enalaprilat-anhydrous and Hypertension

Hypertensive emergency is defined as a systolic blood pressure > 180 mmHg or a diastolic blood pressure > 120 mmHg with evidence of new or progressive end-organ damage. The purpose of this paper is to review advances in the treatment of hypertensive emergencies within the last 5 years.. New literature and recommendations for managing hypertensive emergencies in the setting of pregnancy, stroke, and heart failure have been published. Oral nifedipine is now considered an alternative first-line therapy, along with intravenous hydralazine and labetalol for women presenting with pre-eclampsia. Clevidipine is now endorsed by guidelines as a first-line treatment option for blood pressure reduction in acute ischemic stroke and may be considered for use in intracranial hemorrhage. Treatment of hypertensive heart failure remains challenging; clevidipine and enalaprilat can be considered for use in this population although data supporting their use remains limited.

Topics: Administration, Oral; Antihypertensive Agents; Blood Pressure; Brain Ischemia; Emergencies; Enalaprilat; Female; Guideline Adherence; Heart Failure; Humans; Hydralazine; Hypertension; Infusions, Intravenous; Intracranial Hemorrhages; Labetalol; Nifedipine; Pre-Eclampsia; Pregnancy; Pyridines; Stroke

Perioperative hypertension is commonly encountered in patients that undergo surgery. While attempts have been made to standardize the method to characterize the intraoperative hemodynamics, these methods still vary widely. In addition, there is a lack of consensus concerning treatment thresholds and appropriate therapeutic targets, making absolute recommendations about treatment difficult. Nevertheless, perioperative hypertension requires careful management. When treatment is necessary, therapy should be individualized for the patient. This paper reviews the pharmacologic agents and strategies commonly used in the management of perioperative hypertension.

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Enalaprilat; Fenoldopam; Hemodynamics; Humans; Hydralazine; Hypertension; Incidence; Labetalol; Nicardipine; Nitroglycerin; Nitroprusside; Perioperative Care; Postoperative Complications; Propanolamines; Pyridines; Surgical Procedures, Operative; Vascular Resistance; Vasodilator Agents

Severe hypertension is a common clinical problem in the United States, encountered in various clinical settings. Although various terms have been applied to severe hypertension, such as hypertensive crises, emergencies, or urgencies, they are all characterized by acute elevations in BP that may be associated with end-organ damage (hypertensive crisis). The immediate reduction of BP is only required in patients with acute end-organ damage. Hypertension associated with cerebral infarction or intracerebral hemorrhage only rarely requires treatment. While nitroprusside is commonly used to treat severe hypertension, it is an extremely toxic drug that should only be used in rare circumstances. Furthermore, the short-acting calcium channel blocker nifedipine is associated with significant morbidity and should be avoided. Today, a wide range of pharmacologic alternatives are available to the practitioner to control severe hypertension. This article reviews some of the current concepts and common misconceptions in the management of patients with acutely elevated BP.

Topics: Antihypertensive Agents; Aortic Aneurysm; Aortic Dissection; Clonidine; Diazoxide; Enalaprilat; Female; Fenoldopam; Humans; Hypertension; Labetalol; Nicardipine; Nifedipine; Nitroprusside; Phentolamine; Pre-Eclampsia; Pregnancy; Propanolamines; Trimethaphan

Topics: Aged; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Enalaprilat; Female; Humans; Hypertension; Intraoperative Complications; Oral Surgical Procedures, Preprosthetic; Time Factors; Tongue Diseases

Hypertensive emergency is a condition in which there is elevation of both systolic and diastolic blood pressure with the presence of acute target organ disease. Hypertensive urgency is a condition where the blood pressure is elevated (diastolic > 120 mmHg) with the absence of acute target organ disease. Hypertensive emergencies are best managed with parenteral drugs and careful intraarterial blood pressure monitoring. Hydralazine has been widely used in treatment of hypertension in eclampsia and preeclampsia, and its safety has been demonstrated in these patients. Sodium nitroprusside (SNP) has the most reliable antihypertensive activity, which begins immediately after its administration and ends when the infusion is stopped. As with diazoxide, it should be used with caution in patients with impaired cerebral flow. SNP is the preferred drug in obtaining controlled hypotension in patients undergoing neurovascular surgery. Intravenous nitroglycerin is useful in patients prone to myocardial ischemia, but should be avoided in patients with increased intracranial pressure. Esmolol is effective in controlling both supraventricular tachyarrhythmias and severe hypertension. Its short onset of duration of action make it useful in the emergent setting, but because of its negative inotropic effect its use should be avoided in patients with low cardiac output. Verapamil should not be used in patients with preexisting conduction abnormalities. Nicardipine is a potent arteriolar vasodilator without a significant direct depressant effect on myocardium. As with other afterload reducing agents, it should not be used in patients with severe aortic stenosis. Because angiotensin-converting enzyme (ACE) inhibitors generally cause cerebral vasodilatation, enalaprilat may be particularly beneficial for patients who are at high risk of developing cerebral hypotensive episodes secondary to impaired cerebral circulation. Fenoldopam, a selective post-synaptic dopaminergic receptor (DA1) has been shown to be effective in treating severe hypertension with a lower incidence of side effects than SNP. Hypertensive urgencies can usually be managed with oral agents. Oral nifedipine, captopril, clonidine, labetalol, prazosin, and nimodipine have all been shown to be effective in these situations.

Topics: Administration, Oral; Antihypertensive Agents; Emergencies; Enalaprilat; Female; Humans; Hydralazine; Hypertension; Infusions, Parenteral; Labetalol; Nicardipine; Nitroglycerin; Nitroprusside

Topics: Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Captopril; Coronary Disease; Enalaprilat; Hemodynamics; Humans; Hypertension; Myocardial Infarction

Overall, the worldwide experience on enalapril to date is very encouraging. The drug produces good to excellent responses in 54 to 66 percent of patients with essential hypertension and is at least as effective as either diuretics or beta blockers. The effects of enalapril compared with those of diuretics confirm that patients more dependent upon the renin-angiotensin system respond better. When hydrochlorothiazide is administered concomitantly with enalapril, almost all patients respond, with good long-term maintenance. In patients with severe hypertension, Blocadren or Aldomet may be added in addition to hydrochlorothiazide and will produce additional benefit. Enalapril attenuates the adverse metabolic effects of hydrochlorothiazide, particularly hypokalemia. Overall, although the efficacy of enalapril and that of captopril are similar, enalapril is better tolerated and does not appear to be associated with any significant occurrence of captopril-type side effects, particularly the skin rash and loss of taste. As expected, enalapril and other converting inhibitors may be associated with azotemia in patients with bilateral renovascular hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Cell Count; Blood Pressure; Captopril; Dipeptides; Drug Evaluation; Drug Therapy, Combination; Enalapril; Enalaprilat; Humans; Hydrochlorothiazide; Hypertension; Peptidyl-Dipeptidase A; Posture; Propranolol; Renin-Angiotensin System

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Dipeptides; Drug Administration Schedule; Enalapril; Enalaprilat; Heart Failure; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Kidney; Kidney Failure, Chronic; Norepinephrine; Prostaglandins; Renal Circulation; Renin

