Enalapril Therapy Research Articles

Effect of Enalapril in Subjects With Hypertension Associated With Moderate to Severe Renal Dysfunction

The purpose of this study was to define the effect of the angiotensin-converting enzyme inhibitor, enalapril maleate, on blood pressure, renal function, protein excretion, and potassium homeostasis in patients with hypertension associated with moderate to severe renal dysfunction. Nine patients, having an initial inulin clearance between 9 and 48 mL/min/1.73 m2, were treated with enalapril monotherapy (n = 6) or enalapril/furosemide (n = 3) combination therapy. Systolic and diastolic blood pressures were well controlled. Supine plasma renin activity was stimulated; the supine plasma aldosterone level was suppressed, with a resultant increase in the serum potassium level. Clinical hyperkalemia was not observed. Glomerular filtration rate, assessed by inulin and creatinine clearances, was not significantly changed. Effective renal plasma flow, assessed by paraaminohippurate clearance was significantly increased, with a resultant decrease in filtration fraction. Importantly, urinary protein excretion was markedly reduced. These results suggest that enalapril therapy produces efferent arteriolar dilitation with preservation of the glomerular filtration rate. Enalapril therapy may also blunt the effects of angiotensin II on transglomerular passage of protein, as demonstrated by reduced proteinuria. These findings suggest that interruption of the renin-angiotensin system in patients with preexisting renal disease may have renal protective effects.

Enalapril: A New Angiotensin Converting Enzyme Inhibitor

Enalapril maleate is a new angiotensin converting enzyme inhibitor marketed in the U.S. by Merck Sharp and Dohme. It has been demonstrated to actively interfere with the renin-angiotensin-aldosterone system. This is reflected by both hemodynamic (decreased blood pressure) and humoral (increased plasma renin, angiotensin I, and decreased angiotensin II) responses to enalapril therapy. Activity in the kallikrein-bradykinin system is still controversial. Enalapril maleate is a prodrug which is quickly absorbed, hydrolyzed by the liver to the active metabolite enalaprilic acid, and excreted 33 percent in the bile and 61 percent in the urine. The therapeutic dosage range is 10-40 mg/d, maximum of 40 mg, given once or twice daily. The onset and duration of action are dose related. Vertigo and headache have been the most commonly reported side effects. Clinical comparison of enalapril to hydrochlorothiazide, beta-adrenergic blockers, and captopril find it efficacious in the treatment of essential hypertension. Efficacy in treating congestive heart failure and hypertension secondary to renal artery stenosis has also been demonstrated for both angiotensin converting enzyme inhibitors. The overall efficacy and safety of enalapril and captopril appear equivalent when used at low doses in patients with uncomplicated hypertension.

Changes in blood pressure and body fluid volumes during diuretic therapy in patients with essential hypertension who receive enalapril.

We evaluated the effect of additional chlorthalidone therapy on blood pressure and body fluid volumes in 10 patients with essential hypertension who did not respond to chronic converting enzyme inhibition with enalapril. Values assessed after 3 days and 6 weeks of combined enalapril and chlorthalidone therapy were compared with initial values during enalapril monotherapy. After 3 days the mean arterial pressure (MAP), plasma volume (PV), blood volume (BV), and extracellular fluid volume (ECFV) decreased. There was a positive correlation between the percentage decreases in MAP and BV. After 6 weeks the MAP decreased further, but the decreases in PV, BV, and ECFV were less pronounced. At this time there was a positive correlation between the percentage decreases in MAP and ECFV. Our results support the hypothesis that contraction of the ECFV is an antihypertensive mechanism of diuretics. The antihypertensive effect of diuretics is enhanced during converting enzyme inhibition, while the body remains protected against volume deficits, possibly by the lower blood pressure itself.

