In vitro relaxation of arteries and veins by prazosin: alpha-adrenergic blockade with no direct vasodilation.

Controversy exists regarding the mechanism by which prazosin lowers blood pressure without a marked increase in heart rate; a mechanism involving both sympatholytic activity and direct smooth muscle relaxation has been suggested. alpha-Adrenergic receptor blockade by prazosin is well documented and occurred to exogenous norepinephrine and to field stimulation in vitro in rat arteries and veins. A parallel shift of the norepinephrine concentration response curves in the aorta and mesenteric artery contrasted with a nonparallel shift and a marked depression of maximal norepinephrine responses in the inferior vena cava, portal, iliac and femoral veins. Nonspecific direct acting vasodilators will antagonize contractile responses to all agonists. However, prazosin (10(-8) M) specifically antagonized norepinephrine-induced responses. Concentration response curves to potassium chloride or to serotonin were not affected in these rat tissues. In addition, prazosin (up to 10(-6) M) did not significantly relax aortic tissue previously contracted with potassium chloride or serotonin, whereas the vasodilator, nitroglycerin, produced a clear relaxation. Prazosin only reduced the tone of vessels contracted with norepinephrine. These data indicate that prazosin exhibits minimal, if any, direct smooth muscle relaxant properties in concentrations higher than those producing alpha-adrenergic receptor blockade, and relaxes rat veins by a mechanism involving alpha-adrenergic receptor blockade.     

Therapeutic assessment of urapidil or angiotensin-converting enzyme inhibition in systemic hypertension

The antihypertensive efficacy of urapidil, a postsynaptic alpha blocker with an additional central action, was compared with that of the angiotensin I converting enzyme inhibitor captopril under conditions of general practice (multicenter study). The study was performed in a double-blind, randomized, parallel-group fashion. After a 2-week washout and placebo phase, 295 essential hypertensive patients (World Health Organization grades I and II) were treated for 12 weeks with either urapidil or captopril, initially with urapidil, 60 mg twice daily or captopril, 25 mg twice daily, with the possibility of adjusting the dose according to blood pressure response after 2 weeks of treatment. Blood pressure values at the end of the 12-week treatment decreased significantly in the group receiving urapidil (n = 142, all dosages), from 175/103 to 154/89 mm Hg (p less than 0.001), and in the group receiving captopril (n = 153, all dosages) from 175/103 to 154/90 mm Hg (p less than 0.001); these values corresponded to 62% urapidil and 58% captopril responder rates (diastolic blood pressure less than or equal to 90 mm Hg), respectively. The computer-assisted frequency distribution of the patients with controlled diastolic blood pressure (less than or equal to 90 mm Hg) over the duration of the study demonstrated comparable efficacy for both drugs. Adverse effects were observed in 45 patients in the urapidil group and in 18 patients in the captopril group (vertigo, nausea, headache). The results revealed that the 2 antihypertensive agents with different modes of action controlled blood pressure with equal efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension

Some evidence suggests that long-term angiotensin-converting enzyme (ACE) inhibition may become less effective, thereby increasing angiotensin II levels, which could be inhibited by the addition of an angiotensin receptor blocker. We conducted a meta-analysis of randomized trials with searches of MEDLINE, EMBASE, and Cochrane databases. Overall, the combination of an ACE inhibitor and an angiotensin receptor blocker reduced ambulatory blood pressure by 4.7/3.0 mm Hg (95% confidence interval [CI], 2.9 to 6.5/1.6 to 4.3) compared with ACE inhibitor monotherapy and 3.8/2.9 mm Hg (2.4 to 5.3/0.4 to 5.4) compared with angiotensin receptor blocker monotherapy. Clinic blood pressure was reduced by 3.8/2.7 mm Hg (0.9 to 6.7/0.8 to 4.6) and 3.7/2.3 mm Hg (0.4 to 6.9/0.2 to 4.4) compared with ACE inhibitor and angiotensin receptor blocker, respectively. However, the majority of these studies used submaximal doses or once-daily dosing of shorter-acting ACE inhibitors and, when a larger dose of shorter-acting ACE inhibitor was given or a longer-acting ACE inhibitor was used, there was generally no additive effect of the angiotensin receptor blocker on blood pressure. Proteinuria was reduced by the combination compared with ACE inhibitor and angiotensin receptor blocker monotherapy, an effect that was independent of blood pressure in several studies, suggesting that the combination could have benefits in proteinuric nephropathies. None of the studies was of sufficient size and duration to determine whether there may be safety concerns. In conclusion, although there is a small additive effect on blood pressure with an ACE inhibitor-angiotensin receptor blocker combination, the routine use of this combination in uncomplicated hypertension is not recommended until more carefully controlled studies are performed.     