In chronic renal failure, clearance of enalapril is reduced. Hence, a renoprotective effect may be achieved with lower doses than conventionally used. Since marked inter-patient variation in concentrations of enalaprilat has been shown in patients with renal failure despite equivalent dosage of enalapril, a direct comparison of the effect of high versus low plasma concentrations of enalaprilat on the progression of renal failure was undertaken.. Forty patients with a median glomerular filtration rate (GFR) of 17 (6-35) ml/min/1.73 m2 were studied in an open-label, randomised trial comparing patients with a high (>50 ng/ml) with patients with a low (<10 ng/ml) target trough plasma concentration of enalaprilat. The dose of enalapril was titrated accordingly. The patients were followed for 12 months or until they needed renal replacement therapy. GFR was measured at 3-month intervals by the plasma clearance of 51Cr-EDTA, and the individual rates of progression of renal failure were calculated as the slope of GFR versus time plot.. In the high-concentration group, the median enalaprilat trough concentration was 92.9 ng/ml (21.8-371.0 ng/ml) and in the low-concentration group it was 9.1 ng/ml (2.5-74.8 ng/ml) at 3 months follow-up (P<0.001). The median daily doses of enalapril were 10 mg (2.5-30 mg) and 1.88 mg (1.25-5 mg) in the high and low groups, respectively (P<0.001). In the high-concentration group, the mean+/-SE decline in renal function was 6.1+/-1.5 ml/min/1.73 m2 per year and in the low-concentration group it was 4.3+/-14.4 ml/min/1.73 m2 per year (P=0.48). Five patients in the high-concentration group reached end-stage renal failure whereas none in the low-concentration group did (P=0.04). There were no statistically significant differences in blood pressure level, concomitant antihypertensive therapy or urinary albumin excretion. However, the high-enalaprilat concentration group had an overall higher plasma potassium concentration of 0.42 mmol/l than the low group (P<0.001).. In patients with moderate to severe renal insufficiency, a low concentration of enalaprilat afforded the same degree of renoprotection, blood pressure control and minimisation of proteinuria as a high concentration, during 12 months of follow-up. The high-dosage treatment was associated with a more pronounced tendency to hyperkalaemia. Thus, there seems to be no indication for increasing the daily dose of enalapril beyond what achieves adequate blood pressure control in this group of patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dose-Response Relationship, Drug; Enalapril; Enalaprilat; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged

Hypertension in pediatric patients after surgical repair of coarctation of the aorta can be difficult to control and may lead to morbidity. The renin-angiotensin system mediates at least part of this hypertension. Enalaprilat, the only intravenous angiotensin-converting enzyme inhibitor, is used to treat hypertension in pediatric patients in other settings. However, its effect on postoperative hypertension during the early postoperative period in patients undergoing surgical repair of coarctation of the aorta is unknown.. Prospective, randomized, double-blind study.. Operating room and the pediatric intensive care unit.. Fourteen consecutive pediatric patients between the ages of 1 and 18 yrs scheduled to undergo surgical repair of coarctation of the aorta.. Patients were randomized to receive enalaprilat or saline placebo. Infusions were begun intraoperatively within 15 mins of aortic repair and repeated every 6 hrs.. Plasma renin activity was measured at baseline and on postoperative day 1. Blood pressure was determined at 30 mins and at 2, 4, and 6 hrs after infusion and scored relative to the preoperative blood pressure. The blood pressure in the enalaprilat group was consistently lower at 30 mins, 2 hrs, and 4 hrs after infusion (p <.05), but not at 6 hrs. Plasma renin activity was significantly lower in the placebo group on postoperative day 1. Length of stay in the pediatric intensive care unit trended shorter in the treated group.. Conclusions are limited by a small cohort. Angiotensin-converting enzyme inhibitor therapy resulted in improved blood pressure control after coarctation repair. Further improvement of blood pressure control may be achievable by use of a larger dose of enalaprilat or a 4-hr enalaprilat-dosing interval.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Aortic Coarctation; Blood Pressure Monitoring, Ambulatory; Child; Child, Preschool; Cohort Studies; Double-Blind Method; Enalaprilat; Female; Humans; Hypertension; Infant; Infusions, Intravenous; Intensive Care Units, Pediatric; Length of Stay; Male; Monitoring, Physiologic; Placebos; Postoperative Complications; Prospective Studies; Renin; Renin-Angiotensin System; Statistics, Nonparametric; Thoracotomy; Time Factors

We compared the efficacy of the combination of enalaprilat/labetalol with that of enalaprilat/nicardipine to prevent emergence postcraniotomy hypertension. A prospective, randomized open labeled clinical trial was designed to compare the incidence of breakthrough hypertension (systolic blood pressure [SBP] > 140 mm Hg) and adverse effects (hypotension, tachycardia, and bradycardia) between the two drug combinations. Secondarily, the effects of the drugs on SBP, mean blood pressure, and diastolic blood pressure were evaluated over the course of the study. Forty-two patients received enalaprilat 1.25 mg IV at dural closure followed by either multidose nicardipine 2 mg IV or labetalol 5 mg IV to maintain the SBP below 140 mm Hg. SBP was similarly controlled in both groups. There was a marginally smaller incidence of failures and adverse effects with labetalol. Blood pressure profiles were similar for both groups.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Aged; Analysis of Variance; Anesthesia Recovery Period; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Bradycardia; Brain Neoplasms; Calcium Channel Blockers; Chi-Square Distribution; Craniotomy; Enalaprilat; Female; Humans; Hypertension; Hypotension; Incidence; Labetalol; Male; Middle Aged; Nicardipine; Prospective Studies; Tachycardia; Treatment Outcome

The aim of the present study was to assess the possible differences in hemodynamic and neurohumoral responses to local ACE inhibition in the human forearm of patients with essential hypertension with either quinaprilat or enalaprilat. Forearm vascular responses to infusion of quinaprilat or enalaprilat (0.5 microg/dL/min) into the brachial artery were studied in 12 male patients with essential hypertension. The experiments were performed in a randomized, double-blind, crossover fashion. Before and during ACE inhibition, the vasoconstrictor response to four cumulative doses of angiotensin I (Ang I) was studied. Forearm blood flow was assessed using venous occlusion plethysmography. Local quinaprilat infusion induced a more rapid (even after 15 minutes; median vasodilation quinaprilat 29% vs. enalaprilat --1%, P < 0.02) and longer lasting forearm vasodilation as compared with enalaprilat. After 15 minutes of local ACE inhibition, the vasoconstrictor response to Ang I was completely blocked by both ACE inhibitors. We conclude that in patients with essential hypertension quinaprilat induces a more rapid and longer lasting vasodilatation than enalaprilat. These effects of quinaprilat are possibly related to its higher affinity for vascular ACE. On the other hand, the fact that these effects of quinaprilat were observed despite a similar degree of ACE inhibition as during enalaprilat may suggest that quinaprilat directly stimulates another vasodilatating mechanism.

