor antagonists block the effects of angiotensin II through preferential binding to angiotensin II receptor subtype AT1 on the cell membrane. Compared with angiotensin-converting enzyme inhibitors, they may provide more complete blockade of the renin-angiotensin system and be associated with a lower frequency of cough as a side effect.     

Human pharmacokinetic/pharmacodynamic profile of irbesartan: a new potent angiotensin II receptor antagonist

BACKGROUND: Inhibition of the renin-angiotensin system has been the focus of considerable research as the enzymatic pathway resulting in the production of angiotensin II is implicated in the development of hypertension and cardiovascular disease. ANGIOTENSIN CONVERTING ENZYME INHIBITORS: Blocking the renin-angiotensin system with angiotensin converting enzyme (ACE) inhibitors is an effective blood pressure control measure, but is less than ideal due to incomplete blockade and the effects of concomitant blockade of kinase II. ANGIOTENSIN II RECEPTOR ANTAGONISTS: Angiotensin II receptor antagonists block the renin-angiotensin system at the receptor level, and thus impede the system regardless of the pathway responsible for the formation of ACE. Irbesartan is a new, unique angiotensin II receptor antagonist with favorable pharmacokinetic/pharmacodynamic properties that are close to ideal for an antihypertensive agent. Irbesartan is a specific AT1 receptor antagonist with rapid oral bioavailability (peak plasma concentrations occurring at 1.5-2 h after administration) and a long half-life (11-15 h) that provides 24-h blood pressure control with a single daily dose. The maximal blood pressure fall occurs between 3 and 6 h after the dose. Unlike other angiotensin II receptor antagonists, irbesartan is relatively unaffected by food or drugs. CONCLUSIONS: The pharmacokinetic/pharmacodynamic properties of irbesartan have been demonstrated to provide superior blood pressure control and tolerability in all classes of hypertension and patient populations.     

Renal effects of guanabenz: a new antihypertensive

In order to determine the effects of guanabenz upon renal function, clearance studies were performed on hypertensive volunteers during sustained steady-state water diuresis. The data reveal an acute fall in renal hemodynamics and a marked reduction in sodium excretion during the 3rd and 4th hour after administration. Tha antinatriuresis was due to decreased filtration and enhanced distal nephron reabsorption of sodium, principally in association with secretion of potassium. Chronic administration of guanabenz for one week produced a sustained reduction in blood pressure, but there was no change in either body weight or 24-hour urinary sodium excretion. Repeat clearance studies revealed no change with either renal hemodynamics or sodium clearance. The data suggest that the acute antinatriuresis is a transient hemodynamic event and chronic therapy with guanabenz will not be complicated by sodium retention, a feature characteristic of other antihypertensive agents.     

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients

We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.     

Angioedema associated with angiotensin II receptor antagonist losartan

Angioedema has not been associated with losartan therapy in hemodialysis patients, as it has been with angiotensin converting enzyme (ACE) inhibitors. We report the case of a hemodialysis patient who previously had angioedema after therapy with ACE inhibitors and again had angioedema while taking losartan. We suggest caution in using losartan in patients with known sensitivity to ACE inhibitors manifested by angioedema.     

Antinociceptive effects of angiotensin-converting enzyme inhibitors and an angiotensin II receptor antagonist in mice

Potential involvement of brain endogenous angiotensin II in the nociception was investigated in mice by using ACE inhibitors and an angiotensin II antagonist. The mice were allocated to the groups which were orally treated with spirapril (5 mg/kg), trandolapril (5 mg/kg), enalapril (30 mg/kg), losartan (10 mg/kg), or vehicle for 1 day (single dose groups) and 7 days (repeated doses groups). Significantly longer jump latencies were obtained for the groups repeatedly treated with spirapril, trandolapril and losartan, while the group with enalapril gained no effect. In contrast, the single dosing of all agents failed to show antinociceptive effect. The brain ACE activity was determined ex vivo immediately after the hot-plate test, and showed to be suppressed for the groups repeatedly treated with spirapril or trandolapril. In the group repeatedly treated with losartan, ex vivo autoradiography depicted the marked decrease in angiotensin II-binding capacity to the sites containing exclusively AT1 receptors within the blood-brain barrier. The antinociceptive effects of repeated doses of spirapril and losartan were reversed by naloxone. These results suggest that brain endogenous angiotensin II is likely to be involved in central nociceptive mechanisms by its antagonistic interaction with endogenous opioid system.     

Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects

The Salford static knee instrument (SSKI) was developed to determine the quantitative assessment of the human knee joint in vivo by utilizing the technique of applied displacement and measurement of resistive load as proposed by Butler et al. (1). The instrument was used in parallel with the device developed by Al-Turaiki (2) which utilized the opposite method of assessment. The objective of the research was to examine which of the two techniques provided the more reliable and accurate method of knee assessment. Fourteen patients with suspected isolated rupture of the anterior cruciate ligament (ACL) were subjected to anterior-posterior drawer testing on both devices. The results showed that each instrument produced results which confirmed the clinical diagnosis by indicating a significant decrease in anterior stiffness when comparing the injured and uninjured knees. [SSKI device (p = 0.000) and Al-Turaiki (2) device (p = 0.002) statistical significant difference testing with Bonferonni Alpha correction p = 0.0125]. The results showed the Salford static knee instrument indicated a 58 per cent decrease in anterior stiffness and the Al-Turaiki (2) device a 35 per cent decrease when comparing the injured and uninjured knees. In conclusion it is suggested that the application of displacement and measurement of load as proposed by Butler et al. (1) may be the most appropriate technique for precise clinical diagnosis of pathological human knee joint instability.     

Metabolites of the angiotensin II antagonist tasosartan: the importance of a second acidic group

Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensin II antagonist series, a second acidic group can improve receptor binding activity but decrease in vivo activity after oral dosing. The metabolic introduction of a second acidic group in tasosartan bypasses this problem and contributes to the excellent profile of the compound. A molecular modeling study provides a rationale for the role of the enol group of 8 in AT1 receptor binding.     

Newborn infants' memory for speech sounds retained over 24 hours.

Newborn infants were exposed to speech sounds in 2 sessions separated by 24 hrs. Their habituation and recovery to these sounds were assessed by spontaneous head orienting toward the sound's location. 36 neonates were assigned to 1 of 3 groups: a no-change group that heard the same word both days, a change group that heard a different word each day, and a Day 2 age-control group that heard 1 of the 2 words for the 1st time on Day 2. Both groups habituated to the sound on Day 1 and recovered head turning after the 24-hr delay, but infants who heard the same word again responded less than did age controls. In addition, these infants also began turning away from the sound, unlike the other 2 groups. Following habituation, all groups displayed comparable levels of recovery by turning toward a novel posttest stimulus. Neonates appeared to retain memory for a specific sound over a 24-hr period when presented with the same sound over both days. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In vitro pharmacological properties of KRH-594, a novel angiotensin II type 1 receptor antagonist

Although most people are thought to receive their highest acute exposures to gasoline while refueling, relatively little is actually known about personal, nonoccupational exposures to gasoline during refueling activities. This study was designed to measure exposures associated with the use of an oxygenated fuel under cold conditions in Fairbanks, Alaska. We compared concentrations of gasoline components in the blood and in the personal breathing zone (PBZ) of people who pumped regular unleaded gasoline (referred to as regular gasoline) with concentrations in the blood of those who pumped an oxygenated fuel that was 10% ethanol (E-10). A subset of participants in a wintertime engine performance study provided blood samples before and after pumping gasoline (30 using regular gasoline and 30 using E-10). The biological and environmental samples were analyzed for selected aromatic volatile organic compounds (VOCs) found in gasoline (benzene, ethylbenzene, toluene, m-/p-xylene, and o-xylene); the biological samples were also analyzed for three chemicals not found in gasoline (1,4-dichlorobenzene, chloroform, and styrene). People in our study had significantly higher levels of gasoline components in their blood after pumping gasoline than they had before pumping gasoline. The changes in VOC levels in blood were similar whether the individuals pumped regular gasoline or the E-10 blend. The analysis of PBZ samples indicated that there were also measurable levels of gasoline components in the air during refueling. The VOC levels in PBZ air were similar for the two groups. In this study, we demonstrate that people are briefly exposed to low (ppm and sub-ppm) levels of known carcinogens and other potentially toxic compounds while pumping gasoline, regardless of the type of gasoline used.     

