Effects of enalapril on the cardiovascular response to treadmill exercise in patients with mild to moderate systemic hypertension

The effects of the angiotensin converting enzyme inhibitor enalapril on exercise-induced changes in blood pressure and heart rate were evaluated in 15 patients in the early stages of systemic hypertension. Multistage treadmill exercise was performed before and after eight weeks of enalapril administration, and the results of the two trials were compared. In patients at rest, enalapril decreased systolic blood pressure from 172 +/- 18 to 147 +/- 14 mmHg and diastolic blood pressure from 99 +/- 9 to 88 +/- 8 mmHg (both P less than 0.001). In patients at peak exercise, enalapril decreased systolic blood pressure from 216 +/- 13 to 195 +/- 18 mmHg and diastolic blood pressure from 106 +/- 12 to 99 +/- 12 mmHg (both P less than 0.001). There was also a significant decrease in blood pressure during the recovery period after treadmill exercise. Enalapril reduced heart rate at peak exercise (P less than 0.05), but not at rest or during recovery. Thus enalapril alleviated the response of blood pressure to exercise in hypertensive patients and may help prevent hypertensive complications during daily activities.     

Cardiac and hormonal effects of enalapril in hypertension

Systolic time measurements, echocardiography, and bicycle exercise testing with cardiac output determinations (CO2 rebreathing) were used to evaluate cardiac performance in 16 male hypertensives at the end of a 4-wk placebo period and after 12 wk of treatment with increasing doses (maximum = 40 mg/day) of enalapril maleate (N = 11) and of placebo (N = 5). The effect of exercise on plasma renin activity (PRA) and plasma norepinephrine (NE) concentration was also measured. Mean arterial pressure was reduced by 10 mm Hg or more in all but one subject who received enalapril. In both the enalapril- and placebo-treated subjects, the preejection period/left ventricular ejection time ratio and fractional shortening of the left ventricle at rest and cardiac output and stroke volume during moderate exercise did not change during the study. Enalapril induced a compensatory rise in PRA (N = 10). Compared to plasma NE concentration, 1124 +/- 380 pg/ml (mean +/- SD), during exercise at the end of the initial placebo period, there was attenuation of the rise of plasma NE concentration, 851 +/- 290, at the same load of exercise during enalapril therapy. Unchanged cardiac performance despite effective long-term lowering of blood pressure with enalapril may relate to inhibition of angiotensin II-mediated facilitation of NE release from peripheral nerve endings.     

Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits.

To investigate the mechanism by which angiotensin-converting enzyme (ACE) inhibition attenuates atherogenesis, we have studied the effects of a non-sulfhydryl ACE inhibitor, enalapril, and an angiotensin receptor antagonist, SC-51316, in cholesterol-fed rabbits. After 3 mo of enalapril treatment (10 mg/kg per d, p.o.) the percent plaque areas in the thoracic aortas of treated animals were significantly reduced (controls: 86.8 +/- 3.5%; treated: 31.1 +/- 8%, P < 0.001). Aortic cholesterol content was also reduced (controls: 31.4 +/- 3.2 mg/g tissue; treated: 7.4 +/- 1.8 mg/g, P < 0.001). Enalapril had no significant effect on plasma lipid levels or conscious blood pressure. In a second study, the angiotensin II receptor antagonist SC-51316 was administered at a dose equivalent to enalapril at blocking angiotensin pressor effects in vivo (30 mg/kg per d, p.o.). Evaluation after 3 mo indicated no significant attenuation of aortic atherosclerosis. These results demonstrate that: (a) enalapril attenuates atherogenesis without affecting either blood pressure or plasma lipid levels; (b) antioxidant activity, found with sulfhydryl-containing ACE inhibitors, is not necessary for reducing plaque formation; and (c) the attenuation of atherogenesis by ACE inhibition may not be due to blockade of the renin-angiotensin system. Alternatively, one must consider the multiple effects of ACE inhibition on other hormone systems, such as bradykinin, or the possibility that alternate angiotensin II receptors may be involved in atherosclerosis.     

Coronary haemodynamic effects of angiotensin II in mild essential hypertension in man.