Topics: Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Enalaprilat; Forearm; Heart Rate; Humans; Hypertension; Isoquinolines; Male; Middle Aged; Peptidyl-Dipeptidase A; Regional Blood Flow; Tetrahydroisoquinolines; Vasodilation

In a prospectively designed randomized study, we compared the efficacy of sublingual nitroglycerine and intravenous enalaprilat in the out-of-hospital treatment of 46 hypertensive patients with pulmonary edema (defined as rales over both lungs and systolic blood pressure > 200 mm Hg and diastolic blood pressure > 100 mg). The out-of-hospital treatment consists of oxygen (6 Ll/min) via a face mask, furosemide 80 mg i.v., opioids 10 mg s.c., and either sublingual nitroglycerine (n = 23; initial dose: 0.8 mg; repetitive application of 0.8 mg every 10 min until a cumulative dose of 3.2 mg) or intravenous enalaprilat (initial dose: 2.5 mg; repetitive application of 2.5 mg every 30 min until a cumulative dose of 10 mg). The aim of the antihypertensive treatment was a reduction of systolic blood pressure below 160 mm Hg and diastolic blood pressure below 90 mm Hg until admission to the emergency department. In the emergency room, an arterial and venous blood sample was taken to determine the respiratory (pO2, pCO2) and metabolic status (pH value; base-excess; serum lactate) of the patient. Successful antihypertensive treatment was observed in 13/23 (57%) patients of the enalaprilat group and 15/23 (65%) patients of the nitroglycerine group (p = 0.54). Systolic and diastolic blood pressure on admission were similar in both treatment groups (systolic RR: enalaprilat: 179 [31] mm Hg; nitroglycerine: 184 [38] mm Hg; p = 0.59; diastolic RR: enalaprilat: 96 [14] mm Hg; nitroglycerine: 101 [14] mm Hg; p = 0.12). No significant differences were observed between the enalaprilat and the nitroglycerine groups concerning respiratory and metabolic parameters on admission (pO2: 67 [15] vs. 64 [17] mm Hg; p = 0.50; pCO2: 46 [9] vs. 47 [13]; p = 0.75; pH value: 7.27 [0.12] vs. 7.27 [0.09]; p = 0.98; BE: -4.2 [3.7] vs. -5.7 [4.1]; p = 0.23; lactate: 4.2 [3.3] vs. 4.2 [2.7]; p = 0.98). Intravenous enalaprilat did not exhibit any advantage compared to nitroglycerine in terms of blood pressure reduction or respiratory and metabolic parameters on admission to the emergency room. We conclude that enalaprilat is no substitute for nitroglycerine in the out-of-hospital treatment of hypertensive patients with pulmonary edema.

Topics: Administration, Sublingual; Adult; Aged; Aged, 80 and over; Blood Pressure; Emergency Medical Services; Enalaprilat; Female; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Nitroglycerin; Oxygen; Prospective Studies; Pulmonary Edema; Treatment Outcome; Vasodilator Agents

Angiotensin-converting enzyme (ACE) inhibitors are well established as long-term antihypertensives and have also been proved useful in hypertensive emergencies. Therefore, we investigated whether intraoperative i.v. enalaprilat may reduce the incidence of perioperative hypertensive reactions in coronary artery bypass grafting (CABG).. Thirty-eight male patients chronically treated for arterial hypertension and scheduled for CABG randomly and double-blindly received either enalaprilat 30 micrograms.kg-1 or NaCl 0.9% at the time of skin incision. Intraoperatively, increases of mean arterial pressure (MAP) > 85 mmHg or > 80 mmHg during cardiopulmonary bypass (CPB) were treated by an urapidil bolus. The total intraoperative amount of urapidil was documented for both groups. Systemic and pulmonary hemodynamics as well as the plasma levels of epinephrine, norepinephrine, arginine vasopressin and renin were measured intraoperatively and up to 2 h after admission to the intensive care unit.. Mean arterial pressure, cardiac index and systemic vascular resistance did not differ between the enalaprilat and the control group. Renin plasma levels significantly increased after infusion of enalaprilat and did not change in the placebo group. Catecholamine and arginine vasopressin plasma levels increased significantly during CPB and remained high in the postoperative period without any intergroup difference. The same amount of urapidil had to be given in the two groups to maintain MAP below the defined limit.. We conclude that infusing 30 micrograms.kg-1 enalaprilat in patients chronically treated for arterial hypertension does not prevent hypertensive reactions during CABG.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Coronary Artery Bypass; Dopamine; Double-Blind Method; Enalaprilat; Female; Hemodynamics; Hormones; Humans; Hypertension; Injections, Intravenous; Intraoperative Period; Male; Middle Aged

The appropriate dose of intravenous enalaprilat to be used in the treatment of hypertensive crisis is controversial. There has been no comparative study of the efficacy and safety of different dosages of enalaprilat in hypertensive patients.. Sixty-five consecutive patients with hypertensive urgencies (systolic blood pressure > 210 mm Hg and/or diastolic blood pressure > 110 mm Hg) or emergencies (diastolic blood pressure > 100 mm Hg and evidence of end-organ damage, ie, angina pectoris, hypertensive encephalopathy, or congestive heart failure) admitted to an emergency department from January 1, 1994, to September 30, 1994, were identified. The patients were randomized to receive different doses of enalaprilat (0.625, 1.25, 2.5, and 5 mg). Response to treatment was defined as a stable reduction of systolic blood pressure to below 180 mm Hg and diastolic blood pressure to below 95 mm Hg within 45 minutes after the start of treatment and relief of symptoms in patients with hypertensive emergencies.. In 41 (63%) of 65 patients, the treatment goal was reached. Twenty-four patients (37%) failed to achieve the goal of treatment within 45 minutes after administration of enalaprilat. The response rates in the 0.625-mg, 1.25-mg, 2.5-mg, and 5-mg groups were 67%, 65%, 59%, and 62%, respectively. The proportion of patients initially randomized who responded to treatment was not different between any of the four groups of enalaprilat doses. There were no significant differences according to enalaprilat dose with respect to changes in systolic, diastolic, and mean arterial blood pressure. No severe side effects were observed.. Enalaprilat is a safe antihypertensive drug with moderate efficacy in the treatment of hypertensive crisis. As doses above 0.625 mg alter neither response rates nor the magnitude of blood pressure reduction, we recommend 0.625 mg as the initial dose in the treatment of hypertensive crisis.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Emergencies; Enalaprilat; Female; Humans; Hypertension; Injections, Intravenous; Male; Middle Aged; Time Factors

Twenty-four patients undergoing elective coronary artery bypass surgery were studied. Either the angiotensin-converting enzyme (ACE) inhibitor enalaprilat, 0.06 mg/kg, (n = 12), or saline solution (= control group; n = 12), was randomly and blindly administered intravenously when the mean arterial blood pressure (MAP) increased to 90 mmHg after induction of anesthesia. Cardiorespiratory parameters were studied before injection, during the subsequent 30 minutes, precardiopulmonary bypass (CPB), post-CPB, and at the end of surgery. MAP was significantly reduced 5 minutes after administration of enalaprilat. The peak reduction of blood pressure was observed after 30 minutes (from 98 +/- 4 to 68 +/- 8 mmHg). Even immediately before CPB (112 +/- 12 minutes after injection of enalaprilat), MAP and systemic vascular resistance were significantly lower than baseline values. Heart rate remained almost unchanged in both groups. Cardiac index increased slightly in the enalaprilat patients (maximum: +0.75 L/min/m2 20 minutes after injection). Filling pressures (central venous pressure, pulmonary capillary wedge pressure) were also significantly reduced by enalaprilat. There were no differences from the control patients with regard to changes in right ventricular hemodynamics (right ventricular ejection fraction, right ventricular end-diastolic volume, right ventricular end-systolic volume), pulmonary gas exchange (PaO2), or intrapulmonary right-to-left shunting (Qs/Qt). VO2 increased only in the enalaprilat patients (from 179 +/- 28 to 230 +/- 30 mL/min) (p < 0.05). Cardiorespiratory parameters did not differ between the two groups post-CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Pressure; Cardiac Output; Cardiac Volume; Cardiopulmonary Bypass; Central Venous Pressure; Coronary Artery Bypass; Elective Surgical Procedures; Enalaprilat; Heart; Heart Rate; Humans; Hypertension; Injections, Intravenous; Middle Aged; Oxygen Consumption; Placebos; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Respiration; Single-Blind Method; Stroke Volume; Vascular Resistance; Ventricular Function, Right