Enalapril and the Kidney

Essential hypertension is characterized by increased renal vascular resistance, which also has definite implications for renal sodium handling. We studied the possibility of correcting these abnormalities by inhibiting angiotensin-converting enzyme with enalapril. Enalaprilic acid produced renal vasodilation. This, particularly postglomerular, vasodilation was accompanied with an increase in sodium excretion. The natriuresis was positively correlated to initial plasma renin activity. During continuous treatment with enalapril up to 12 weeks, this vasodilation persisted in 22 patients with essential hypertension. We also showed that orally administered enalapril induces natriuresis, both during a 50-mmol and during a 200-mmol sodium intake a day. This natriuresis caused a net negative sodium balance of approximately 120-140 mmol Na after 1 week of enalapril therapy. This was accompanied with a fall in body weight. We conclude that enalapril in essential hypertension alleviates the angiotensin-II-mediated abnormalities in renal hemodynamics and sodium excretion.

Renovascular Hypertension: Treatment with the Oral Angiotensin-Converting Enzyme Inhibitor Enalapril

Sixteen patients with an established diagnosis of renovascular hypertension were entered in an open study of enalapril (MK421), an oral angiotensin-converting enzyme (ACE) inhibitor, for treatment of their hypertension. Initial blood pressure was 178.9 +/- 6.3/106.2 +/- 3.1 mm Hg during conventional therapy on a median of 3 different antihypertensive agents. All antihypertensive therapy was ceased and the patients admitted to hospital. Following introduction of enalapril, blood pressure fell to 161.5 +/- 6.9/90.6 +/- 4.1 mm Hg at 24 h (p less than 0.01 systolic and diastolic). Blood pressure control (diastolic blood pressure, phase V, less than 95 mm Hg) was achieved with monotherapy in 7 patients and in a further 5 patients with addition of a diuretic. Renal function was compromised in 4 patients, requiring cessation of enalapril in 2 instances. Enalapril is an oral ACE inhibitor useful in the treatment of renovascular hypertension. Close monitoring of renal function is necessary during the introduction of enalapril therapy in patients with renovascular hypertension.

Comparison of effects of enalapril plus hydrochlorothiazide versus standard triple therapy on renal function in renovascular hypertension

Renal function and antihypertensive drug efficacy were determined in a prospective, double-blind, multicenter study comparing enalapril plus hydrochlorothiazide with standard triple therapy (hydrochlorothiazide, timolol, and hydralazine) in 75 patients with documented renovascular hypertension. Both groups had significant mean decreases in systolic and diastolic blood pressures. Effective control of diastolic hypertension occurred in 96 percent of patients receiving enalapril compared with 82 percent of patients receiving the triple-drug regimen. Effective renal plasma flow was significantly increased by enalapril therapy. In contrast, the glomerular filtration rate had a bimodal response. In 80 percent of enalapriltreated patients, there was no significant change in the inulin clearance, although in 20 percent of patients (10), there was a 28 percent decrease in the inulin clearance with a concomitant 12 percent increase in renal plasma flow. Seven of the 10 patients had unilateral renal artery stenosis, but in all 10, it was high-grade stenosis (more than 80 to 90 percent stenosis). Although a significant rise in the serum creatinine level occurred in one patient in association with diuretic therapy, volume repletion reversed this azotemia. No oliguric acute renal failure occurred in the enalapril-treated group. The cause of the decrease in glomerular filtration rate induced by enalapril plus hydrochlorothiazide in a minority of patients with renal artery stenosis appears to be quite complex. Although the abolishment of the autoregulation of glomerular filtration secondary to blockage of antiotensin II appears to be a primary cause, the roles of decreased arterial pressure, renal counterbalance, concurrent diuretic therapy, and other hemodynamic factors that may maintain glomerular ultrafiltration pressure must also be considered. The results of this study show that enalapril plus hydrochlorothiazide is effective in treating renovascular hypertension. Special care is needed for a small group of patients with renovascular hypertension in whom there is a decrease in the glomerular filtration rate with this therapy. This may identify a subset of patients with unilateral or bilateral high-grade renal artery stenosis in whom alternative therapy—percutaneous angioplasty or surgical intervention—may be considered.