1. The present investigation was carried out to elucidate the possible role of the renin-angiotensin system in modulating coronary vasomotor responses in eight patients with uncomplicated mild essential hypertension with no electrocardiographic-echocardiographic evidence of left ventricular hypertrophy. 2. Systemic and coronary haemodynamics were monitored at baseline and during intravenous infusion of angiotensin II at a subpressor dose (3 ng min-1 kg-1 for 15 min) and at a pressor dose (13 ng min-1 kg-1 for 15 min) both at rest and during handgrip exercise. Infusion of the subpressor dose of angiotensin II decreased coronary sinus blood flow at rest (207 +/- 10 versus 182 +/- 9 ml/min, P less than 0.05) without a significant change in mean arterial pressure, heart rate or mean right atrial pressure. The performance of handgrip at baseline and during infusion of the subpressor dose of angiotensin II resulted in 55% (321 +/- 13 versus 207 +/- 10 ml/min) and 44% (263 +/- 16 versus 182 +/- 9 ml/min) increases in coronary sinus blood flow, respectively, in response to comparable increments in the rate-pressure product. At rest, infusion of the pressor dose of angiotensin II increased both coronary sinus blood flow (235 +/- 11 versus 207 +/- 10 ml/min, P less than 0.01) and the rate-pressure product (134 +/- 5 versus 111 +/- 8 mmHg beats/min, P less than 0.01). The increase in coronary sinus blood flow during isometric exercise was less than control (309 +/- 18 versus 321 +/- 13 ml/min, P less than 0.01). 3. It is thus concluded that (1) the opposite effects of angiotensin II on coronary blood flow are dose-dependent, and that (2) angiotensin II competes with the ability of the coronary arteries to dilate during handgrip exercise.     

Blood pressure dependency on vasopressin and angiotensin II in prazosin-treated conscious normotensive rats

The role of the sympathetic nervous system, angiotensin II and vasopressin in limiting the hypotensive effect of prazosin (0.25 mg i.v.) was investigated in conscious normotensive rats. Within 45 min, mean blood pressure fell from 120 +/- 1 to 98 +/- 1 mm Hg (mean +/- S.E.M., P less than .001) while pulse rate rose from 463 +/- 9 to 500 +/- 9 beats/min (P less than .01). The blood pressure response to prazosin tended to be most pronounced in the rats with the smallest increase in heart rate (r = 0.58, P less than .001). Plasma norepinephrine and epinephrine levels were higher in prazosin-treated rats than in the controls (P less than .001). In the animals receiving prazosin, plasma renin activity was 4 times (P less than .001) and plasma vasopressin 7 times (P less than .01) higher than in the controls. Blockade of angiotensin II with saralasin (10 micrograms/min) further decreased blood pressure of the prazosin-treated rats by 22 +/- 4 mm Hg (P less than .001). In contrast, dPVDAVP (25 micrograms), a vasopressin antagonist, had no effect. Prazosin decreased the pressor response to methoxamine (10 micrograms) by 80% (P less than .001) but not to angiotensin II (60 ng). However, prazosin enhanced the reflex bradycardia induced by angiotensin II (P less than .001). These data demonstrate that both the sympathetic and the renin angiotensin system are markedly stimulated by prazosin; they both appear to limit its acute hypotensive action. In contrast, although plasma vasopressin is also increased, its pressor action is effectively buffered, probably due to enhanced baroreflex sensitivity.     

Enalaprilat,losartan and LU 135252 in coronary blood flow regulation

BACKGROUND: High plasma levels of angiotensin II are found in several pathologies such as hypertension, heart failure and myocardial infarction. The effect of high concentrations of angiotensin II on coronary circulation is not well defined. The aim of the present study was to assess coronary blood flow regulation during tachycardia in the presence of elevated coronary plasma levels of angiotensin II, and the changes induced by ACE inhibition and blockade of angiotensin II and endothelin-A receptors. DESIGN: Left anterior coronary artery was catheterized in 38 pigs to infuse the study drugs. Saline was infused for 15 min. Then, the first atrial pacing was performed. The pigs were distributed to: Group 1 (n = 7) angiotensin II; Group 2 (n = 7) enalaprilat + angiotensin II; Group 3 (n = 9) the bradykinin B2 antagonist HOE 140 + enalaprilat + angiotensin II; Group 4 (n = 7) losartan + angiotensin II; and Group 5 (n = 8) endothelin-A receptor antagonist LU 135252 + angiotensin II. After giving these infusions, a second pacing was repeated. RESULTS: The increase in coronary blood flow induced by pacing with angiotensin II was reduced from 181 +/- 21% to 116 +/- 37% (P = 0.006 vs. saline). Enalaprilat, losartan and LU 135252 restored the capacity of coronary blood flow to increase during pacing (151 +/- 39%, 162 +/- 35% and 161 +/- 16%, respectively; P = NS, vs. saline), while HOE 140 abolished the effect of enalaprilat. CONCLUSIONS: Moderately elevated coronary concentrations of angiotensin II reduced coronary blood flow during pacing. Enalaprilat, losartan and LU 135252 restored the hyperaemic coronary flow to similar values observed with saline. The beneficial effect of ACE inhibition is mediated through an increase in bradykinin.     