The efficacy of intravenous enalaprilat in lowering postoperative hypertension.. Prospective, randomized, controlled, single blind trial.. Surgical ICT in a university hospital (tertiary care center).. 18 neurosurgical patients subjected to the extirpation of a supratentorial intracerebral tumour were studied after detection of postoperative hypertension. This was defined as a constant elevation of systolic arterial pressure over 160 mmHg or diastolic arterial pressure over 95 mmHg.. Enalaprilat 0.015 mg kg-1 was injected within 5 min to 9 patients.. Central haemodynamics and systemic oxygenation were assessed at baseline before enalaprilat injection, and repeatedly during four hours after the injection. The statistical analysis was performed with analysis of variance for repeated measurements. As compared to control patients, the blood pressure lowering effect of enalaprilat became evident within 15 min and lasted for over four hours (p = 0.008). It was mainly due to the reduced systemic vascular resistance. Enalaprilat also induced a small decline in myocardial perfusion pressure. Cardiac performance, preload, heart rate and systemic oxygenation were not affected by enalaprilat.. We found intravenous enalaprilat effective and safe in lowering postoperative hypertension following neurosurgery as assessed by it's effects on central haemodynamics and systemic oxygenation.

Topics: Adult; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Cardiac Output; Enalaprilat; Female; Heart Function Tests; Hemodynamics; Humans; Hypertension; Middle Aged; Oxygen Consumption; Postoperative Complications; Prospective Studies; Single-Blind Method; Statistics, Nonparametric; Supratentorial Neoplasms

The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of administration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostaglandin E2 (PGE2), which are likely to be involved in the mechanism of enalapril-induced cough, might also be affected by its time of administration. Enalapril 5 mg or placebo was given orally at 10:00 h (day trial) or 22:00 h (night trial) to 12 patients with essential hypertension. Serum concentrations of total drug (enalapril + enalaprilat, its active metabolite) during the day and night trials did not differ significantly at any time. However, serum enalaprilat tended to be higher and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Remarkable increases in plasma BK were observed in two patients in the day trial and one of them also complained of cough. However, no such increase in plasma BK or subsequent adverse effect were recorded in the night trial. Plasma substance P and PGE2 did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected by the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect might be diminished or eliminated by a switch to night-time administration.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bradykinin; Cough; Dinoprostone; Enalapril; Enalaprilat; Female; Half-Life; Humans; Hypertension; Male; Middle Aged; Substance P

To evaluate the hormonal, blood pressure, and peritoneal transport effects of intraperitoneal enalaprilat and oral enalapril.. A nonrandomized, nonblinded, prospective clinical trial was performed.. The study was conducted at the Clinical Research Unit at the Medical College of Virginia, a tertiary care center.. Six continuous ambulatory peritoneal dialysis (CAPD) patients with hypertension were enrolled in the study. All 6 patients received intraperitoneal enalaprilat. Five of the patients also received oral enalapril.. Hormonal, clinical, and transport parameters were investigated in patients given intraperitoneal enalaprilat and oral enalapril. Standardized 2-L exchanges were performed during a control period, following 2.5 mg intraperitoneal enalaprilat and after a week of oral enalapril. Inulin, blood urea nitrogen (BUN) and creatinine clearances, and glucose absorption were determined during these exchanges.. After intraperitoneal enalaprilat, both systolic and diastolic blood pressure significantly declined, reaching maximal decreases of -21.7 +/- 14.2% at 95 +/- 92 minutes, and of -23.3 +/- 15.4% at 105 +/- 105 minutes, respectively. Plasma angiotensin converting enzyme (ACE) activity was suppressed below detectable limits at four hours following intraperitoneal enalaprilat, and remained suppressed throughout all sampling time points following oral enalapril treatment. There was no significant change in drain volumes, glucose absorption, or BUN, creatinine, or inulin clearances, whether enalaprilat was administered intraperitoneally or enalapril orally.. This study demonstrates that intraperitoneal administration of enalaprilat is a rapidly effective route of administration of this ACE inhibitor. There were no changes in peritoneal transport characteristics demonstrated.

Topics: Administration, Oral; Adult; Aldosterone; Biological Transport; Blood Pressure; Enalapril; Enalaprilat; Female; Humans; Hypertension; Male; Peptidyl-Dipeptidase A; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Prospective Studies; Renin

To determine the cardiopulmonary actions of the intravenous administration of the angiotensin-converting enzyme inhibitor enalaprilat in hypertensive trauma patients.. Prospective, before/after trial.. Intensive care unit (ICU) of a university hospital.. Twenty critically injured and hypertensive ICU patients. All patients were receiving continuous sedation (fentanyl and midazolam) for at least 2 days before the injection of enalaprilat and had a mean arterial pressure (MAP) of > 95 mm Hg. "Responders" were defined as having a decrease in MAP of > 15% within 30 mins after enalaprilat injection.. Intravenous administration of 0.06 mg/kg of the angiotensin-converting enzyme inhibitor enalaprilat. Repeated doses were given when no sufficient response (decrease of MAP of > 15% within 30 mins after injection) was seen ("nonresponders").. In addition to standard hemodynamic monitoring, right ventricular hemodynamics and oximetric variables were also documented. Measurements were carried out before enalaprilat injection (during hemodynamic steady state [baseline values]) and at 1, 5, 10, 20, 30, 60, and 120 mins after enalaprilat administration.. MAP was successfully controlled in 17 of 20 patients (maximum decrease -27 mm Hg [-26%]). In the three other patients, even reinjection of enalaprilat (0.06 mg/kg) did not sufficiently reduce MAP. In the 17 responders, heart rate did not increase, whereas central venous pressure, pulmonary arterial pressure, and pulmonary artery occlusion pressure decreased significantly after intravenous administration of enalaprilat. Cardiac index changed only slightly (mean maximum +0.70 L/min/m2 [+18%]). Right ventricular ejection fraction increased from 36% to 45% (p < .05); right ventricular end-diastolic and end-systolic volume index decreased significantly. Both systemic and pulmonary vascular resistance indices decreased within the investigation period (-31% and -16%, respectively). Pao2/FIO2, intrapulmonary right-to-left shunting, and oxygen extraction ratio were not altered. Oxygen delivery index (+17%) and oxygen consumption index (+20%) increased during the investigation period (p < .04).. The intravenous administration of enalaprilat successfully decreased blood pressure in most of our patients. Mechanisms other than the renin-angiotensin system also appear to be involved in hypertensive, critically ill patients. Pulmonary function was not altered; right ventricular function, and both oxygen consumption and oxygen delivery improved in the enalaprilat responder group. Thus, the availability of intravenous enalaprilat seems to enlarge our armamentarium for treating hypertension in the critically ill patient.

