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Tolvaptan is a selective arginine vasopressin V2-receptor antagonist that is used as an aquaretic agent. This trial investigated the pharmacokinetics and pharmacodynamics of 15- to 60-mg single oral doses of tolvaptan in healthy Korean men. A dose block-randomized, placebo-controlled, double-blind, single ascending dose trial was conducted with 46 subjects receiving tolvaptan (15, 30, or 60 mg) or placebo. To determine pharmacokinetics and pharmacodynamics, blood and urine samples were collected at baseline and up to 48 hours after drug administration. Urine volume and fluid intake were measured for 24 hours starting the day before dosing (day -1) as baseline, and on the day of drug administration (day 1). Tolvaptan showed dose-linear pharmacokinetic characteristics regarding area under the concentration-time curve. Changes from baseline in 24-hour urine volume and 24-hour fluid balance correlated significantly with area under the concentration-time curve from time 0 to the last measurable time. Dose-dependent increases were observed in serum osmolality, serum sodium concentration, and free water clearance in the 4- to 8-hour interval after dosing, and these increases were maintained for at least 24 hours. Single 15- to 60-mg doses of tolvaptan exhibited linear pharmacokinetics and resulted in substantial, dose-dependent aquaresis in healthy Korean men.

Aims: Enhanced heart rate (HR) is a compensatory mechanism in chronic heart failure (CHF), preserving cardiac output, but at the cost of increased left ventricular (LV) oxygen consumption and impaired diastolic function. The HR reduction (HRR) induced by the If current inhibitor ivabradine prevents LV systolic dysfunction in CHF, but whether HRR improves LV diastolic function is unknown., Methods: LV diastolic function and remodeling were assessed in rats with CHF after coronary ligation after long-term (90 days, starting 7 days after ligation) and delayed short-term (4 days, starting 93 days after ligation) ivabradine treatment (10 mg·kg·d)., Results: Long- and short-term HRR reduced LV end-diastolic pressure, LV relaxation, and LV end-diastolic pressure-volume relation. Simultaneously, LV hypoxia-inducible factor-1α expression was reduced. Long-term and, to a more marked extent, short-term HRR increased endothelial cell proliferation, associated after long-term HRR with the prevention of CHF-related LV capillary rarefaction. Long-term and, to a lesser extent, short-term HRR increased endothelial nitric oxide synthase expression, associated after long-term HRR with improved nitric oxide-dependent coronary vasodilatation., Conclusions: Long-term HRR induced by ivabradine improves diastolic LV function probably involving attenuated hypoxia, reduced remodeling, and/or preserved nitric oxide bioavailability, resulting from processes triggered early after HRR initiation: angiogenesis and/or preservation of endothelial nitric oxide synthase expression.

We studied the effect of hydrochlorothiazide (HCTZ), the angiotensin-converting enzyme inhibitor benazepril, the calcium channel blocker amlodipine, or a combination of benazepril/amlodipine or benazepril/HCTZ on systolic blood pressure (BP) and end-organ injury (left ventricular hypertrophy, proteinuria, and endothelium-dependent relaxation to acetylcholine) in hypertensive Dahl salt-sensitive rats fed either a normal-salt (0.5% NaCl) or high-salt (4% NaCl) diet for 6 weeks. Rats fed a high-salt diet developed hypertension and significant end-organ injury. Monotherapy with HCTZ (75 mg/L in drinking water) or amlodipine (10 mg/kg/day by gavage) reduced systolic BP and proteinuria; benazepril (40 mg/kg/day by gavage) decreased proteinuria without significantly lowering systolic BP. In rats receiving a high-salt diet, only HCTZ reduced left ventricular hypertrophy, whereas endothelium-dependent relaxation was improved by amlodipine and benazepril but not by HCTZ. Combining benazepril with either amlodipine or HCTZ dramatically reduced systolic BP and end-organ injury. These data clearly support clinical studies suggesting that combination therapy is more effective than monotherapy for systolic BP control and prevention of end-organ injury. Complementary mechanisms of action of agents from different antihypertensive classes appear to facilitate the greater benefit on BP and end-organ injury.