The effect of renal function on enalapril kinetics

Enalapril maleate (MK-421), a nonmercapto-containing angiotensin converting enzyme (ACE) inhibitor, is converted in vivo to enalaprilat (MK-422), the active diacid. We evaluated serum profiles and urinary excretion of oral enalapril maleate in patients with renal disease (group I, creatinine clearance less than 3 ml/min, patients undergoing dialysis, n = 10; group II, creatinine clearance 10 to 79 ml/min, n = 9) compared with healthy subjects (group III, creatinine clearance greater than 80 ml/min, n = 10). Group I received a 10 mg dose during a day while not receiving dialysis and a 10 mg dose 1 hour before dialysis 2 weeks later. Groups II and III received a single 10 mg dose. Blood samples and urine were collected for 48 hours. Impaired renal function resulted in elevated serum and plasma concentrations of enalapril maleate and decreased excretion rates and urinary recovery of enalapril maleate and enalaprilat. The data suggest an apparent increase in the extent of metabolism of enalapril maleate to enalaprilat or an increase in nonrenal elimination of unchanged enalapril maleate in renal disease compared with normal health. Enalaprilat was dialyzable.     

Relationship of serum ACE inhibition to oral dose of enalapril in normotensive volunteers

OBJECTIVES: To determine the relationship between oral dose of enalapril and parameters describing serum angiotensin converting enzyme (ACE) inhibition. METHODS: Four different oral doses of enalapril maleate (2.5, 5, 10 and 20 mg) were administered to six healthy normotensive volunteers, in a four-period crossover study. Serum ACE inhibition profiles were determined in each case using a synthetic substrate, hippuryl-histidyl-leucine (HHL). Pharmacodynamic parameters of the drug (Emax and AUEC0-->24) were calculated and their relationship to oral doses investigated using linear regression analysis. RESULTS: There was no significant relationship between drug dose and the two pharmacodynamic parameters (Emax and AUEC0-->24). The r2 values were 0.548 (F=3.63, P=0.153) and 0.6360 (F=5.24, P=0.106) for Emax and AUEC0-->24, respectively. CONCLUSION: The extent of serum ACE inhibition, as the main determinant of the blood pressure lowering effect of enalapril, is not dose-dependent within the single dose range of 2.5-20 mg.     

Renal and vascular effects of S21402, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase,in healthy subjects with hypovolemia

OBJECTIVE: To examine the mechanism of action of dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase, also called vasopeptidase inhibitors, we compared the effects of S21402 [(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido]propionic acid], which belongs to this pharmacologic class, with those of captopril, an ACE inhibitor, on blood pressure, endocrine parameters, and renal in healthy subjects with hypovolemia. METHODS: Ten subjects participated to this double-blind, 2-period, randomized, crossover study. Hypovolemia was induced in these subjects with a 7-day treatment of hydrochlorothiazide. They received a single oral dose of 50 mg captopril or 250 mg S21402 on the last day of diuretic treatment. Blood pressure was measured, and urine and blood samples were collected before and during a 12-hour period after drug administration. RESULTS: The plasma angiotensin II/angiotensin I ratio and aldosterone concentration decreased to the same degree with both drugs, 3 hours after dosing. Compared with captopril, S21402 increased levels of plasma atrial natriuretic peptide (P <.05) and urinary cyclic guanosine monophosphate (P <.001); these increases were the result of inhibition of neutral endopeptidase activity (P <.001). The increase in plasma renin concentration related to ACE inhibition was less marked (P <.001) after S21402 than after captopril. S21402, but not captopril, increased urinary sodium excretion (P <.05), without modifying blood pressure and creatinine clearance, whereas blood pressure transiently fell after captopril administration (P <.05). CONCLUSIONS: In healthy hypovolemic subjects, the vasopeptidase inhibitor S21402 exhibits a natriuretic effect and does not affect blood pressure or glomerular filtration rate. In these conditions, the acute endocrine, vascular, and renal effects of vasopeptidase inhibition differ from those of ACE inhibition.     