Topics: Acute Disease; Adult; Aged; Analysis of Variance; Enalaprilat; Female; Heart; Hemodynamics; Humans; Hypertension; Injections, Intravenous; Lung; Male; Middle Aged; Prospective Studies; Time Factors; Wounds and Injuries

The cardiovascular effects and pharmacokinetics of once-daily enalapril were studied after single-dose and subchronic treatment in eight patients with hypertension by use of ambulatory blood pressure monitoring. Enalapril, 10 mg, was given at either 7 AM or 7 PM in a randomized crossover design. In addition, inhibition of serum converting enzyme was studied. Subchronic treatment at 7 AM significantly reduced blood pressure during the day but was less effective at night. Subchronic dosing at 7 PM significantly further decreased nighttime blood pressure followed by a slow increase during the day, with no effect on elevated afternoon values. Peak concentrations of enalaprilat were found 3.5 hours (morning) and 5.6 hours (evening) after drug intake (p < 0.05), whereas peak effects occurred 7.4 hours (morning) and 12 hours (evening) after drug administration. In conclusion, 24-hour blood pressure profiles in patients with hypertension were significantly influenced by the time of enalapril dosing. Differences in effect profiles could not be attributed to similar changes in pharmacokinetics or to different time courses of angiotensin converting enzyme inhibition.

Topics: Adult; Blood Pressure; Cardiovascular System; Circadian Rhythm; Enalapril; Enalaprilat; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Time Factors

Hypertension is a major risk factor for the development of heart failure. Despite significant progress in our knowledge of the physiopathology of heart failure, the cause for decompensation in patients with left ventricular hypertrophy (LVH) is still obscure. The angiotensin converting enzyme inhibitor enalaprilat has been found to improve electromechanical coupling of heart cells in animal models. To assess the effects of enalaprilat on ventricular electromechanical coupling in humans, we studied the His bundle electrograms and hemodynamics in 22 hypertensive patients with LVH. Patients received either 2.5 mg enalaprilat or saline placebo intravenously in a double-blind protocol. There were no significant changes in heart rate, and atrioventricular and His-Purkinje conduction times. Ventricular activity duration was reduced from 110 +/- 11 msec to 88 +/- 13 msec after enalaprilat administration (P < .01). Enalaprilat decreased peak-systolic and end-diastolic left ventricular pressures, and arterial and pulmonary pressures, as well as pulmonary and systemic vascular resistances. End-systolic wall stress decreased 18% (P < .01), ejection fraction increased 11% (P < .01), and end-diastolic pressure-volume ratio decreased 50% (P < .001) after enalaprilat administration. There were no significant changes in these parameters after saline infusion. It is concluded that enalaprilat reduces ventricular activation duration and improves ventricular performance in hypertensive patients with LVH. Data suggest that enalaprilat significantly improves excitation-contraction coupling in these patients.

Topics: Action Potentials; Cardiac Catheterization; Double-Blind Method; Electrocardiography; Electrophysiology; Enalaprilat; Female; Heart Conduction System; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Myocardial Contraction; Prospective Studies; Ventricular Function, Left

In a randomized, cross-over, single-dose study of 19 elderly hypertensive patients (aged 62-84 y, SBP greater than 160 mmHg, DBP greater than 100 mmHg, creatinine clearance 11-93 ml.min-1) we have studied the pharmacokinetics of the angiotensin converting enzyme (ACE) inhibitor enalapril after a single oral dose of either 10 mg enalapril or 10 mg enalapril + 25 mg hydrochlorothiazide. The pharmacokinetics of enalapril were unaffected by hydrochlorothiazide, but there was a significant reduction in renal clearance and a significant increase in AUC(0-24 h) of enalaprilat after hydrochlorothiazide, resulting in higher serum concentrations of the active drug. This was independent of the individual degree of renal impairment and might be due either to an initial reduction of GFR by hydrochlorothiazide or to interference with the tubular secretion of enalaprilat. The relationships between serum enalaprilat and serum ACE activity were similar after both treatments, both consistent with a value for Ki of enalaprilat of about 0.1 nmol.l-1. Thus, serum ACE activity was not affected by hydrochlorothiazide but completely reflected the pharmacokinetics of enalaprilat in both treatments.

Topics: Administration, Oral; Aged; Aged, 80 and over; Blood Pressure; Creatinine; Enalapril; Enalaprilat; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Metabolic Clearance Rate; Middle Aged

Hypertensive patients with left ventricular hypertrophy (LVH) have increased prevalence of ventricular arrhythmias. Slow conduction velocity at the level of hypertrophic myocardial cells has been one of the postulated mechanisms for these arrhythmias. To assess the effects of angiotensin converting enzyme inhibition on modification in ventricular conduction velocities, we studied 25 hypertensive patients with LVH using signal averaged electrocardiography (SAECG) in a randomized double-blind placebo controlled and cross-over trial. Data were acquired at baseline and 10 min after a double-blind intravenous infusion of saline placebo or 2.5 mg enalaprilat. Sequential cross-over was done the next day. Root mean square vector was 55 +/- 5 microV at baseline, 55 +/- 5 microV after placebo and 54 +/- 4 microV after enalaprilat (P = NS). Low amplitude signal < 40 msec was 45 +/- 4 msec at baseline, 45 +/- 4 msec after placebo, and 43 +/- 4 msec after enalaprilat (P = NS). There was no change in filtered QRS (fQRS) duration between baseline (113 +/- 10 msec) and placebo (113 +/- 11 msec) measurements. However, after enalaprilat infusion, there was a significant reduction in fQRS to 106 +/- 7 msec (P = .04), and five patients (20%) with late potentials had normalization of this feature (P = .001). The data suggest that angiotensin converting enzyme inhibition with enalaprilat reduces conduction velocity delay in hypertensive patients with LVH.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Cell Communication; Double-Blind Method; Electrocardiography; Enalaprilat; Female; Heart; Heart Conduction System; Humans; Hypertension; Hypertrophy, Left Ventricular; Infusions, Intravenous; Male; Middle Aged; Myocardium; Peptidyl-Dipeptidase A