Enalapril: a review of human pharmacology.

Enalapril, an orally-active, long-acting, nonsulphydryl angiotensin-converting enzyme (ACE) inhibitor, is extensively hydrolysed in vivo to enalaprilat, its bioactive form. Bioactivation probably occurs in the liver. Metabolism beyond activation to enalaprilat is not observed in man. Administration with food does not affect the bioavailability of enalapril; excretion of enalapril and enalaprilat is primarily renal. Peak serum enalaprilat concentrations are reached 4 hours post-dose, and the profile is polyphasic with a prolonged terminal half-life (greater than 30 hours) due to the binding of enalaprilat to ACE. Steady-state is achieved by the fourth daily dose, with no evidence of accumulation. The effective accumulation half-life following multiple dosing is 11 hours. Higher serum concentrations and delayed urinary excretion occur in patients with severe renal insufficiency. Enalapril reduces blood pressure in hypertensive patients by decreasing systemic vascular resistance. The blood pressure reduction is not accompanied by an increase in heart rate. Furthermore, cardiac output is slightly increased and cardiovascular reflexes are not impaired. Once- and twice-daily dosage regimens reduce blood pressure to a similar extent. Enalapril increases renal blood flow and decreases renal vascular resistance. Enalapril also augments the glomerular filtration rate in patients with a glomerular filtration rate less than 80 ml/min. Enalapril reduces left ventricular mass, and does not affect cardiac function or myocardial perfusion during exercise. There is no rebound hypertension after enalapril therapy is stopped. Enalapril does not produce hypokalaemia, hyperglycaemia, hyperuricaemia or hypercholesterolaemia. When combined with hydrochlorothiazide, enalapril attenuates the undesirable diuretic-induced metabolic changes. Therapeutic doses of enalapril do not affect serum prolactin and plasma cortisol in healthy volunteers or T3, rT3, T4 and TSH in hypertensive patients. Enalapril has natriuretic and uricosuric properties. The antihypertensive effect of enalapril is potentiated by hydrochlorothiazide, timolol and methyldopa, but unaffected by indomethacin and sulindac. No interactions occur between enalapril and frusemide, hydrochlorothiazide, digoxin and warfarin. The bioavailability of enalapril is slightly reduced when propranolol is coadministered, but this does not appear to be of any clinical significance. Enalapril increases cardiac output and stroke volume and decreases pulmonary capillary wedge pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of enalapril, a new angiotensin-converting enzyme inhibitor, in a controlled trial in heart failure

Angiotensin-converting enzyme inhibitors are effective vasodilators in the treatment of congestive heart failure. Enalapril, a new angiotensin-converting enzyme inhibitor, or placebo, in addition to digoxin and diuretic drugs, were given to 17 patients with chronic congestive heart failure who were followed up for 12 weeks. In random double-blind fashion, nine patients received enalapril and eight received placebo. Cardiac dimensions and function improved slightly but insignificantly in both groups. Treadmill exercise duration increased from a mean value (+/- standard deviation) of 9.1 +/- 3.2 to 12.0 +/- 3.5 minutes during enalapril administration (p less than 0.025) and was unchanged during placebo administration (10.1 +/- 3.7 versus 11.1 +/- 5.2 minutes). Maximal oxygen consumption also increased during enalapril therapy (15.8 +/- 3.4 to 18.4 +/- 4.4 ml/min per kg, p less than 0.05) and remained unchanged during placebo treatment (16.0 +/- 6.4 versus 17.0 +/- 4.6 ml/min per kg). Clinical functional class (Yale scale) improved 3.1 +/- 1.9 points (p less than 0.01) during enalapril treatment but not during placebo treatment (0.8 +/- 3.5 points, no significant difference). No significant side effects were observed. Thus, enalapril appears to be a clinically effective and useful new angiotensin-converting enzyme inhibitor for the management of chronic congestive heart failure.