Acute and chronic effects of the angiotensin-converting enzyme inhibitor captopril in severe hypertension

In this study the acute and chronic effect of the converting enzyme inhibitor captopril was investigated in a relatively large number of patients (acute: n = 78, chronic: n = 67) with various forms of severe hypertension, the majority of cases being resistant to a standardized triple therapy (100 mg of hydrochlorothiazide or 80 to 500 mg of furosemide, 320 mg of propranolol and 200 mg of hydralazine). Up to an observed period of 240 minutes, a single oral dose of 25 mg of captopril led to a significant and marked decrease in systolic and diastolic blood pressure. The acute antihypertensive effect of captopril was more pronounced in patients with renovascular than in those with essential or renal parenchymal hypertension. Similar differences among the three groups of patients were also observed during chronic treatment. Over a period of 18 months, patients with renovascular hypertension showed both a more pronounced decrease in mean diastolic blood pressure values and a significantly higher percentage of cases with excellent blood pressure control (diastolic blood pressure 95 mm Hg or less). Under long-term conditions, about 90 percent of all patients required a diuretic and a substantial percentage also needed propranolol as a third drug. Positive correlations between pretreatment plasma renin activity levels and captopril-induced blood pressure reduction were found under acute conditions only. The most frequent side effects were skin manifestations, taste disturbances, dizziness and unproductive cough. Serious adverse effects were rare and included one case of leukopenia and one of the nephrotic syndrome, both being reversible after withdrawal of captopril.Our results demonstrate that captopril is a very potent blood pressure lowering agent in severe hypertension especially in cases of renovascular hypertension. However, currently the potential risk of serious side effects should induce the physician to reserve this drug for those patients with truly resistant hypertension.     

Effect of direct vasodilation with hydralazine versus angiotensin-converting enzyme inhibition with captopril on mortality in advanced heart failure: the Hy-C trial.

To compare the benefit of angiotensin-converting enzyme inhibition and direct vasodilation on the prognosis of advanced heart failure, 117 patients evaluated for cardiac transplantation who had severe symptoms and abnormal hemodynamic status at rest were randomized to treatment with either captopril or hydralazine plus isosorbide dinitrate (Hy-C Trial). Comparable hemodynamic effects of the two regimens were sought by titrating vasodilator doses to match the hemodynamic status achieved with nitroprusside and diuretic agents, attempting to achieve a pulmonary capillary wedge pressure of 15 mm Hg and a systemic vascular resistance of 1,200 dynes.s.cm-5. Treatment with the alternate vasodilator was started because of poor hemodynamic response or side effects (40% of patients in the captopril group and 22% in the hydralazine group). Adequate hemodynamic response in patients with a serum sodium level less than 135 mg/dl was more likely with hydralazine than with captopril (71% vs. 33%, p = 0.04). Isosorbide dinitrate was prescribed in 88% of the hydralazine-treated patients and 84% of the captopril-treated patients. The hemodynamic improvements from each regimen were equivalent. After 8 +/- 7 months of follow-up, the actuarial 1-year survival rate was 81% in the captopril-treated patients and 51% in the hydralazine-treated patients (p = 0.05). The improved survival with captopril resulted from a lower rate of sudden death, which occurred in only 3 of 44 captopril-treated patients compared with 17 of 60 hydralazine-treated patients (p = 0.01). In the subset of patients who continued treatment with the initial vasodilator, results were similar to those for the entire treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic AT1 receptor blockade and angiotensin-converting enzyme (ACE) inhibition in (CHF 146) cardiomyopathic hamsters: effects on cardiac hypertrophy and survival.