Our study attempted to evaluate the importance of changes in the circulating renin-angiotensin-aldosterone system (RAAS) and in hemodynamics in relation to observed changes in cardiovascular structure. We studied previously untreated men (n = 28) with essential nonmalignant hypertension and a supine casual diastolic blood pressure > 95 mm Hg on three to four separate (> 1-week interval) occasions measured in triplicate. We used intraarterial blood pressure, dye-dilution technique, plethysmography (hands), eye-ground photos, M-mode echocardiography, radio immunoassays, and multiple regression analysis. Patients were randomized to 6 months of double-blind treatment with either enalapril or hydrochlorothiazide, following 4 to 6 weeks on placebo. We found that enalapril blocked the plasma angiotensin converting enzyme (ACE) with a secondary increment in plasma renin activity (PRA) and reductions in angiotensin II (AII) and aldosterone. Blood pressure was lowered through a reduction in total peripheral resistance (TPR). Hydrochlorothiazide increased PRA, AII, and aldosterone, and lowered blood pressure mainly through a reduction in cardiac output. Enalapril was significantly more effective than hydrochlorothiazide in reversing structural changes in the retinal and hand vasculature as well as in the heart. A reduction in cardiac hypertrophy was seen even in the occasional enalapril-treated patient, in whom little or no reduction in blood pressure occurred. In the stepwise regression analyses, the changes in retinal and hand vascular structure were most strongly related to various changes in the RAAS, explaining 15 to 34% of the variance. For the changes in cardiac structure, the type of therapy (enalapril or hydrochlorothiazide) appeared to be the most important factor, explaining between 29 and 50% of the variance. The changes in cardiac structure were even more strongly related to changes in the RAAS for the enalapril treated patients and explained up to 55% of the variance in cardiac structure. It can be concluded that the reversal of structural vascular changes during antihypertensive therapy was more dependent on the blockade of the RAAS than on lowering of the blood pressure.

Topics: Blood Pressure; Cardiovascular System; Double-Blind Method; Electrocardiography; Enalaprilat; Hemodynamics; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Radioimmunoassay; Regression Analysis; Renin; Renin-Angiotensin System

To assess the vascular involvement of renin-angiotensin system inhibition in human hypertension, acute effects of intravenous enalaprilat on brachial artery diameter, blood flow, and blood velocity were investigated in hypertensive patients by pulsed Doppler technique and compared with effects of saline vehicle. Compared with saline vehicle, enalaprilat reduced blood pressure (P less than 0.001) and increased brachial arterial diameter (P less than 0.01) and brachial blood flow (P less than 0.01). Enalaprilat effect on arterial pulse pressure was dependent on preinjection pulse pressure (r = -0.76; P less than 0.001), but its effect on mean blood pressure was not dependent on preinjection mean blood pressure. On the other hand, enalaprilat effect on arterial blood flow was negatively correlated with preinjection blood pressure (r = -0.64; P less than 0.02). The findings point to different responses of large and small arteries to intravenous enalaprilat.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Brachial Artery; Double-Blind Method; Enalapril; Enalaprilat; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Random Allocation; Regional Blood Flow; Renin-Angiotensin System

This study was designed to assess whether the acute blood pressure response of an individual hypertensive patient to a calcium antagonist or an angiotensin converting enzyme (ACE) inhibitor is a good predictor of the long-term efficacy of these drug classes in this particular patient. The concept that good responses to ACE inhibitors and calcium antagonists may be mutually exclusive was also tested. Sixteen patients were included in a randomized crossover trial of enalapril, 20 mg daily, and diltiazem, 120 mg daily, for 6 weeks each. Blood pressure was measured by ambulatory blood pressure recording. During the washout phase, the acute effect of nifedipine, 10 mg p.o., and enalaprilat, 5 mg i.v., was evaluated. Nifedipine and enalaprilat reduced blood pressure equally well. The long-term blood pressure reduction induced by enalapril and diltiazem was similar. The acute blood pressure response to a given drug was not a good predictor of the result obtained with long-term therapy. No age dependency of the antihypertensive effect of either drug class was apparent. There was no evidence that a good response to one drug excluded a similarly good response to the other.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Diltiazem; Enalapril; Enalaprilat; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Random Allocation; Time Factors

The antihypertensive effect and tolerability of enalaprilat, an intravenously administered angiotensin converting enzyme inhibitor, was studied in 65 patients with moderate or severe hypertension. In this randomized, double-blind study, enalaprilat was compared with placebo in 42 (22 enalaprilat, 20 placebo) moderate hypertensive (diastolic blood pressure [BP] 100 to 114 mm Hg) patients. It was compared with furosemide in 23 (12 enalaprilat, 11 furosemide) severe hypertensive (diastolic BP 115 to 130 mm Hg) patients. Enalaprilat (1.25 or 5.0 mg), placebo (5% dextrose) or furosemide (40 or 80 mg) was given every 6 hours intravenously up to 48 hours. In the moderate hypertension stratum, the mean supine diastolic BP was significantly (p less than or equal to 0.01) reduced from baseline at all timepoints in the enalaprilat group. These diastolic BP reductions were significantly (p less than or equal to 0.01) greater in the enalaprilat group than the placebo at 1 to 24 hours (-12 vs -4 mm Hg), with 59% of the patients responding to enalaprilat compared with 30% of the patients responding to placebo. An even greater reduction (p less than or equal to 0.01) was seen at 25 to 48 hours (-14 vs -7 mm Hg, with 73% enalaprilat vs 58% placebo responders). Significant (p less than or equal to 0.01) reductions in mean, supine systolic BP were also seen at 1 to 24 hours (-22 vs -2 mm Hg) and 25 to 48 hours (-24 vs -8 mm Hg) during the 48 hours of the double-blind treatment phase in the enalaprilat group compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antihypertensive Agents; Double-Blind Method; Enalapril; Enalaprilat; Female; Furosemide; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Multicenter Studies as Topic; Placebos; Random Allocation

The hormonal and hypotensive effects of a single oral 10 mg dose of enalapril (MK-421), were assessed by a double-blind randomized trial in 12 subjects with essential hypertension, during a 100 and 40 mmol/day sodium intake. Peak serum MK-421 appeared 1 h following oral dosage. The bioactive conversion product of MK-421 (the parent diacid MK-422) appeared later, was maximal 4 h following dosage, and was still detectable 24 and 32 h later. Serum angiotensin-converting enzyme (ACE) activity was inhibited maximally at 4 h (by 57 +/- 4% of control activity) and had a similar time course to the serum MK-422 level. Plasma angiotensin II and aldosterone fell during ACE inhibition, but no change in bradykinin was detected. Reciprocal rises in plasma renin and angiotensin I occurred with a similar time course to ACE inhibition. Sodium depletion did not alter drug levels, basal serum ACE nor the time course of its inhibition. The initial blood pressure was however significantly lower when the subjects had been on the 40 mmol/day sodium diet. Blood pressure fell in all subjects and the fall was maximal 4-8 h following MK-421. There was a close correlation between plasma drug level, ACE inhibition and the hypotensive effect. These results suggest that regardless of the final mechanism for the antihypertensive action of MK-421 it is a consequence of its inhibition of ACE.

Topics: Adult; Aged; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Clinical Trials as Topic; Diet, Sodium-Restricted; Dipeptides; Double-Blind Method; Enalapril; Enalaprilat; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Random Allocation; Renin; Sodium

The renal effects of the new angiotensin converting enzyme inhibitor enalapril (MK-421) and of its active metabolite MK-422, were investigated in patients with essential hypertension. Together with a reduction in blood pressure, renal blood flow increased after intravenous injection of MK-422. Glomerular filtration as well as fractional sodium excretion increased. The latter was explained by the inhibition of both proximal and distal tubular sodium reabsorption. During oral enalapril therapy renal blood flow remained elevated, whereas glomerular filtration did not differ significantly from pretreatment values. Body weight fell after 12 weeks of therapy, a possible consequence of the 'diuretic' effect of enalapril which may contribute to the antihypertensive action of the drug. In conclusion, enalapril had either no, or even beneficial, effects on renal function.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Electrolytes; Enalapril; Enalaprilat; Glomerular Filtration Rate; Humans; Hypertension; Injections, Intravenous; Kidney; Renal Circulation

Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS, respectively. After 3 weeks, MAP was -10.9 ± 2.1 mmHg lower in RD BPH/2J compared to baseline and -2.1 ± 2.2 mmHg in sham BPH/2J (P < 0.001, n = 8-10). RD had no effect in BPN/3J (P > 0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J, but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (-12 vs -3 mmHg, P < 0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice as RD induced a sustained fall in MAP, which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved.