Intrarenal vascular effects of angiotensin I and angiotensin II

The effects of angiotensin I (250 pmol) and angiotensin II (7.5 pmol) on total renal blood flow and its cortical distribution were examined in 25 dogs anesthetized with pentobarbital. These peptides were administered as bolus injections directly into the left renal artery. Right and left renal blood flows were measured with noncannulating electromagnetic flow probes. The distribution of renal cortical blood flow was measured with 15-micrometers radioactive microspheres. Because angiotensin I is converted to angiotensin II extrarenally as well as intrarenally, the distribution of renal blood flow in response to the bolus injection of angiotensin agonists was measured before these peptides could have recirculated through the kidney. This maneuver precluded the possibility that blood flow changes were due to the extrarenal formation of vasoactive metabolites of angiotensin I or angiotensin II. Control total renal blood flow averaged 3.0 +/- 0.1 ml.min-1.g kidney wt-1 and was decreased 25% by both angiotensin I and angiotensin II. Outer renal cortical flow (zone I) was 5.1 +/- 0.3 ml.min-1.g-1 and was decreased to 3.9 +/- 0.3 ml.min-1.g-1 by both angiotensin I and angiotensin II. On the average, angiotensin I decreased inner cortical renal blood flow from a control of 1.8 +/- 0.2 to 1.2 +/- 0.2 ml.min-1.g-1; angiotensin II decreased inner cortical renal blood flow from a control of 1.9 +/- 0.2 to 1.4 +/- 0.2 ml.min-1.g-1. Analysis on a per-experiment basis revealed that angiotensin I, compared with angiotensin II, produced a proportionally greater decrease in inner cortical renal blood flow relative to its effects on outer cortical blood flow.     

Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis

Administration of angiotensin II causes an increase in portal pressure, and plasma concentration of angiotensin II is elevated in patients with cirrhosis, suggesting that angiotensin II may be involved in the pathogenesis of portal hypertension in cirrhosis. We evaluated the effect of the orally active angiotensin II receptor antagonist, losartan, on portal pressure in patients with cirrhosis and portal hypertension. Thirty patients with severe (hepatic venous pressure gradient [HVPG] >/= 20 mm Hg) and 15 patients with moderate (HVPG < 20 mm Hg) portal hypertension at baseline measurement were treated with an oral dose of 25 mg losartan once daily for 1 week and compared with 15 (HVPG >/= 20 mm Hg) and 10 (HVPG < 20 mm Hg), respectively, cirrhotic controls. On the seventh day, HVPG was determined again, and blood pressure, heart rate, body weight, and parameters of liver and kidney function were recorded. Losartan induced a significant (P <.001) decrease of HVPG in the patients with severe (-46.8% +/- 15.5%) and moderate (-44.1% +/- 14.7%) portal hypertension, while no significant change was seen in the controls. Losartan caused a slight but significant (P <.01) fall in mean arterial blood pressure (-3.1 +/- 5.0 and -3.5 +/- 4.3 mm Hg, respectively). One patient treated with losartan had a short symptomatic hypotensive reaction after the first dose of losartan that did not recur despite continued treatment. No deterioration of liver or kidney function was observed. The present study indicates that angiotensin II blockade with orally administered losartan is safe and highly effective in the treatment of portal hypertension.     

