Enalaprilic Acid Research Articles

Pharmacology of angiotensin converting enzyme inhibitors: A review

Two angiotensin converting enzyme inhibitors are currently available for clinical use. Captopril, a sulfhydryl-containing compound, is a direct acting enzyme inhibitor. Enalapril is a non-sulfhydryl pro-drug that requires enzymatic conversion to enalaprilic acid, a potent angiotensin converting enzyme inhibitor. Both drugs lower blood pressure, suppress blood pressure response to angiotensin I infusion, and elevate plasma renin activity. Enalapril bioavailability is unaffected by food, whereas captopril availability is suppressed by food. Dose adjustments are necessary for patients with congestive heart failure and renal failure.

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.

Evaluation of Angiotensin Converting Enzyme (ACE) in the Pharmacokinetics and Pharmacodynamics of ACE Inhibitors

The increasing number of angiotensin converting enzyme (ACE) inhibitors means that compounds with different enzyme kinetics, pharmacokinetics, bioavailability, and pharmacodynamics will appear. They will, however, all inhibit ACE, and their hypotensive effect will be a consequence of this action. Enalapril (MK-421) is an esterified prodrug, which in man is converted by the liver to the bioactive potent ACE inhibitor enalaprilate (enalaprilic acid, MK-422). This probably accounts for the slower plasma appearance of MK-422 and the longer duration of action of enalapril. The clinical significance of deesterification by the liver needs further study but minor abnormalities of liver function, such as occur in congestive heart failure, do not affect the rate of deesterification and hence the plasma enalaprilat levels. A close relationship between the plasma drug level, degree of ACE inhibition, and the hormonal and hypotensive effect can be demonstrated after both acute and chronic enalapril administration to hypertensive patients. Chronic therapy with enalapril leads to induction of ACE but in humans this is not sufficient to lead to resistance or tolerance to the drug. Enalapril offers an exciting new approach to the treatment of hypertension with some distinct advantages over conventional antihypertensive therapy.

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.

Naloxone reverses the effects of enalapril and enalaprilic acid on the pressor responses to afferent vagal stimulation

The effects of intracisternal injection of enalapril (MK 421) or its bioactive form enalaprilic acid (MK 422) (0.075 mg/kg) on the pressor responses elicited by afferent stimulation of the vagus were investigated in the urethane-anaesthetized dog. The angiotensin converting enzyme inhibitors (ACEl)-induced decrease in the systolo-diastolic pressor responses to vagal stimulation was reversed by naloxone (0.1 mg/kg iv). The same doses of ACEl injected by intravenous route remain inactive. These data support evidence for an additional central site of action of ACEl and suggest the involvement of central opioid mechanisms in the hypotensive properties of ACEl.

Enalapril (MK421) activation in man: importance of liver status.

The in vitro conversion of enalapril (MK421) to enalaprilic acid (MK422) in human autopsy tissues was examined. MK422 was measured by radioimmunoassay. Human cadaver liver was the only tissue in which significant conversion was demonstrated. The esterase activity was stable after post mortem. Autopsy liver tissues from patients with elevated ante mortem liver function tests were found to have a reduced rate of deesterification.

Preservation of ischemic myocardium by a new converting enzyme inhibitor, enalaprilic acid, in acute myocardial infarction

Enalaprilic acid (MK-422), the biologically active diacid of the converting enzyme inhibitor enalapril, was studied in myocardial ischemia (MI). Acute left coronary artery ligation was produced in 62 male Sprague-Dawley rats, and infarct size was determined by left ventricular free wall (LVFW) creatine kinase (CK) activity. Administration of enalaprilic acid (2 mg/kg) 2 minutes and 24 hours after MI significantly blunted the reduction in LVFW CK activity at 48 hours after ligation, when compared to the MI rats given vehicle (6.4 ± 0.5 vs 4.7 ± 0.2 IU/mg protein, respectively; p < 0.01). The percentage of LVFW spared was significantly ( p < 0.01) increased from 28 ± 2% to 45 ± 5% by MK-422. MK-422 also significantly blunted the loss of LVFW CK activity 48 hours after a coronary ligation (10 minutes) followed by reperfusion, when compared to vehicle (10.1 ± 0.6 vs 8.3 ± 0.6 IU/mg protein, respectively; p < 0.05). This represents a significant increase in the percentage of LVFW spared, 65 ± 5% vs 85 ± 6% ( p < 0.05). These data indicate a significant protective action afforded by MK-422 in two different protocols of ischemic damage to the myocardium and suggest a role for the renin-angiotensin system in the extension of ischemic damage.