Fluid retention and extracellular volume expansion are frequently encountered complications of congestive heart failure (HF) that can cause morbidity and mortality. Tolvaptan (Otsuka) is an orally administered nonpeptide vasopressin (VP) V2 receptor antagonist that inhibits water reabsorption in the kidney by competitively blocking VP binding, resulting in water diuresis without significantly changing total electrolyte excretion. In the 24-hour period following a 30-mg dose of tolvaptan, urine excretion rate increases and declines as plasma concentrations rise and fall; this uneven effect results in 80% of daily urine output in the first 12 hours. Therefore, the current study was designed to assess the pharmacodynamic effects, pharmacokinetics, and clinical safety of tolvaptan 30 mg QD plus placebo versus 15 mg BID over 7 days in patients with NYHA Class II/III heart failure and persistent fluid overload, SBP > or = 90 mm Hg, and a serum creatinine < or = 3.0 mg/dL. Patients were withdrawn from diuretics for 48 hours before randomization. Statistics were performed with ANCOVA for continuous variables and Mantel-Haenszel mean score test stratified by center for categorical variables. Thirty-nine of 40 patients completed days 1 and 7. There were no significant clinical, pharmacokinetic, or pharmacodynamic differences between the dosing regimens over time. Based on these findings, tolvaptan 30 mg was chosen as the comparator for placebo in a large phase 3 survival trial.

Diabetic nephropathy is a serious complication of diabetes associated with a poor prognosis which deteriorates to end-stage renal disease. Increased urinary excretion of protein and albumin are early clinical markers for diabetic renal disease and increased risk of cardiovascular disease. Diabetes causes activation of the renal endothelin system inducing renal damage. We analyzed the effects of SLV306, an inhibitor of both neutral endopeptidase and endothelin-converting enzyme, on diabetes-induced alterations of kidney function and morphology in rats with streptozotocin-induced diabetes. The effects of SLV306 (30 mg/kg per day), captopril (10 mg/kg per day), and placebo on urinary protein and albumin excretion as well as on blood pressure were studied in diabetic rats in comparison to non-diabetic control rats. The rats were treated for 20 weeks. At the end of the study kidney morphology was also analyzed using computer-aided image analysis systems. Serum glucose and blood pressure were similar in all diabetic groups. No side-effects were observed with SLV306 and captopril treatment. Protein excretion was 17.3 +/- 3.0 mg/24 hours in untreated diabetic rats. Protein excretion decreased significantly in the SLV306 (4.8 +/- 0.9 mg/24 hours; P = 0.03 vs untreated diabetic rats) as well as in the captopril (5.1 +/- 1.0 mg/24 hours; P = 0.03 vs untreated diabetic rats) -treated diabetic rats. Albumin excretion was 0.51 +/- 0.12 mg/24 hours in the untreated diabetic group and decreased likewise in the SLV306-treated diabetic rats (0.09 +/- 0.03 mg/24 hours; P = 0.04 vs untreated diabetic rats). The captopril-treated diabetic rats showed a strong trend towards reduced albumin excretion (0.12 +/- 0.04 mg/24 hours; P = 0.06 vs untreated diabetic rats). Computer-aided image analysis revealed that renal interstitial matrix content was significantly decreased in diabetic rats treated with either the angiotensin-converting enzyme inhibitor or the neutral endopeptidase/endothelin-converting enzyme inhibitor as compared to untreated diabetic rats. It was found that SLV306 decreases renal matrix protein content as well as protein and albumin excretion in diabetic rats independent of blood pressure. These effects are comparable to those of angiotensinconverting enzyme inhibition.

Although recent clinical studies have indicated that angiotensin II receptor blocker is as effective in treating heart failure as an angiotensin-converting enzyme inhibitor, it is unknown whether their effects are different. Dahl salt-sensitive rats were treated with an angiotensin-converting enzyme inhibitor benazepril, and an angiotensin II receptor blocker candesartan from 11 weeks old. We examined cardiac geometry and function by echocardiography, and histology and gene expression by high-density oligonucleotide arrays using Affymetrix U34 (Affymetrix, Santa Clara, CA, U.S.A.). Dahl salt-sensitive rats fed a high salt diet showed a marked increase in blood pressure and developed concentric hypertrophy at 11 weeks, followed by left ventricle dilation and congestive heart failure by 20 weeks after birth. Although both medications had only a mild antihypertensive effect, they strongly suppressed the development of cardiac hypertrophy, fibrosis and heart failure to the same extent. Gene expression pattern examined by Affymetrix GeneChip (Affymetrix) is quite different between the two drug groups, indicating that angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor prevent heart failure by different mechanisms.