Captopril and angiotensin II receptor antagonist therapy in a pacing model of heart failure

Twenty-four splenectomized dogs were subjected to rapid right ventricular pacing (RRVP) at 250 beats/min for five weeks. During the final three weeks, four groups six dogs were untreated or treated with captopril alone, with the angiotensin II type 1 (AT1) receptor antagonist L158,809 alone or with the two drugs combined by constant intravenous infusion. Hemodynamic studies were carried out during light anesthesia at baseline, and after two and five weeks of pacing. Total vascular capacitance and stressed blood volume were calculated from the mean circulatory filling pressure during transient circulatory arrest after acetylcholine administration at three different circulating volumes. Central blood volume and cardiac output were measured by thermodilution. Severe heart failure was present in the untreated group after five weeks of RRVP, characterized by low cardiac output and total vascular capacitance, high right atrial and pulmonary capillary wedge and mean circulatory filling pressure, plus increased stressed and central blood volumes. While L158,809 had not effect, captopril alone or combined with L158,809 ameliorated the reduction in total vascular capacitance, and reduced right atrial and mean circulatory pressure and stressed blood volumes. Combined therapy reduced pulmonary capillary wedge pressure. Thus, angiotensin-converting enzyme inhibition with captopril was effective in this model of chronic low output heart failure, whereas AT1 receptor antagonism was not.     

Pharmacological profile of valsartan, a non-peptide angiotensin II type 1 receptor antagonist. 5th communication: hemodynamic effects of valsartan in dog heart failure models

Hemodynamic effects of valsartan ((S)-N-valeryl-N-?[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]meth yl?valine, CAS 137862-53-4, CGP 48933), a non-peptide angiotensin II type 1 receptor antagonist were examined in dogs with heart failure induced acutely by coronary artery ligation and chronically by rapid-ventricular pacing. Coronary artery ligation induced decrease in cardiac output and increase in left ventricular end-diastolic pressure. Valsartan at 10 mg/kg i.v. reduced blood pressure, heart rate, left ventricular pressure, left ventricular end-diastolic pressure and total systemic resistance. Similar changes were observed with enalaprilat at 0.1 mg/kg i.v. Rapid left ventricular pacing for 2 weeks reduced cardiac contractility. Valsartan, administered at a dose of 100 mg/kg/d p.o. for 2 weeks, lowered left ventricular end-diastolic pressure. Valsartan reduced preload and afterload in these two dog heart failure models.     

Effect of an endothelin antagonist on hemodynamic responses to angiotensin II

We determined changes in blood pressure, cardiac output, and total peripheral conductance evoked by intravenous infusions of angiotensin II (Ang II) in conscious, unrestrained normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) before and after pretreatment with bosentan, a nonselective endothelin antagonist. Blood pressure was recorded by radiotelemetry and cardiac output by ultrasonic transit-time flow probes. Bosentan per se failed to affect basal blood pressure and evoked only small changes in cardiac output and total peripheral conductance in both strains. The pressor effects of Ang II were exaggerated in SHR compared with WKY. Strikingly, bosentan pretreatment blunted the increases in blood pressure, the fall in cardiac output, and the decreases in conductance evoked by lower doses of Ang II but not higher doses of the peptide. This effect was observed in both rat strains but was more pronounced in SHR. These data suggest that endothelin contributes to the hemodynamic effects of Ang II in both SHR and WKY and that endothelin may contribute to the exaggerated pressor responsiveness of SHR to Ang II.     

Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade

It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type I (AT1) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8 [angiotensin II] (10 micrograms/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertension.     

The effects of perceived discrimination on ambulatory blood pressure and affective responses to interpersonal stress modeled over 24 hours.