Effect of enalapril at rest and during isometric and dynamic exercise in essential hypertensive patients

Vasodilator drugs reduce peripheral vascular resistance but lead to a secondary baroreflex-mediated chronotropic effect. After angiotensin-converting enzyme inhibition, blood pressure falls without associated tachycardia. In a previous study it was observed that enalapril increased vagal tone in essential hypertensive patients. In order to evaluate the effect of enalapril on sympathetic stimulation 10 mild to moderate hypertensive patients were studied during static (hand grip) and dynamic exercise (bicycle ergometer), after 2 weeks of placebo and after 1 month of treatment with 20-40 mg enalapril once daily. Enalapril significantly reduced blood pressure and the rate-pressure product at rest and at peak dynamic exercise. There was no effect on supine and maximal heart rate. Enalapril also significantly reduced blood pressure during hand grip, but did not interfere with the rate of the increase. Thus, enalapril does not seem to interfere with sympathetic adaptation to stress.     

Determination of enalapril and enalaprilat by enzyme linked immunosorbent assays: application to pharmacokinetic and pharmacodynamic analysis

We have developed two enzyme linked immunosorbent assay (ELISA) methods for determining enalapril and enalaprilat in plasma. In this study, 48 healthy subjects received an oral dose of either 10 or 20 mg of enalapril and plasma concentrations of enalapril and enalaprilat were determined by their specific ELISA methods. These plasma concentrations and blood pressure measurements were applied to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of both enalapril and enalaprilat. The enalapril values for the area under the curve (AUC(0)--> infinity ) were 480 +/- 216 and 832 +/- 325 ngh/mL, maximum plasma concentrations (C(max)) were 310 +/- 187 and 481 +/- 185 ng/mL, and times required to reach the maximum concentration t(max) were 1.13 +/- 0.22 and 1.09 +/- 0.33 h for 10 and 20 mg doses, respectively. The enalaprilat values for AUC(0)--> infinity were 256 +/- 122 and 383 +/- 158 ngh/mL, C(max) values were 57 +/- 29 and 72.9 +/- 33.6 ng/mL and t(max) values were 4.28 +/- 1.45 and 4.05 +/- 01.22 h for 10 and 20 mg doses, respectively. The C(max) values of enalapril were approximately 10 times higher than those in the literature, which were determined by angiotensin converting enzyme (ACE) inhibition assays following alkaline hydrolysis, but similar to those of enalaprilat. The PD profiles revealed a significant correlation between enalaprilat concentrations in plasma and the decrease in systolic and diastolic blood pressures (r = -0.95 with P < 0.001 and r = -0.95 with P < 0.001), respectively, following a single oral dose of enalapril. These ELISA methods have the advantage of being simple, accurate, sensitive, and do not depend on enalaprilat binding to ACE. Such methods can be used for analysis and kinetic testing of enalapril and enalaprilat in biological fluids.     

Angiotensin inhibition reduces glomerular damage and renal chemokine expression in MRL/lpr mice

Beneficial effects of angiotensin II inhibition during inflammatory renal disease may involve both hemodynamic and nonhemodynamic mechanisms. To analyze whether angiotensin II inhibition has protective effects on lupus-like, autoimmune-mediated renal damage in MRL/lpr mice, four groups of mice were treated orally for 6 weeks with: 1) vehicle, 2) enalapril (3.0 mg/kg per day), 3) candesartan cilexetil (5.0 mg/kg), or 4) amlodipine (10 mg/kg) as a blood pressure control (n = 9-12/group). All antihypertensive treatments lowered blood pressure to a similar level compared with vehicle group (enalapril: 99.8 +/- 8.3 mm Hg; candesartan: 101 +/- 9 mm Hg; amlodipine: 103.8 +/- 6.7 mm Hg; vehicle: 113.5 +/- 4.6 mm Hg). Vehicle-treated mice developed a moderate glomerular injury with albuminuria (35.1 +/- 39.0 microg/mg of creatinine). Glomerular lesions consisted of immune complex deposition and mesangial expansion with increased mesangial cell proliferation. Amlodipine treatment had no significant protective effects. In contrast to vehicle- and amlodipine-treated mice, those subjected to angiotensin II blockade with enalapril or candesartan had reduced albuminuria, glomerular expansion, and mesangial proliferation. This was associated with significantly reduced renal chemokine mRNA expression compared with vehicle treatment. Our results show that inhibition of angiotensin II has protective effects on the glomerular damage of MRL/lpr mice that extend beyond hemodynamics and involve down-modulation of glomerular inflammation, reduction of mesangial cell proliferation, and decrease in chemokine expression.     