Heart rate (HR) and heart rate variability (HRV) are risk markers in cardiac disease. HRV is also an index of the sympathovagal modulation of heart rate. Their relations have been rarely analyzed. We aimed to study such relations in normal adult conscious rats by using a novel bradycardic agent, a sinus node inhibitor, S-16257. Placebo-drug crossover designs were used while monitoring HR with telemetry and analyzing HRV in both time and frequency domains. S-16257 (2 mg/kg; n = 10) decreased HR by 29% and markedly increased HRV in parallel. By using various combinations of S-16257, atropine (2 mg/kg), and propranolol (4 mg/kg), a positive relation was shown between RR interval and various indexes of HRV: the slower the HR, the greater the HRV. Nevertheless, there is one exception to this correlation. When S-16257 was associated with both atropine and propranolol, the deep bradycardia was accompanied by a reduction of HRV, which indicates that the physiologic negative correlation between HR and HRV is not an intrinsic property of the pacemaker but is highly dependent on the two components of the autonomic system.

In a multicenter, randomized, double-blind, placebo-controlled study, we evaluated the efficacy and tolerability of the combination of benazepril, 10 mg, and amlodipine, 2.5 or 5 mg once daily, compared with benazepril, 10 mg, monotherapy in patients with hypertension inadequately controlled with angiotensin-converting enzyme (ACE)-inhibitor monotherapy. After a 2-week placebo and 4-week single-blind benazepril, 10 mg once daily, run-in period, 448 patients, 213 men and 235 women, aged 24-73 years (mean, 55 years), with mean diastolic blood pressure (DBP) > or =95 and < or =120 mm Hg at the end of the benazepril run-in period, were randomized to receive one of the following treatments once daily for 8 weeks: (a) benazepril, 10 mg, plus placebo (BZ10); (b) benazepril, 10 mg, plus amlodipine, 2.5 mg (BZ10/AML2.5); or (c) benazepril, 10 mg, plus amlodipine, 5 mg (BZ10/AML5). Before the patients were admitted to the trial, at the end of the placebo run-in and the benazepril run-in period and at the end of weeks 4 and 8 of the treatment period, sitting and standing blood pressure (BP), heart rate (HR), and body weight were measured 22-26 h after the intake of the trial medication. Both BZ10/AML2.5 and BZ10/AML5 combinations showed better antihypertensive activity than did BZ10 monotherapy at the terminal visit as demonstrated by (a) the 24-h postdosing sitting and standing systolic BP (SBP) and DBP values, which were statistically lower with combination therapy than with BZ10; (b) the success rate, which was statistically higher with both the combinations (69.2% in the BZ10/AML2.5 and 65.8% in the BZ10/AML5 group) compared with the BZ10 group (40.5%). The tolerability was good in the three treatment groups. No significant abnormal laboratory data were detected. There was no difference in efficacy and safety/tolerability between the BZ10/AML2.5 and BZ10/AML5 groups.

Arrhythmias occur 24 h after occlusion of the left anterior descending (LAD) coronary artery in the canine heart and have been attributed to the abnormal spontaneous activity in subendocardial Purkinje fibers, which are markedly depolarized. The major current underlying normal automaticity in these fibers is i(f). Although the i(f) activation range is generally considered to be more negative than the diastolic membrane potential in these depolarized fibers in infarcts, this activation range has been shown to shift in a positive direction in response to hormonal influences. Thus i(f) could still mediate automaticity in these fibers in infarcts. Furthermore, recent reports indicate that a depolarizing diastolic current, probably i(f), also can be measured in ventricular muscle during abnormal experimental conditions, which may occur during ischemia. To test whether there is a role of i(f) currents in sustaining ventricular ectopy, we administered the selective i(f) channel blocker, zatebradine, 24 h after LAD ligation in canine hearts. We report that intravenous injections of zatebradine (0.25 or 1.0 mg/kg) significantly slow ventricular rhythms (with average reductions of 19 or 26%, respectively). Moreover, because zatebradine also slows sinus nodal rate, it can lead to an increased incidence of ectopic beats. However, during right atrial pacing, when sinus slowing has no effect on ventricular rhythms, capture of ventricular rhythms occurs at lower rates in the presence of zatebradine. The reduction of capture threshold is comparable to the reduction in the rate of the ectopic rhythm. Thus zatebradine eliminated the arrhythmia when the right atrium was paced at the original sinus rate.

Angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), are two mechanistically similar enzymes involved in the metabolism of several vasoactive peptides. Selective inhibitors of ACE are effective antihypertensive agents in high-renin, renovascular rats and normal-renin, spontaneously hypertensive rats (SHR), but are not effective in the low-renin, deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In contrast, NEP inhibitors are only effective in the low-renin model of hypertension. Treatment with a combination of selective inhibitors or with a dual inhibitor of both enzymes produces an antihypertensive response regardless of basal plasma renin activity. In this study, we compared the activities of MDL 100,173, a novel subnanomolar inhibitor of both ACE and NEP, with those of equimolar doses of captopril, a selective ACE inhibitor, following intravenous administration in these three rat models of hypertension. Treatment with MDL 100,173 significantly lowered blood pressure compared to vehicle treatment in all three models, whereas captopril treatment lowered blood pressure in the renovascular and SHR models only. Administration of MDL 100,173 also significantly elevated diuresis and natriuresis compared to either vehicle or captopril treatment in the SHR and DOCA-salt rats. Urinary excretion of atrial natriuretic peptide (ANP) was increased by MDL 100,173 treatment in all three models of hypertension. Treatment with captopril did not alter urine, sodium, or ANP excretion in any of the models. However, plasma-renin activity was elevated by both MDL 100,173 and captopril '''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' ''''''''

Effects of novel, nonpeptide vasopressin V1 and V2 receptor antagonists on partially nephrectomized and salt-loaded spontaneously hypertensive rats (SHR), which develop severe hypertension and progressive nephrosclerosis, were investigated. SHR were 5/6-nephrectomized and fed a high salt diet. The rats were divided into four groups: group 1 was an untreated control, group 2 received the V1 antagonist OPC-21268, group 3 received the V2 antagonist OPC-31260, and group 4 received both the V1 and V2 antagonists. The V1 antagonist alone or combined with the V2 antagonist significantly decreased the increase in blood pressure (BP) of groups 2 and 4 rats, but the V2 antagonist alone did not reduce the increase in BP of the group 3 rats. The V2 antagonist alone or combined with the V1 antagonist induced a significant diuresis of rats in groups 3 and 4. The increase in urinary protein excretion and the progression of renal hyaline arteriolosclerosis were attenuated by the V1 antagonist with or without the V2 antagonist in rats in groups 2 and 4, but not by the V2 antagonist alone in rats in group 3. This implies that the progressive nephrosclerosis in SHR with partial renoablation and salt-loading was associated with V1 agonism.

Heart rate (HR) is a major factor determining the severity of myocardial ischemia, and HR reduction is an effective therapy for myocardial ischemia. We tested the effects of HR reduction induced by either UL-FS 49 or atenolol on regional myocardial blood flow, function, and infarct size (IS) in a porcine model of 90-min low-flow ischemia and 2-h reperfusion. In 24 Göttinger miniswine, the left anterior descending coronary artery (LAD) was cannulated and hypoperfused at constant inflow to reduce anterior systolic wall thickening (AWT, sonomicrometry) by approximately 85%. Eight swine served as a placebo group, and 8 other swine received UL-FS 49 (0.60 mg/kg intravenously, i.v.) after 10-min ischemia. In the remaining 8 swine, atenolol was infused after 10-min ischemia at a dosage [mean 1.75 +/- 1.20 (SD) mg/kg i.v.] to mimic the HR reduction observed with UL-FS 49. Systemic hemodynamics, subendocardial blood flow (ENDO, microspheres) and AWT were measured under control conditions, at 10 and 90 min of ischemia. In the swine receiving UL-FS 49 or atenolol, additional measurements were made 5 min after administration of the respective drug. After 2-h reperfusion, IS (percentage of area at risk) was determined with TTC-staining. Five minutes after administration of UL-FS 49, HR was decreased from 113 +/- 9 to 83 +/- 13 beats/min (p < 0.05) and remained unchanged when ischemia was prolonged to 90 min. In the swine receiving atenolol, HR was reduced from 117 +/- 14 to 93 +/- 7 beats/min (p < 0.05) 5 min after drug administration and decreased further to 87 +/- 10 beats/min when ischemia was prolonged to 90 min. After 10 min of ischemia, AWT in the placebo, UL-FS 49, and atenolol group was decreased to 7.0 +/- 5.5, 6.4 +/- 3.5, and 6.2 +/- 3.3% (all p < 0.05 vs. control), respectively. The reduction in ENDO was also comparable among the three groups. In the placebo group, AWT remained unchanged when ischemia was prolonged to 90 min (4.4 +/- 2.6%). In swine receiving atenolol, AWT tended to increase (13.6 +/- 10.5%), whereas in swine receiving UL-FS 49, AWT was significantly increased to 21.4 +/- 7.1% (p < 0.05 vs. 10-min ischemia and vs. the placebo and atenolol groups). IS was significantly reduced in swine receiving atenolol (3.9 +/- 3.5%) or UL-FS 49 (5.8 +/- 4.6%) as compared with the placebo-group (10.4 +/- 8.9%).(ABSTRACT TRUNCATED AT 400 WORDS)