OBJECTIVE: We have reported that angiotensin II AT1 receptors are upregulated and that there are no AT2 receptors in the ventricles of cardiomyopathic hamsters. Since the upregulation was present even when no histological lesions were detectable, these results suggested that angiotensin II plays a role in the genesis/maintenance of this pathology. A survival study was conducted to compare the effects of an angiotensin II AT1 receptor antagonist, losartan (L), to those of a placebo (P). Since the angiotensin-converting enzyme (ACE) inhibitor quinapril (Q) has been shown to have beneficial effects in this animal model, a Q group was included. METHODS: Male Syrian cardiomyopathic hamsters (CHF 146, n = 360) were orally administered P, low- (30 mg/kg/day) or high-dose (100 mg/kg/day) L, or Q (100 mg/kg/day), starting at day 50 of life. Inbred control hamsters (CHF 148, n = 180) were treated with P or L (100 mg/kg/day) as controls. Animals were sacrificed at intervals to evaluate cardiac hypertrophy. Kaplan-Meier analysis was performed to assess differences in survival. RESULTS: High-dose L had no effects on the survival of control hamsters. There was an unexpected dose-dependent decrease in the survival of cardiomyopathics treated with L (low-dose, P = 0.14; high-dose, P = 0.0015) compared to an increase with Q (P = 0.0003). Cardiac hypertrophy compared to P was increased with L but significantly decreased with Q in cardiomyopathics. CONCLUSIONS: In this model, losartan did not improve survival compared to placebo and quinapril and, if anything, increased mortality. Our results suggest that AT1 receptor antagonists and ACE inhibitors are not necessarily equivalent or interchangeable in terms of their effects on cardiac hypertrophy and survival in selected progressive heart failure models.     

Role of N-acetyl-seryl-aspartyl-lysyl-proline in the antifibrotic and anti-inflammatory effects of the angiotensin-converting enzyme inhibitor captopril in hypertension

Angiotensin-converting enzyme inhibitors (ACEis) are known to have antifibrotic effects on the heart and kidney in both animal models and humans. N-acetyl-seryl-aspartyl-lysyl-proline is a natural inhibitor of proliferation of hematopoietic stem cells and a natural substrate of ACEi that was reported to prevent cardiac and renal fibrosis in vivo. However, it is not clear whether N-acetyl-seryl-aspartyl-lysyl-proline participates in the antifibrotic effects of ACEi. To clarify this issue, we used a model of aldosterone-salt-induced hypertension in rats treated with the ACEi captopril either alone or combined with an anti-N-acetyl-seryl-aspartyl-lysyl-proline monoclonal antibody. These hypertensive rats had the following: (1) left ventricular and renal hypertrophy, as well as increased collagen deposition in the left ventricular and the kidney; (2) glomerular matrix expansion; and (3) increased ED1-positive cells and enhanced phosphorylated-p42/44 mitogen-activated protein kinase in the left ventricle and kidney. The ACEi alone significantly lowered systolic blood pressure (P=0.008) with no effect on organ hypertrophy; it significantly lowered left ventricular collagen content, and this effect was blocked by the monoclonal antibody as confirmed by the histological data. As expected, the ACEi significantly decreased renal collagen deposition and glomerular matrix expansion, and these effects were attenuated by the monoclonal antibody. Likewise, the ACEi significantly decreased ED1-positive cells and inhibited p42/44 mitogen-activated protein kinase phosphorylation in the left ventricle and kidney, and these effects were blocked by the monoclonal antibody. We concluded that in aldosterone-salt-induced hypertension, the antifibrotic effect of ACEi on the heart and kidney, is partially mediated by N-acetyl-seryl-aspartyl-lysyl-proline, resulting in decreased inflammatory cell infiltration and p42/44 mitogen-activated protein kinase activation.     

Cardiovascular effects and regional blood flow distribution associated with angiotensin converting enzyme inhibition (captopril) in essential hypertension

Systemic and regional hemodynamics and cardiac structural changes were studied in 12 patients with mild to moderately severe essential hypertension before and then 90 minutes and 12 weeks after administration of captopril. Mean arterial pressure was reduced from 111 mm Hg to 96 mm Hg (p less than 0.001), and this was mediated through a fall in total peripheral resistance from 26 +/- 2 units to 23 +/- 2 units (p less than 0.01). The decreased total peripheral resistance was distributed to all circulations studied: kidney, skeletal muscle, skin and the splanchnic organs. Furthermore, left ventricular (LV) mass index diminished without altering myocardial contractility at rest. Thus, captopril lowered arterial pressure through systemic arteriolar dilatation in patients with mild to moderately severe essential hypertension and also reduced LV mass even in patients without evidence of LV hypertrophy.     