Pharmacokinetics and pharmacodynamics profiles of enalapril maleate in healthy volunteers following determination of enalapril and enalaprilat by two specific enzyme immunoassays

BACKGROUND AND OBJECTIVES: Most of the pharmacokinetic (PK) parameters for enalapril and enalaprilat were established following determination of the drug and its metabolite, using angiotensin converting enzyme (ACE) inhibition assays. In these methods, enalapril has to be hydrolysed to enalaprilat first and then assayed. The purpose of this study was to re-estimate the PK parameters of enalapril and enalaprilat in healthy volunteers using two specific enzyme immunoassays for enalapril and enalaprilat. METHODS: The rate and extent of absorption of enalapril and enalaprilat from a 10-mg dose of two enalapril maleate commercial brands (Renetic and Enalapril) were estimated using a two-way-cross over design with 1-week washout period. Blood pressure was also measured at specified time intervals and correlated to enalaprilat plasma concentrations. RESULTS: For enalapril, the AUC(o-->infinity) values (Mean+/-SD) were 450.0+/-199.5 and 479.6+/-215.6 ng h/mL, Cmax values were 313.5+/-139.6 and 310.1+/-186.6 ng/mL, Tmax values were 1.06+/-0.30 h and 1.13+/-0.22 h, and t1/2 ranged between 0.3 to 6.1 h (1.6+/-1.5) and 0.40 to 5.05 h (1.3+/-1.0), for the two brands. For enalaprilat, the AUC(o-->infinity) values were 266.9+/-122.7 and 255.9+/-121.8 ng h/ml, Cmax values were 54.8+/-29.5 and 57.2+/-29.0 ng/mL, Tmax values were 4.6+/-1.6 h and 4.3+/-1.45 h, and t1/2 ranged between 1.1 to 10.5 h (4.5+/-2.9) and 0.6 to 9.4 h (3.5+/-2.5) for the two brands. CONCLUSIONS: Cmax values for enalapril are about 10 times those published in the literature and the rate and extent of absorption of the two brands of enalapril and their deesterification to enalaprilat following the administration of either brand were bioequivalent. Secondly, enalaprilat concentrations at 12-24 h following a single oral dose of enalapril in healthy volunteers were lower than those reported in the literature. The values reported here correlated with the return of blood pressure to predose level. Thirdly, enzyme immunoassays for enalapril and enalaprilat are better than ACE inhibition assays and can be used in bioequivalence assessment of enalapril and enalaprilat and for therapeutic drug monitoring in a clinical laboratory setting.     

Phenobarbital in the genetically obese Zucker rat. I. Pharmacokinetics after acute and chronic administration

We measured both pulmonary and plasma angiotensin converting enzyme (ACE) activity in conscious rabbits before and for 6 days after administration of captopril (2 mg/kg i.v.). Pulmonary ACE activity was measured by means of modified indicator-dilution techniques after bolus injection of [3H]benzoyl-phenyl-alanyl-alanyl-proline ( BPAP , synthetic substrate for ACE). Plasma ACE activity was also determined radiometrically with [3H] BPAP as substrate. In addition, we measured the systemic pressor response to i.v. bolus dose of angiotensin I both before and after captopril. Twenty-four hours after captopril, pulmonary metabolism of BPAP had decreased from control of 73 +/- 5 to 8 +/- 2%; even 6 days after drug treatment there was still evidence of inhibition. In contrast, plasma ACE activity was significantly (P less than .05) reduced within 15 min of treatment (to 20% of control levels) but recovered within 24 hr. The time course of changes in the pressor response to angiotensin I, after captopril, resembled that of plasma ACE activity. Mean systemic arterial blood pressure was 81 +/- 4 torr at control and reached its nadir at 24 hr (64 +/- 2 torr; P less than .05); thereafter a gradual recovery ensued, similar in time course to that of pulmonary ACE. These data suggest that inhibition of plasma ACE and also the pressor response to angiotensin I are unrelated temporally to the hypotensive effects of captopril.     