Clinical and hemodynamic experience with enalapril in congestive heart failure

The renin-angiotension system is activated in many patients with congestive heart failure (CHF), resulting in angiotensin-mediated vasoconstriction and aldosterone-mediated sodium and water retention. To evaluate the effectiveness of enalapril, a new converting enzyme inhibitor, enalapril was administered to patients either orally or intravenously in a single dose, and hemodynamic and hormonal responses were measured. Patients were then placed on oral enalapril therapy for 1 month, and treadmill exercise duration and invasive hemodynamics were compared with baseline pretreatment data. With single-dose administration, both oral and intravenous enalapril reduced systemic vascular resistance and increased cardiac output. However, the effects of oral enalapril were hot manifest for 3 to 4 hours, because oral enalapril is a pro-drug form that requires hepatic deesterification. In contrast, intravenous enalapril resulted in significant hemodynamic and hormonal changes 15 to 30 minutes after administration. During long-term therapy, enalapril was associated with improved symptomatology, increase of treadmill exercise duration and sustained hemodynamic improvement. Enalapril was effective therapy for chronic CHF. Optimal short-term response may require coadministration of both intravenous and oral preparations of enalapril; however, the magnitude of the short-term response was comparable for both preparations. Long-term therapy is most effective when the drug is administered as a twice-daily regimen.

Systolic blood pressure responses to enalapril maleate (MK 421, an angiotensin converting enzyme inhibitor) and hydrochlorothiazide in conscious Dahl salt-sensitive and salt-resistant rats.

Systolic blood pressure responses to enalapril maleate (MK 421, a new angiotensin converting enzyme inhibitor (CEI] and hydrochlorothiazide (HTZ) were studied in conscious Dahl salt-sensitive (DS) and salt-resistant (DR) rats maintained on a high salt (8.0% NaCl) and a normal salt (0.4% NaCl) diet. The DS rats were severely hypertensive after 3 weeks on the high salt diet whereas the systolic blood pressure (SBP) of the DR rats were normotensive. Oral treatment with enalapril (15-100 mg X kg-1 X day-1) and HTZ (60-400 mg X kg-1 X day-1) caused a significant reduction of SBP in the DS rats with the high salt diet (P less than 0.001); however, this was not observed until after 4 weeks of treatment when the dosage was 30 and 150 mg X kg-1 X day-1, respectively. Furthermore, enalapril therapy alone significantly reduced the SBP of all groups of rats regardless of diet or Dahl strain (P less than 0.001), but this was not observed until the end of the 7th week of therapy in DR rats on 8.0% NaCl and the end of the 3rd week of therapy for DR and DS rats on 0.4% NaCl. These results suggest that enalapril may lower SBP by mechanisms other than those related to an action as a CEI.

Hemodynamic and antihypertensive effects of the new oral angiotensin-converting-enzyme inhibitor MK-421 (enalapril).

The antihypertensive, hemodynamic, and humoral effects of the new converting-enzyme inhibitor enalapril (MK-421) were assessed by sequential studies during 3 months of uninterrupted treatment (20 mg twice daily) in 10 hypertensive patients. Six achieved good blood pressure (mean arterial pressure) control with enalapril alone (from 126 +/- 7.0 mm Hg pretreatment to 105 +/- 1.6 mm Hg at 3 months, p less than 0.05). The other four required the addition of diuretics (hydrochlorothiazide 25 mg orally twice daily) at different stages of follow-up, with resultant blood pressure control (128 +/- 9.6 mm Hg pretreatment to 113 +/- 1.9 mm Hg at 2 months after the addition of diuretics). Neither the acute nor long-term blood pressure response could be predicted from the pretreatment levels of plasma renin activity. The blood pressure reduction during enalapril therapy was characterized by a decrease in total peripheral resistance (53 +/- 2.5 U X M2 pretreatment to 38 +/- 3.0 U X M2 at 3 months, p less than 0.05) with no significant change in cardiac output or heart rate. This lack of reflex tachycardia could not be ascribed to baroceptor dysfunction since the response to head-up tilt (the increase in diastolic blood pressure, in heart rate, and in plasma catecholamines) was normal and not significantly different from pretreatment response. Average blood volume did not change (91% +/- 4.3% of normal in the pretreatment period to 93% +/- 2.9% after 3 months of therapy, p = NS) despite the significant lowering of arterial pressure with enalapril alone (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic and clinical response to enalapril, a long-acting converting-enzyme inhibitor, in patients with congestive heart failure.