Vascular and renal effects of vasopeptidase inhibition and angiotensin-converting enzyme blockade in spontaneously diabetic Goto-Kakizaki rats

BACKGROUND: The renin-angiotensin system plays an important role in the pathogenesis of diabetes-induced vascular and renal complications. Vasopeptidase inhibitors simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase. OBJECTIVE: To compare the effectiveness of vasopeptidase inhibition and ACE inhibition in preventing hypertension, endothelial dysfunction and diabetic nephropathy in spontaneously diabetic Goto-Kakizaki (GK) rats. METHODS: Eight-week-old GK rats received omapatrilat (40 mg/kg) or enalapril (30 mg/kg) for 12 weeks, either during a normal-sodium or high-sodium diet (7% w/w). Blood pressure, arterial functions and renal morphology were determined. RESULTS: Blood pressure and albuminuria were increased in GK rats compared to non-diabetic Wistar controls. Endothelium-dependent vascular relaxation in response to acetylcholine (ACh) and endothelium-independent vascular relaxation in response to sodium nitroprusside (SNP) were impaired in GK rats. Experiments with N-nitro-L-arginine methyl ester (L-NAME), diclofenac, and L-NAME + diclofenac suggested that cyclooxygenase and endothelium-derived hyperpolarizing factor components of endothelium-dependent vascular relaxation were also impaired. A high-sodium diet aggravated hypertension and diabetes-induced vascular and renal complications. Omapatrilat and enalapril normalized blood pressure and albuminuria during the normal-sodium diet, and effectively ameliorated diabetes-induced renal complications also during the high-sodium diet. However, omapatrilat improved endothelium-dependent relaxation to ACh to a greater extent (85 +/- 5%) than enalapril (68 +/- 6%, P < 0.05). Diclofenac pre-incubation eliminated this difference between omapatrilat and enalapril in ACh-induced vascular relaxation, suggesting that it was mediated, at least in part, via the cyclooxygenase pathway. CONCLUSIONS: Despite comparable blood pressure-lowering and renoprotective properties, omapatrilat may be more effective in preventing vascular dysfunction during diabetes compared to enalapril in GK rats.     

Antifibrotic effect of Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension

OBJECTIVE: N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a potent natural inhibitor of hematopoietic stem cell proliferation which is degraded mainly by angiotensin-converting enzyme (ACE). In vitro, Ac-SDKP inhibits collagen production by cardiac fibroblasts; while in vivo it blocks collagen deposition in the left ventricle (LV) of rats with hypertension or myocardial infarction (MI). In addition, it reportedly prevents and reverses macrophage infiltration in the LV of rats with MI. We tested the hypothesis that when Ac-SDKP is infused at doses that cause plasma concentrations similar to those observed after ACE inhibition, it mimics the anti-inflammatory and antifibrotic effects of ACE inhibitors (ACEi) in the heart, and, further, that these effects are independent of changes in blood pressure. DESIGN AND METHODS: Rats were divided into five groups: (1) controls, (2) Ang II (750 microg/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 microg/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 microg/kg per day, s.c.). We measured LV cell proliferation, inflammatory cell infiltration, cytokine expression, hypertrophy and fibrosis. RESULTS: Plasma Ac-SDKP was five-fold higher in rats given ACEi and four- and ten-fold higher in rats given 400 and 800 microg/kg per day Ac-SDKP, respectively. ACEi significantly decreased Ang II-induced cell proliferation (Ki-67), LV macrophage/mast cell infiltration, transforming growth factor-beta, connective tissue growth factor and collagen deposition without affecting hypertension, LV hypertrophy or myocyte cross-sectional area, and these effects were mimicked by exogenous Ac-SDKP (400 microg/kg per day) which raised plasma Ac-SDKP to levels similar to ACEi. BP was not decreased by either ACEi or Ac-SDKP. CONCLUSIONS: We concluded that Ac-SDKP may be an important mediator of the anti-inflammatory and antifibrotic effects of ACEi in hypertension independent of its hemodynamic effects.     

Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition

OBJECTIVE: Angiotensin-converting enzyme inhibitors (ACEI) show an antiproteinuric and thus nephroprotective effect in patients suffering from glomerulonephritis. Angiotensin II-receptor-antagonists (AT1RA) are also efficacious in reducing proteinuria. The study was performed to investigate the antiproteinuric effect of AT1RA candesartan in patients diagnosed with chronic glomerulonephritis by biopsy, and who were already being treated with an ACEI. METHODS: A total of 12 patients with a persistent proteinuria of at least 1 g/day who were already being treated with an ACEI for more than 3 months were included. The study was performed using a double-blind, placebo-controlled and randomized method with two treatment periods of 8 weeks (placebo or candesartan 8 mg/day) and a wash-out period of 4 weeks in between. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin- and PAH-clearances at the beginning and the end of each treatment period. RESULTS: Proteinuria significantly decreased from 2 +/- 0.4 g/day to 1.3 +/- 0.3 g/day (P < 0.05) with the addition of candesartan treatment, whereas it remained unchanged (from 1.8 +/- 0.3 g/day to 1.9 +/- 0.3 g/day) under placebo. GFR (candesartan: from 66 +/- 13 to 58 +/- 11 ml/min per 1.73 m2, placebo: from 64 +/- 11 to 62 +/- 13 ml/min per 1.73 m2) and ERPF (candesartan: from 329 +/- 44 to 304 +/- 37 ml/min per 1.73 m2, placebo: from 362 +/- 48 to 315 +/- 46 ml/min per 1.73 m2) did not alter significantly after 8 weeks of treatment. The addition of candesartan treatment significantly reduced systolic blood pressure (from 129 +/- 3 to 123 +/- 2 mmHg, P < 0.05) and diastolic blood pressure (from 79 +/- 2 to 76 +/- 2 mmHg, P < 0.05) compared with placebo (systolic: 128 +/- 3 to 127 +/- 3 mmHg, diastolic: 79 +/- 2 to 79 +/- 2 mmHg). CONCLUSION: Candesartan promotes a complementary antiproteinuric and a small antihypertensive effect after a treatment period of 8 weeks in patients with chronic glomerulonephritis when given in conjunction with an ACEI. Renal hemodynamics did not vary significantly.     

Hyperkalemia in azotemic patients during angiotensin-converting enzyme inhibition and aldosterone reduction with captopril

Thirty-three hypertensive patients with a wide range of renal function were studied during initiation of angiotensin-converting enzyme inhibition with captopril to evaluate changes in potassium levels concomitant with reduction of aldosterone excretion. Ten patients (Group I) with low levels of plasma renin activity had no change in either aldosterone excretion or potassium during the first week of therapy. Twenty-three other patients (Group II) had decreased aldosterone excretion of an average of 63 percent, often reversing secondary hyperaldosteronism. This was associated with a rise in serum potassium from 3.6 ± 0.1 to 4.4 ± 0.1 mEq/liter (p < 0.001). Serum potassium levels during captopril therapy were inversely related to glomerular filtration rate (creatinine clearance) and transiently exceeded 6.0 mEq/liter in markedly azotemic subjects. Despite rising potassium levels, nine patients had reduced aldosterone excretion to subnormal levels, sometimes for many months. During initiation of converting-enzyme inhibition, potassium-sparing agents and supplements should be discontinued and serum potassium levels should be monitored closely, particularly in patients with impaired renal function.     

Circulatory and extracirculatory effects of angiotensin-converting enzyme inhibition.

The antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors cannot be fully explained by their actions on the circulating renin-angiotensin system (RAS). Agents such as captopril or enalapril maintain efficacy during long-term therapy even when plasma concentrations of converting enzyme or angiotensin II are not fully suppressed. Components of the entire RAS exist at several sites, thereby making it possible for drugs to produce effects at extracirculatory locations. An ACE inhibitor such as quinapril that has a comparatively short plasma concentration half-life binds strongly to plasma ACE as well as to ACE in key tissues including artery wall, heart, and kidney. The effects of ACE inhibition on the tissue RAS are of potential importance in fully explaining the blood pressure-lowering effects of these drugs. ACE inhibitors might also reduce blood pressure by blocking nonhemodynamic actions of angiotensin II. They affect vascular properties by increasing compliance of arteries and they act on baroreceptors and central regulatory mechanisms. Furthermore, ACE inhibitors affect other neuroendocrine systems, including aldosterone, kinins, and prostaglandins; attenuation of sympathetic activity can contribute further to their antihypertensive properties. Actions independent of circulating renin effects do not necessarily require plasma ACE inhibition throughout a 24-hour period. Sustained antihypertensive effects by drugs with short durations of plasma ACE inhibition give credibility to therapeutic targets beyond the circulating RAS.     