Effect of intermediate-dose naloxone on cardiovascular and sympathoneural adjustments to exercise.

The effects of intermediate-dose naloxone on sympathetic nerve activity and cardiovascular adjustments to exercise were examined in two series of experiments. In the first series 10 normal male volunteers, mean age 28 +/- 5 (SD) years received i.v. naloxone, mean 0.28 +/- 0.6 mg/kg in 0.1 mg/kg aliquots 60-90 min after 45 min of submaximum treadmill exercise. Naloxone had no detectable effect on supine blood pressure, heart rate, plasma norepinephrine, or epinephrine concentrations or muscle sympathetic nerve burst frequency at rest or during the strain phase of the Valsalva manoeuvre, but decreased slightly sympathetic burst incidence at rest (p less than 0.05). In the second study, 8 of these subjects repeated the exercise protocol 15 to 20 min after 0.1 mg/kg i.v. naloxone. Supine blood pressure, heart rate, plasma norepinephrine and epinephrine concentrations before and 15 min after naloxone were virtually identical. A comparison of results from both study days did not reveal a naloxone effect on blood pressure during or up to 60 min after exercise, whereas the heart rate response to exercise was attenuated (p less than 0.002). Intermediate-dose naloxone has no apparent effects on blood pressure during and after exercise, attenuates the chronotropic response to exercise, and has only modest inhibitory effects on muscle sympathetic nerve activity.     

Response of sympathetic nervous system activity to exercise in patients with congestive heart failure

To investigate the serial sympathetic nervous system response to exercise, plasma norepinephrine (NE) and epinephrine (E) concentrations were measured at rest, during each stage of treadmill exercise, and immediately and 5 minutes after exercise in 68 congestive heart failure (CHF) patients (NYHA functional class I 24, II 25, III 19) and 30 normal subjects. Circulatory responses of NYHA class II patients increased at early stages of exercise. Systolic blood pressure and double product at peak exercise were significantly lower in NYHA class III patients. Plasma NE response of NYHA class I patients was similar to that of normal subjects. However, plasma NE at rest, and during and after exercise were significantly higher in NYHA classes II and III patients than in normal subjects and NYHA class I patients (peak NE (pg ml-1); Normals: 547 +/- 37, I: 535 +/- 53, II: 867 +/- 87, III: 1033 +/- 157). There was no significant difference in plasma E levels among the four groups. NE response to exercise was augmented according to the severity of heart failure, which suggested compensatory activation of sympathetic nervous system activity. Circulatory responses were reduced in NYHA class III patients despite the exaggerated compensatory activation of the sympathetic nervous system. Blunted circulatory responses to increased NE concentration in NYHA class III patients might relate to a decreased cardiac responsiveness to sympathetic activity in severe CHF patients.     

Antihypertensive therapy with Ca2+. Antagonist verapamil and/or ACE inhibitor enalapril in NIDDM patients.

OBJECTIVE: To assess the efficacy and tolerance of a diuretic-free antihypertensive therapy with a Ca2+ antagonist and an angiotensin-converting enzyme (ACE) inhibitor in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: After a 2-wk washout and a 4-wk placebo phase, 47 hypertensive patients with NIDDM randomly received verapamil or enalapril alone and, if blood pressure remained elevated, both agents combined over 30 wk. RESULTS: Verapamil or enalapril alone normalized blood pressure to less than 90 mmHg diastolic in 30 patients; verapamil decreased mean +/- SE blood pressure from 159/98 +/- 3/1 to 146/87 +/- 3/2 mmHg (n = 18, P less than 0.001) and enalapril from 166/99 +/- 5/2 to 146/86 +/- 3/1 mmHg (n = 12, P less than 0.001). In 17 patients who were still hypertensive after 10 wk of monotherapy, combination of both drugs decreased blood pressure from 170/104 +/- 4/2 to 152/90 +/- 4/2 mmHg (P less than 0.001). Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total lipids, high-density and low-density lipoprotein cholesterol, apolipoproteins A-I and B, creatinine, and urinary albumin-creatinine ratio were not significantly modified. CONCLUSIONS: In hypertensive patients with NIDDM, a diuretic-free therapy based on the Ca2+ antagonist verapamil and/or the ACE inhibitor enalapril can effectively decrease blood pressure without adversely affecting carbohydrate and lipid metabolism.     