Enalapril, a new oral angiotensin converting-enzyme inhibitor, was administered to nine patients with severe congestive heart failure. Short-term hemodynamic response was noted within 2 hr and persisted for up to 24 hr. At peak effect mean arterial pressure fell from 83.4 +/- 10(SD) to 72.1 +/- 16.2 mm Hg (p less than .01), right atrial pressure from 13.6 +/- 6.0 to 10.4 +/- 7.5 mm Hg (p less than .01), pulmonary arterial pressure from 38.9 +/- 4.8 to 31.9 +/- 4.8 mm Hg (p less than .01), pulmonary capillary wedge pressure from 28.2 +/- 3.5 to 22.1 +/- 5.1 mm Hg (p less than .01), and total pulmonary resistance from 875 +/- 304 to 697 +/- 291 dynes-sec-cm-5 (p less than .05). Cardiac index was not changed, but there was a significant redistribution of regional blood flow with an increase of renal blood flow after enalapril. Plasma renin activity rose significantly from 6.2 to 28.6 ng/ml/hr, whereas plasma norepinephrine did not change after enalapril. Seven patients were treated with enalapril for 4 weeks. Five patients reported symptomatic improvement. Five of six patients tested had an increase in both exercise time (NS) and maximum oxygen consumption (NS). Repeat hemodynamic evaluation in six patients after long-term enalapril therapy showed a persistent effect with significant reductions in right atrial pressure from 13.8 +/- 7.2 to 7.1 +/- 4.7 mm Hg and in mean arterial pressure from 82.5 +/- 10.4 to 76.6 +/- 5.3 mm Hg and a significant increase in cardiac index from 2.1 +/- 0.5 to 2.5 +/- 0.5 l/min/m2 (all p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Enalapril: A new angiotensin-converting enzyme inhibitor in chronic heart failure: Acute and chronic hemodynamic evaluations

Hemodynamic effects of the new oral angiotensin-converting enzyme inhibitor, enalapril, were evaluated acutely in 15 patients with chronic heart failure and in 7 patients after 4 weeks of maintenance therapy. Initial hemodynamic effects were characterized by a significant increase in cardiac index (from 2.1 +/- 0.7 to 2.6 +/- 0.7 liters/min per m2) and a decrease in pulmonary capillary wedge pressure (from 30 +/- 6 to 24 +/- 7 mm Hg), right atrial pressure (from 14 +/- 5 to 11 +/- 4 mm Hg), mean arterial pressure (from 96 +/- 16 to 80 +/- 17 mm Hg) and systemic vascular resistance (from 1,820 +/- 480 to 1,200 +/- 410 dynes . s . cm-5) without any significant change in heart rate, pulmonary artery pressure and pulmonary vascular resistance. During maintenance therapy, the dose of diuretic drugs had to be increased because of systemic venous hypertension. Repeat hemodynamic study showed that after chronic therapy, cardiac index (2.1 +/- 0.7 vs. 3.0 +/- 0.08 liters/min per m2) and stroke volume index (24 +/- 10 vs. 36 +/- 7 ml/m2) remained elevated and pulmonary capillary wedge pressure was lower than control (30 +/- 6 vs. 16 +/- 6 mm Hg), indicating sustained improvement in left ventricular performance. Plasma renin activity increased and plasma norepinephrine levels decreased after enalapril therapy and these humoral changes persisted during maintenance therapy. All patients receiving chronic therapy had symptomatic improvement. Significant hypotension, which occurred in five patients at the initiation of therapy, appears to be the major side effect.(ABSTRACT TRUNCATED AT 250 WORDS)

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.