Objective: This research examined the impact of perceived discrimination on ambulatory blood pressure (ABP) and daily level affect during social interaction. Design: For 24 hrs, adult Black and White participants wore an ABP monitor and completed palm pilot diary entries about their social interactions. Main Outcome Measures: Mean level and time-trend trajectories of blood pressure and heart rate were examined as well as mean level measures of positive and negative affect after stressful and nonstressful social interactions. Results: Analyses showed that, after controlling for important covariates, perceived discrimination predicted the slopes of both wake and nocturnal ABP responses, with those who reported more discrimination having steeper daytime trajectories for systolic and diastolic blood pressure and less nighttime dipping in heart rate over time as compared to those who had reported relatively infrequent discrimination. High levels of perceived discrimination were also related to positive and negative affective responses after stressful encounters. Conclusions: These results suggest that, regardless of race, perceived discrimination is related to cardiovascular and affective responses that may increase vulnerability to pathogenic processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Electrophysiological effects of clentiazem, a new Ca2+ antagonist, on rabbit hearts

Electrophysiological effects of clentiazem, a new 1,5-benzothiazepine type Ca(2+) antagonist, were examined in comparison with those of diltiazem in excised rabbit heart preparations. In Langendorff-perfused hearts electrically driven at basic cycle lengths of 400-500 ms, clentiazem (10(-8)-10(-6)M) and diltiazem (10(-8)-10(-6)M) caused a concentration-dependent prolongation of the atrio-His bundle conduction time (A-H interval) without affecting the His bundle-ventricular conduction time (H-V interval). The effects of clentiazem were equivalent to those of diltiazem. In isolated rabbit atrioventricular (A-V) node preparations electrically driven at 400- to 500-ms intervals, clentiazem and diltiazem at >10(-6)M concentrations produced concentration-dependent decreases in action potential amplitude (APA), maximum rate of depolarization (V max), and shortened action potential duration at 20 and 50% repolarization (APD(20) and APD(50)), whereas APD(90) was little affected. Application of 10(-6)M clentiazem prolonged effective refractory period (ERP) of the A-V node by approximately 7% of the control, an effect similar to that of diltiazem. In spontaneously beating sinoatrial (S-A) node preparations, clentiazem l0(-6)M or the higher concentration significantly decreased APA, V(max), and slope of slow diastolic depolarization, while reducing the maximum diastolic potential. The inhibitory effects of clentiazem showed strong suppression of APA and V(max) by 31.1 and 47.2% of the control, respectively, whereas both clentiazem (10(-7)-10(-5)M) and diltiazem (10(-7)-10(-5)M) had no effects on parameters of ventricular APs. These results suggest that dentiazem, like diltiazem, has a preferential inhibitory action on cardiac slow Ca(2+) channels.     

Vascular and excretory effects of angiotensin II in the rat isolated perfused kidney: influence of an AT1 and a nonselective AT receptor antagonist

Angiotensin II (AII) is a potent vasoconstrictor which, at physiological plasma concentrations, produces antinatriuresis, whereas high intrarenal concentrations cause natriuresis and diuresis. We examined the effects of a selective AT1 receptor antagonist, losartan, and a nonselective AT receptor antagonist, Sar1Thr8AII, on the response to infusion of AII in the isolated rat kidney perfused at constant pressure with a recirculating modified Krebs-Henseleit buffer. AII increased renal vascular resistance (RVR), glomerular filtration rate (GFR) and urinary volume (UV) and sodium excretion (UNaV) without changing the fractional excretion of water or electrolytes. Thus, changes in GFR can account for the natriuresis/diuresis. Both AII receptor antagonists prevented the increase in RVR. However, losartan was without effect on angiotensin-induced increases in GFR, UV or UNaV, whereas Sar1Thr8 AII also prevented the increases in GFR, UV and UNaV. The angiotensin receptor mediating the increase in GFR can be dissociated from that mediating the increase in RVR, providing functional evidence of angiotensin receptor subtypes in the rat kidney.