Intrapatient comparison of acute hemodynamic, hormonal, and natriuretic responses to captopril versus enalapril in liver cirrhosis

We compared acute hemodynamic, hormonal, and natriuretic responses to a single oral dose of captopril (50 mg) versus enalapril maleate (10 mg) administered to eight patients with biopsy-proved liver cirrhosis. Although the two angiotensin-converting enzyme (ACE) inhibitors lowered (p less than 0.05) blood pressure with no change in heart rate during the early postdose period, captopril produced a greater (p less than 0.05) hypotensive effect than did enalapril. Enalapril caused a greater (p less than 0.01 to 0.05) ACE inhibition than did captopril during the 2- to 48-hour postdose period. Plasma renin activity increased (p less than 0.05) with the two drugs and returned toward baseline by 12 hours after administration. Plasma aldosterone levels, elevated before drug administration, were decreased by the two drugs in a stepwise fashion, but the suppressive effect was greater (p less than 0.01 or p less than 0.05) after captopril than after enalapril. Natriuresis was greater (p less than 0.05) during the first 24-hour period after enalapril than after captopril. The findings indicate that the acute pharmacodynamic responses to the two ACE inhibitors differ in patients with liver cirrhosis. However, the mechanism(s) of the divergent effects of the two drugs and the clinical implications remain obscure from this single-dose study.     

Kinetics and dynamics of enalapril in patients with liver cirrhosis

The pharmacokinetics and pharmacodynamics (blood pressure, heart rate, serum angiotensin-converting enzyme, and plasma renin activity) of enalapril and enalaprilat were studied after oral administration of enalapril maleate (10 mg) to seven biopsy-proven cirrhotic patients and to seven healthy subjects. The mean Cmax, AUC, and urinary excretion of enalapril and enalaprilat were greater and less (p less than 0.01), respectively, and mean oral clearance of enalapril was less (p less than 0.01) in the cirrhotic group than in the healthy group. However, there was no significant difference in the mean total drug (enalapril plus enalaprilat) excretion between the two groups. Blood pressure fell (p less than 0.05) only at 3 or 4 hours postdose, with no change in heart rate in the two groups. Serum angiotensin-convering enzyme (ACE) decreased (p less than 0.001) and plasma renin activity (PRA) increased (p less than 0.05) in the two groups. The magnitude of the percentage of inhibition of ACE activity was comparable between the two groups. Serum enalaprilat concentration correlated (p less than 0.001) with the percentage of inhibition of ACE activity. The results suggest that the bioactivation of enalapril to enalaprilat is considerably impaired in patients with cirrhosis but that the pharmacodynamic effects do not appear to be blunted in those patients. The mechanism and clinical implications remained unclear.     

Angiotensin II augments sympathetically mediated arteriolar constriction in man.

1. In animal studies, angiotensin II facilitates adrenergic neurotransmission by both pre- and post-synaptic mechanisms. We have investigated whether this interaction occurs in forearm resistance vessels in man. 2. The effect of arterial infusion of angiotensin II (320 fmol/min) on sympathetic vasoconstriction produced by lower-body negative pressure (15 mmHg) was studied in six subjects, and that on the response to exogenous noradrenaline (37.5-150 pmol/min) was studied in a further eight subjects. Forearm blood flow was measured by strain-gauge plethysmography. 3. The dose of angiotensin II was chosen to produce no alteration in resting blood flow, and those of noradrenaline were selected to provide a reduction in blood flow equivalent to that produced by lower-body negative pressure. 4. Lower-body negative pressure produced no change in heart rate or diastolic blood pressure, but caused an initial 5 mmHg fall in systolic blood pressure (P less than 0.01). Blood flow was reduced by 21 +/- 6% in both forearms by lower-body negative pressure during saline infusion. During angiotensin II infusion, there was a marked difference in the response to lower-body negative pressure, with blood flow being reduced by 40 +/- 7% in the infused arm, but only by 21 +/- 4% in the control arm (P less than 0.05). Angiotensin II infusion had no effect on resting blood flow or the responses to noradrenaline. 5. We conclude that angiotensin II augments sympathetic vasoconstriction in forearm resistance vessels in man at a concentration that has no direct effect on blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)