Blood pressure response to enalaprilic acid in essential hypertension: dose-response and effect of pre-treatment with furosemide.

Enalaprilic acid (MK 422), the active metabolite of enalapril, has recently become available for intravenous administration. In order to establish the proper dose for rapid blood pressure reduction, 9 patients with moderate to severe essential hypertension on a constant sodium intake of 100 mmol/24h were studied. They received four single doses of MK 422 according to an up-and-down titration schedule. Doses between 5 and 80 mg resulted in effective blood pressure reduction with an onset of action of about 10 minutes. Within this dose range the response was flat. No symptomatic hypotension was observed. The fall in blood pressure was less pronounced in patients with low initial plasma renin activity (PRA). Accordingly, a study was done to show whether the blood pressure response could be augmented by preceding stimulation of PRA by injection of 40 mg furosemide 15 minutes before the administration of MK 422. PRA increased after furosemide, but the blood pressure response to MK 422 was not augmented.

Enalaprilic acid: improving haemodynamics in coronary artery disease

Enalaprilic acid: improving haemodynamics in coronary artery disease

Plasma enalapril levels and hormonal effects after short- and long-term administration in essential hypertension.

Enalapril lowers blood pressure both acutely and during long-term therapy in patients with essential hypertension. After a single 10 mg dose of enalapril a close relationship between plasma enalaprilic acid (MK-422) levels, angiotensin converting enzyme (ACE) inhibition and the acute hypotensive and hormonal effects was demonstrated. During long-term administration of enalapril, a similar relationship between the plasma enalaprilic acid level, ACE inhibition and the hypotensive effect was shown, although the dose-response curve for plasma enalaprilic acid to ACE inhibition was displaced to the right compared to the acute dose-response curve. Several weeks' administration of enalapril was needed to reach stable plateau levels of plasma enalaprilic acid and ACE inhibition. During long-term treatment with enalapril in essential hypertension, there was sustained inhibition of ACE and the associated hormonal changes.

Coronary vascular actions of the converting enzyme inhibitor, enalapril.

Enalapril, a potent angiotensin converting enzyme inhibitor, effectively blocked the constrictor actions of angiotensin I in isolated perfused cat coronary arteries. Enalapril, at concentrations of 25 to 100 micrograms/ml, inhibited angiotensin I by 65 to 80%. Moreover, enalapril at 100 to 200 micrograms/ml, markedly antagonized the coronary vasoconstrictor effects of angiotensin II. At 150 micrograms/ml, enalapril blocked the angiotensin II response by 80 +/- 5%, and at 200 micrograms/ml, it was blocked by 95 +/- 4%. Enalaprilic acid at 0.5 to 1.0 microgram/ml also blocked the angiotensin II response by 94 +/- 5%. Captopril, up to 250 micrograms/ml, failed to significantly antagonize angiotensin II, although it readily blocked angiotensin I in this preparation. The duration of this angiotensin II blockade lasted about 60-90 min. This angiotensin II antagonism may help explain the beneficial effects of enalapril in situations such as acute myocardial ischemia.

Comparative Effects of Enalapril, Enalaprilic Acid and Captopril in Blocking Angiotensin I-Induced Pressor and Dipsogenic Responses in Spontaneously Hypertensive Rats

The role of central angiotensin converting enzyme (ACE), in the maintenance of high blood pressure, was examined in unanesthetized spontaneously hypertensive rats (SHR). Pressor and dipsogenic responses induced by intracerebroventricular (ICV) injections of angiotensin I (AI) were elicited before and 30 min after either captopril (120-800 nanomoles ICV), enalapril (66-460 nanomoles ICV) and enalaprilic acid (70-280 nanomoles ICV). Enalapril was 1.6 (0.7-3.9) and 1.7 (0.9-2.9) times more potent than captopril in inhibiting AI-induced pressor and dipsogenic responses, respectively. Enalaprilic acid was 2.7 (1.1-7.1) and 2.9 (1.9-4.8) times more potent than captopril in inhibiting AI- (ICV administration) induced pressor and dipsogenic responses, respectively. None of the ACE inhibitors, in contrast, reduced the central actions of AII. Basal mean arterial pressure was not reduced by these ACE inhibitors after ICV administration. Administered orally at doses which produced similar hypotensive responses, neither captopril (30 mg/kg) nor enalapril (3 mg/kg) blocked the responses induced by AI given ICV (10 ng). These findings indicate that ACE inhibitors given acutely do not penetrate into the central nervous system sufficiently to block the dipsogenic and pressor responses induced by AI given ICV, and suggest that inhibition of central ACE may not be important to the acute antihypertensive activity of the ACE inhibitors tested.