Topics: Animals; Antihypertensive Agents; Arterial Pressure; Denervation; Enalaprilat; Exercise Test; Hypertension; Kidney; Male; Mice; Mice, Inbred Strains; Pentolinium Tartrate; Peripheral Nerves; Pressoreceptors; Renin-Angiotensin System; Sympathetic Nervous System; Telemetry

The renin-angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5μg/h) or vehicle for 4weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy.

Topics: Angiotensin II; Animals; Cardiomegaly; Chemokine CCL2; Enalaprilat; gamma-Aminobutyric Acid; Glutamic Acid; Heart; Hypertension; Interleukin-10; Interleukin-1beta; Interleukin-6; Kidney; Losartan; Male; Neurotransmitter Agents; Norepinephrine; Organ Size; Paraventricular Hypothalamic Nucleus; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Reninomas are rare juxtaglomerular tumours which can cause severe hypertension and hypokalaemia. Diagnosis can be problematic and these tumours can be difficult to locate on imaging. In this report we aim to demonstrate the value of carefully performed renal vein renin ratios (RVRRs) to assist in locating these tumours.. We report on 3 patients diagnosed with reninoma in our unit. The patients were all female, young (17, 16 and 30 years), severely hypertensive and hypokalaemic (2.5, 2.5 and 3.1 mmol/l). Plasma renin activity (PRA) was elevated (31.9, 274 and 175 ng/ml/h), and aldosterone was high-normal (19.9 ng/dl) or elevated (207 and 109.3 ng/dl). Renal artery stenosis was excluded by renal artery Doppler, DTPA scan and angiography. Renal CT detected the lesion in 2 patients, with one lesion visible on pre- and post-contrast CT and the other on post-contrast CT only. RVRRs were performed several weeks after withdrawing interfering medications, maintaining a <40 mmol/day low-sodium diet and maintaining recumbency overnight the night before and during the procedure. Ratios before and after captopril or enalaprilat administration were obtained and lateralised the tumours in all 3 cases (dominant/non-dominant ratios of 2.3, 4.3 and 3.8). All of the patients underwent nephrectomy yielding a typical juxtaglomerular tumour and resulting in cure of hypertension and hypokalaemia.. Reninoma should be suspected in young hypertensives (especially females) with significant hypokalaemia and high PRA or direct renin concentration after renovascular hypertension has been excluded. CT imaging and carefully performed RVRRs provide the highest likelihood of locating these tumours.

Topics: Adolescent; Adult; Aldosterone; Antihypertensive Agents; Captopril; Enalaprilat; Female; Humans; Hypertension; Hypokalemia; Kidney Glomerulus; Kidney Neoplasms; Neoplasms; Nephrectomy; Renal Artery; Renal Veins; Renin; Tomography, X-Ray Computed; Ultrasonography, Doppler

BPH/2J mice are recognized as a neurogenic model of hypertension primarily based on overactivity of the sympathetic nervous system and greater neuronal activity in key autonomic cardiovascular regulatory brain regions. The medial amygdala (MeAm) is a forebrain region that integrates the autonomic response to stress and is the only region found to have greater Fos during the night and daytime in BPH/2J compared with BPN/3J mice. To determine the contribution of the MeAm to hypertension, the effect of neuronal ablation on blood pressure (BP) was assessed in BPH/2J (n=7) and normotensive BPN/3J mice (n=7). Mice were preimplanted with radiotelemetry devices to measure 24-hour BP and cardiovascular responses to stress, before and 1 to 3 weeks after bilateral lesions of the MeAm. Baseline BP was 121±4 mm Hg in BPH/2J and 101±2 mm Hg in BPN/3J mice (Pstrain<0.001). MeAm lesions reduced BP by 11±2 mm Hg in BPH/2J mice (Plesion<0.001) but had no effect in BPN/3J mice. The hypotensive effect of lesions in BPH/2J mice was similar during both day and night, suggesting that the MeAm has tonic effects on BP, but the pressor response to stress was maintained in both strains. Midfrequency BP power was attenuated in both strains (Plesion<0.05) and the depressor responses to pentolinium after enalaprilat pretreatment was attenuated after lesions in BPH/2J mice (Plesion<0.001; n=3). These findings indicate that the MeAm provides a tonic contribution to hypertension in BPH/2J mice, which is independent of its role in stress reactivity or circadian BP influences.

Topics: Amygdala; Animals; Blood Pressure; Circadian Rhythm; Disease Models, Animal; Enalaprilat; Hypertension; Male; Mice; Mice, Mutant Strains; Pentolinium Tartrate; Sympathetic Nervous System; Telemetry

Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the renin-angiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg i.p.) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg i.p.) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2J mice had greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules. Although there is a major sympathetic contribution to hypertension in BPH/2J mice, the renin-angiotensin system also contributes, doing so to a greater extent during the active period and less during the inactive period. This is the opposite of the normal renin-angiotensin system circadian pattern. We suggest that renal hyperinnervation and enhanced sympathetically induced renin synthesis mediated by lower micro-RNA-181a contributes to hypertension in BPH/2J mice.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalaprilat; Heart Rate; Hypertension; Mice; MicroRNAs; Motor Activity; Nicotinic Antagonists; Pentolinium Tartrate; Renin; Renin-Angiotensin System; Sympathetic Nervous System

Angiotensin-converting enzyme inhibitors (ACEi) may downregulate matrix metalloproteinases (MMPs). We examined whether enalapril affects MMP-2, MMP-8, and MMP-9 levels and activity, and their endogenous inhibitors (tissue inhibitors of MMPs, TIMP-1 and TIMP-2) levels in hypertensive patients. Moreover, we assessed the effects of enalaprilat on MMP-9 and TIMP-1 secretion by human endothelial cells (HUVECs).. Thirty-eight hypertensive patients received enalapril for 8 weeks and were compared with thirty-eight normotensive controls. Blood samples were collected at baseline and after treatment. Plasma ACE activity was determined by a fluorimetric assay. Plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 were measured by ELISA and gelatin zymography. A fluorogenic peptide cleavage assay was used to measure MMP activity. HUVECs cells were stimulated by phorbol-12-myristate-13-acetate (PMA) and the effects of enalaprilat (10(-10) to 10(-6) M) on MMP-9 and TIMP-1 levels were determined.. Enalapril decreased blood pressure and ACE activity in hypertensive patients (P < 0.05), but had no effects on plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 levels, or MMP activity. Enalaprilat had no effects on PMA-induced increases in MMP-9 and TIMP-1 secretion by HUVECs or on MMP activity.. We show consistent evidence, both in vivo and in vitro, that enalapril does not affect MMPs and TIMPs levels in hypertensive patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cell Line; Enalapril; Enalaprilat; Female; Humans; Hypertension; Male; Matrix Metalloproteinases; Tissue Inhibitor of Metalloproteinases