Smart damping modulation of carotid wall energetics in human hypertension: effects of angiotensin-converting enzyme inhibition

Damping is the conversion of mechanical energy of a structure into thermal energy, and it is related to the material viscous behavior. To evaluate the role of damping in the common carotid artery (CCA) wall in human hypertension and the possible improvement of angiotensin-converting enzyme (ACE) inhibition, we used noninvasive CCA pressure (tonometry) and diameter (B-mode echography) waveforms in normotensive subjects (NT group; n=12) and in hypertensive patients (HT group; n=22) single-blind randomized into HT-placebo (n=10) or HT-treated (ramipril, 5 to 10 mg/d during 3 months; n=12). Vascular smooth muscle (VSM) null tonus condition was achieved from in vitro pressure and diameter waveforms (Konigsberg microtransducer and sonomicrometry) measured in explanted human CCA (n=14). Arterial wall dynamics was described by viscous (eta), inertial (M), and compliance (C) parameters, mean circumferential wall stress, viscous energy dissipation (WD), peak strain energy (WSt), damping ratio (xi=WD/WSt), and modeling isobaric indexes CIso and WSt(Iso). The lack of VSM tonus isobarically increased wall stress and reduced eta, CIso, and damping (P<0.01). Wall stress, eta, and WD were greater in HT than in NT (P<0.015) and arrived near normal in HT-treated (P<0.032 respect to HT), with no changes in HT-placebo. Whereas CIso increased in HT-treated (P<0.01) approaching the NT level, xi did not vary among groups. During hypertension, because of the WSt increase, the arterial wall reacts increasing WD to maintain xi. ACE inhibition modulates VSM activation and vessel wall remodeling, significantly improving wall energetics and wall stress. This protective vascular action reduces extra load to the heart and maintains enhanced arterial wall damping.     

Acute and chronic systemic and pulmonary hemodynamic effects of angiotensin converting enzyme inhibition with captopril in hypertensive patients

The effects of the angiotensin converting enzyme inhibitor captopril were studied in 14 patients with essential or renovascular hypertension 75 minutes after ingestion of 25 mg of the drug, and after 2 months of therapy with 150 to 600 mg/day. Captopril acutely decreased mean brachial arterial pressure by 16.3 mm Hg (p < 0.001); the decrease was 7.6 mm Hg (p < 0.01) during long-term therapy at the higher dose level. The changes in mean brachial arterial pressure were significantly related to control plasma levels of angiotensin II. The acute hypotensive effect of captopril was based on a 10 percent decrease (p < 0.01) in systemic vascular resistance with essentially unchanged cardiac output and heart rate. Pulmonary capillary wedge pressure decreased by 2.3 mm Hg (p < 0.001) with unchanged pulmonary vascular resistance. During long-term treatment systemic vascular resistance decreased by 29 percent (p < 0.001). Oxygen consumption increased by 15 percent (p < 0.01) with a concomitant 16 percent Increase in cardiac output (p < 0.01), characterized by an increased stroke volume and unchanged heart rate; one patient experienced angina pectoris that may have been related to these hemodynamic changes. The decrease in pulmonary capillary wedge pressure was maintained, and right atrial pressure decreased (?1.4 mm Hg; p < 0.05).The data indicate that the action of captopril is characterized by arteriolar and possibly venous dilatation. The increase in cardiac output during long-term treatment seems to be associated with a hypermetabolic state and in patients with very severe hypertension, with restoration to normal of mildly decreased left ventricular function.     

Comparative systemic and renal effects of dopamine and angiotensin-converting enzyme inhibition with enalaprilat in patients with heart failure

Renal and systemic hemodynamics were measured during titration of dopamine and serially after intravenous administration of enalaprilat in nine patients with chronic severe congestive heart failure. During titration of dopamine, renal blood flow increased by 99%, from 304 +/- 120 to 604 +/- 234 ml/min (p less than .01) at a dose of dopamine of 2.1 micrograms/kg/min, which produced only a 21% increase in cardiac index, from 1.96 +/- 0.36 to 2.38 +/- 0.35 liters/min/m2 (p less than .05). Cardiac index was increased maximally at a dose of 4.0 micrograms/kg/min dopamine; however, renal blood flow was not further augmented. In contrast, after intravenous administration of enalaprilat, peak improvement of renal blood flow and cardiac index occurred concomitantly. Renal blood flow increased by 35%, from 316 +/- 97 to 427 +/- 107 ml/min (p less than .05), and cardiac index increased by 18%, from 1.99 +/- 0.40 to 2.35 +/- 0.40 liters/min/m2 (p less than .05). At similar increases in cardiac index, dopamine produced a greater increase in renal blood flow than enalaprilat: 604 +/- 234 vs 427 +/- 107 ml/min (p less than .05). Mean systemic arterial pressure, however, was greater with dopamine than with enalaprilat (78.1 +/- 16.7 vs 70.2 +/- 17.2 mm Hg; p less than .05) at peak effect. Thus, although both drugs appear to be potent renal vasodilators in patients with severe congestive heart failure, dopamine may be more effective in augmenting renal blood flow.