Mechanism for hypotensive action of angiotensin converting enzyme inhibitors.

The mechanism(s) for the hypotensive effect of Angiotensin Converting Enzyme (ACE) inhibitors remains elusive. This is because of the multiplicity of the biological actions of angiotensin, the dual role of ACE and the ability of the inhibitors to induce the enzyme. After a single dose of enalapril (MK421), a new ACE inhibitor, in patients with essential hypertension a close linear relationship between the plasma level of enalaprilic acid (MK422) and the degree of ACE inhibition could be demonstrated. Furthermore the degree of ACE inhibition was linearly related to the hormonal changes and to the fall in blood pressure. After chronic administration of enalapril the plasma levels of MK422 were found to be dose dependent. As in the acute study there was also a linear relationship between the plasma level of MK422 and the degree of ACE inhibition. However, the plasma enalaprilic acid level-ACE inhibition dose response curve after chronic administration was shifted to the right, compared to the dose response curve after acute administration suggesting that ACE had been induced during chronic administration of enalapril in humans. There were direct linear relationships between both the degree of ACE inhibition the plasma and enalaprilic acid (MK422) level to the fall in mean arterial pressure. These results suggest that regardless of the final mechanism for the hypotensive action of ACE inhibitors it is a consequence of their inhibition of the enzyme.

Na-K-ATPase in Single Nephron Segments of Hypertension-prone Rats

The mechanism of action of angiotensin converting enzyme (ACE) inhibitors to lower blood pressure remains unclear, but the weight of available data favour peripheral blockade of the formation of angiotensin II (AII). Previous work in rats has shown that the prodrug ACE inhibitor, enalapril (MK-421), lowered blood pressure most effectively when PRA was elevated [sodium deficiency, two-kidney, one figure 8 hypertension, diuretic-treated spontaneously hypertensive rats (SHR)]. In sodium-deficient rats, the enalapril-sensitive component of the blood pressure was greatly reduced after salt loading, and nephrectomy blocked the antihypertensive response to enalapril in SHR. In the present study, further support that the mechanism of action of enalapril involves a reduction in AII has been obtained from rats made hypertensive by continuous intravenous (i.v.) AII infusion for 10 days. Enalapril administered for seven days did not significantly lower blood pressure, suggesting that there were no important non-angiotensin mechanisms (such as bradykinin potentiation) involved in its action. From earlier studies in SHR, the time course for blockade of angiotensin I (AI) pressor responses and the blood pressure reduction did not correspond, suggesting a tissue site of action. In the present studies in adult SHR, a central site of action was ruled out since the parent inhibitor, enalaprilic acid (MK-422), injected into the brain ventricles did not acutely reduce blood pressure. An interaction of enalaprilic acid with the sympathetic nervous system was evaluated in dogs in which adrenergic activity was enhanced as a result of diuretic-induced renin release. Enlaprilic acid did not alter the enhanced hindquarter vasoconstrictor responses to sympathetic nerve stimulation. Enalapril increased renal blood flow, glomerular filtration rate and sodium excretion. The mechanism of the natriuresis in dogs probably involves several mechanisms including a decrease in aldosterone biosynthesis, changes in renal function (glomerular filtration rate and renal blood flow) and possibly blockade of a direct tubular effect of AII on sodium reabsorption. Enalaprlic acid was also studied in a closed chest dog model of acute left ventricular (LV) failure caused by embolization via the left main coronary artery with 50 microns plastic microspheres. Enalaprilic acid at 100 micrograms/kg i.v. reduced preload, afterload and improved LV performance without changing the heart rate. In conclusion, enalapril the prodrug, and enalaprilic acid the active inhibitor, are potentially useful in the treatment of hypertension and LV failure.(ABSTRACT TRUNCATED AT 250 WORDS)