In a double-blind, placebo-controlled, three-period cross-over, randomized study we evaluated the efficacy and tolerability of a fixed combination of benazepril 20 mg and hydrochlorothiazide 25 mg (BN + HCT) as compared with the fixed combination of captopril 50 mg and hydrochlorothiazide 25 mg (CP + HCT) by ambulatory blood pressure monitoring (ABPM) in patients with mild to moderate hypertension. Eighteen outpatients, 16 men and 2 women aged 41-58 years, were randomized to receive BN + HCT, CP + HCT, or placebo, all administered once daily for 4 weeks according to a three-period cross-over arranged in a 3 x 3 latin square design. Patients were checked after an initial 3-week washout period and every 4 weeks thereafter. At each visit, 24-h ABPM was performed by a noninvasive device (Spacelabs 5300); causal BP and heart rate (HR) were also measured. Both fixed combinations had a clear-cut antihypertensive effect in comparison with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

We wished to assess the hemodynamic effects of administration of the combination of the calcium channel blocking agent amlodipine and the angiotensin-converting enzyme (ACE) inhibitor benazeprilat in conscious spontaneously hypertensive rats (SHR). In SHR previously instrumented for measurement of mean arterial blood pressure (MAP) and heart rate (HR), intravenous (i.v.) injection of amlodipine (0.25-4 mg/kg) produced dose-dependent decreases in blood pressure (BP). Administration of benazeprilat (0.1-10 mg/kg i.v.) decreased arterial MAP, and benazeprilat (10 mg/kg) effectively blocked the effects of exogenously administered angiotensin I (AI). In animals surgically prepared for measurement of BP, HR, and hindquarter, renal, and mesenteric blood flows, administration (i.v.) of the combination of amlodipine (0.5 mg/kg) with benazeprilat (10 mg/kg) evoked a decrease in BP that was greater than that elicited by monotherapy. The tachycardic response observed after administration of the combination was no different from that observed after monotherapy with amlodipine. Simultaneous administration of amlodipine and benazeprilat produced reductions in vascular resistance in the hindquarter, renal and mesenteric beds that were greater than the responses evoked by injection of either agent. The major finding of these studies was that dual therapy with amlodipine and benazeprilat produced an additive hypotensive effect in conscious SHR. Regional vasodilation accompanied the large degree of hypotension evoked by the combination.

The pharmacokinetics and pharmacodynamics of benazepril, an angiotensin converting enzyme (ACE) inhibitor, were investigated after administration of a single oral 5-mg dose and 7 more doses on consecutive days to hypertensive patients with normal renal function (NRF) and those with impaired renal function (IRF). The antihypertensive effect of benazepril was observed as early as 30 min after a single dose, and those effects during consecutive dosing were also sustained for 24 h with a lesser diurnal variation in blood pressure (BP). The time to peak (Tmax) and the apparent elimination half-life (t1/2) for benazepril were 0.6-0.7 h and 0.4-0.8 h, respectively. Tmax for its diacid was 1.5-2.4 h in both groups. The area under the plasma concentration-time curve to 24 h (AUC0-24h) for the diacid was significantly greater in the IRF group than in the NRF group. After consecutive dosing of benazepril, AUC0-24h and plasma peak level (Cmax) were significantly increased in the IRF group. Serum ACE activity was markedly suppressed for 24 h after administration, and the inhibition was closely related to plasma diacid levels. A significant inverse correlation was observed between creatinine clearance and the AUC for the diacid. These results suggest that benazepril is rapidly bioactivated to diacid and exhibits rapid onset and long-lasting antihypertensive effects. Dosage reduction might be required to minimize unnecessary drug accumulation in patients with severe IRF.

UL-FS 49 is a sinus node inhibitor that has been reported to reduce heart rate and may be useful in improving myocardial oxygen supply vs. demand. However, previous studies performed in a variety of preparations have produced mixed results regarding the independent inotropic effect of UL-FS 49. To determine whether UL-FS 49 has an inotropic effect, we measured both steady-state hemodynamic responses and transient hemodynamic responses to random preload and afterload changes, both with and without UL-FS 49. We found that under steady-state conditions, the effect of UL-FS 49 is so small that it would be of doubtful physiologic significance: a 3% increase in stroke volume (p = 0.007) and 7% increase in peak positive dP/dt (p = 0.051), in the presence of no statistically significant differences in end-diastolic pressure, end-diastolic volume, peak systolic pressure, end-systolic pressure, or heart rate. The more powerful multiple linear regression modeling of hemodynamic transient sequences resulting from random preload and afterload changes showed that UL-FS 49 is without a statistically significant direct effect on left ventricular function. We conclude that UL-FS 49 has no physiologically important direct effect on left ventricular pump function.

Relative DA1-dopamine-receptor agonist and alpha-adrenoceptor antagonist activities of fenoldopam were determined in pentobarbital anesthetized dogs. The renal vasodilating effect of intravenous infusions of fenoldopam was used as an index of its DA1-agonist activity. Inhibition by fenoldopam of femoral vasoconstriction produced by intraarterial administration of phenylephrine (a relatively selective alpha 1 agonist) and UK 14,304 ( a relatively selective alpha 2 agonist) was used to determine its alpha-adrenoceptor antagonist activity. Intravenous infusions of 0.1 and 0.2 microgram/kg/min of fenoldopam caused dose-related reductions in renal vascular resistance and mean arterial pressure. Higher rates of infusions of fenoldopam (2 and 5 micrograms/kg/min) were given after pretreatment with 50 micrograms/kg/min SCH 23390 (a DA1-selective antagonist) to attenuate DA1-mediated hemodynamic effects. After SCH 23390, the infusion of 5 micrograms/kg/min of fenoldopam produced approximately the same hypotensive and renal vasodilating actions as the 0.2 microgram/kg/min infusion without SCH 23390. Alpha-adrenoceptor blocking activity was not observed with the 0.1, 0.2, and 2 micrograms/kg/min infusions of fenoldopam. The 5 micrograms/kg/min infusion, however, produced 14 and 25% inhibition of the vasoconstrictor effects of phenylephrine and UK 14,304, respectively. These data indicate that fenoldopam decreases renal vascular resistance in doses which are 25 to 50 times less than the dose needed to antagonize alpha adrenoceptors.

In pentobarbital-anesthetized rats prepared for hemodynamic measurements with Doppler flow probes, intravenous (i.v.) infusions of fenoldopam (2.5 - 160.0 micrograms/kg/min during 15 min) decreased mean carotid artery blood pressure, total peripheral, hindquarter, renal, and mesenteric vascular resistances and increased renal blood flow strongly. The hypotensive effects attained a maximum within the first 3 min of infusion but waned by greater than 30% at the end of fenoldopam administration. This tolerance was observed for calculated total peripheral and hindquarter vascular resistances and to a lesser extent for mesenteric resistance. However, it was absent on the renal vascular bed. Pretreatment with either enalapril, pepstatine, or bilateral nephrectomy significantly increased the hypotensive response to fenoldopam and attenuated the development of tolerance. In conscious spontaneously hypertensive rats (SHR), enalapril potentiated strongly the small blood pressure-lowering activity of fenoldopam. The fall in blood pressure produced by fenoldopam was specifically blocked by SCH 23390, an antagonist of DA-1 dopamine receptors. In normotensive vasopressin-supported pithed rats given phenoxybenzamine plus propranolol, fenoldopam, like SCH 23390, blocked the vasodepressor effects of i.v. bolus injection of dopamine and fenoldopam. In pithed rats, fenoldopam evoked a pressor response that was significantly reduced by enalapril, SCH 23390, or bilateral nephrectomy. In conclusion, fenoldopam exerts DA-1 agonist and antagonist effects. The latter property, together with the activation of the renin-angiotensin system, appears to be responsible for the development of tolerance to the fenoldopam evoked-hypotension. The lack of a tolerance at the level of the renal vascular bed is possibly due to the existence of a large population of DA-1 receptors in this region.