Enalapril maleate, available on the market in a variety of different pharmaceutical formulations, is commonly used for the control of systemic arterial hypertension. Many therapeutical failures have been reported thus far in clinical practice with respect to switching between different pharmaceutical formulations of the same product during pharmacological therapy. In the present study, plasma concentrations of enalapril and enalaprilate were measured in hypertensive patients undergoing treatment with different pharmaceutical formulations.. Pharmaceutical formulations studied included the reference brand product, a generic formulation, and a third drug product marketed as "similar"; plasma samples were obtained from 30 hypertensive volunteer patients. Drug was extracted from the plasma by solid phase extraction and determined by liquid chromatography-tandem mass spectrometry. The method was validated for the main analytical parameters.. The analytical method developed in this study, using liquid chromatography-tandem mass spectrometry, was confirmed as suitable for application in the determination of plasma concentrations in patients and subsequently revealed statistically significant differences in plasma concentrations between the 3 treatment groups.. Such differences reinforce the hypothesis that the bioequivalence tests currently proposed by the regulatory authorities to promote interchangeability between pharmaceutical formulations may not in fact represent a definitive parameter for guaranteeing similar plasma concentrations.

Topics: Angiotensin-Converting Enzyme Inhibitors; Calibration; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Enalapril; Enalaprilat; Humans; Hypertension; Limit of Detection; Reproducibility of Results; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Therapeutic Equivalency

Drug induced acute parotitis is a very uncommon complication reported with a few drugs only. There is no case of acute bilateral parotitis reported previously with i.v. enalaprilat. We present here a female patient who developed acute bilateral parotitis within minutes of i.v. enalaprilat injection and recovered within 24 hours of stopping the drug and with symptomatic treatment.

Topics: Adult; Antihypertensive Agents; Enalaprilat; Female; Humans; Hypertension; Parotitis

Intrauterine programming of hypertension is associated with evidence of increased renin-angiotensin system (RAS) activity. The current study was undertaken to investigate whether arterial baroreflex and blood pressure variability are altered in a model of in utero programming of hypertension secondary to isocaloric protein deprivation and whether activation of the RAS plays a role in this alteration. Pregnant Wistar rats were fed a normal-protein (18%) or low-protein (9%) diet during gestation, which had no effect on litter size, birth weight, or pup survival. Mean arterial blood pressure (MABP; 126 +/- 3 mm Hg 9% versus 108 +/- 4 mm Hg 18%; p < 0.05) and blood pressure variability were significantly greater in the adult offspring of the 9% protein-fed mothers. Arterial baroreflex control of heart rate, generated by graded i.v. infusion of phenylephrine and nitroprusside, was significantly shifted toward higher pressure; i.v. angiotensin-converting enzyme inhibitor normalized MABP and shifted the arterial baroreflex curve of the 9% offspring toward lower pressure without affecting the 18% offspring. For examining whether brain RAS is also involved in programming of hypertension, angiotensin-converting enzyme inhibitor and losartan (specific AT(1) receptor antagonist) were administered intracerebroventricularly; both significantly reduced MABP of the 9% but not the 18% offspring. Autoradiographic receptor binding studies demonstrated an increase in brain AT(1) expression in the subfornical organ and the vascular organ of the lamina terminalis in the 9% offspring. These data demonstrate a major tonic role of brain and peripheral RAS on hypertension associated with antenatal nutrient deprivation.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Blood Pressure; Brain; Dietary Proteins; Enalaprilat; Female; Fetus; Hypertension; Male; Pregnancy; Protein Deficiency; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

The existence of tubulointerstitial damage in most cases of progressive human glomerular disease suggests that this compartment of the kidney is likely to be targeted by renoprotective agents which slow the progression of disease. Angiotensin-converting enzyme (ACE) inhibitors have become the cornerstone of renal protection. Since we have proposed that perturbation of the interstitial capillary circulation with consequent chronic hypoxia could be critical to the progressive nature of many renal diseases, we developed a dynamic method of measuring renal cortical pO(2) and sought to determine whether agents which block the renal effects of angiotensin II (AII) could affect interstitial microvascular oxygenation in the normal rat kidney.. Instrumented, anaesthetised adult male Sprague-Dawley rats were studied. Cortical microvascular pO(2 )was measured on the surface of the exposed kidney using protoporphyrin phosphorescence. Blood pressure and renal artery blood flow (Doppler flowmetry) were measured concurrently over a 180-min experimental period. Animals received non-hypotensive doses of enalaprilat (100 microg/kg i.v.) or candesartan (40 microg/kg i.v.) either at the beginning of the experimental period or after an initial decline in cortical microvascular pO(2).. After a 30-min stabilisation period there was a slow decline in pO(2 )from 48.6 +/- 4.1 to 38.5 +/- 6.9 mm Hg in control animals over the 180-min experimental period. Administration of the ACE inhibitor, enalaprilat at the beginning of the experimental period, completely abrogated this decline and protected pO(2) levels throughout this period with no effect on blood pressure or renal blood flow. In separate experiments, administration of enalaprilat after microvascular pO(2) had fallen by 5 mm Hg, resulted in a rise in RBF and pO(2 )within 15 min with pO(2) remaining elevated for up to 60 min post-injection. The angiotensin II AT(1) receptor antagonist, candesartan, had a similar effect to enalaprilat, inducing a rapid and sustained elevation in cortical pO(2).. These studies indicate that blockade of AII raises pO(2 )in the interstitial microvascular compartment of the normal rat kidney. This effect may contribute to the renoprotective action of ACE inhibitors and AII receptor antagonists in slowing the progression of chronic renal diseases.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Enalaprilat; Hypertension; Hypoxia; Kidney Cortex; Male; Microcirculation; Oxygen; Oxygen Consumption; Partial Pressure; Pilot Projects; Porphyrins; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Tetrazoles

Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102 +/- 2 to 181 +/- 12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189 +/- 3 mm Hg) or omapatrilat (184 +/- 8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6 +/- 0.2 vs. 0.5 +/- 0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9 +/- 0.4 pmol/day) compared to enalapril-treated (1.6 +/- 0.2 pmol/day) or untreated (1.5 +/- 0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Desoxycorticosterone; Drinking; Eating; Enalaprilat; Endothelin Receptor Antagonists; Endothelins; Hypertension; Kidney; Male; Protease Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; Sodium; Thiazepines

Abnormalities of nitric oxide (NO) and oxygen radical synthesis and of oxygen consumption have been described in the spontaneously hypertensive rat (SHR) and may contribute to the pathogenesis of hypertension. NO plays a role in the regulation of renal oxygen consumption in normal kidney, so the response of renal cortical oxygen consumption to stimulators of NO production before and after the addition of the superoxide scavenging agent tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) was studied. Baseline cortical oxygen consumption was similar in SHR and Wistar-Kyoto (WKY) rats (SHR: 600 +/- 55 nmol O(2)/min per g, WKY: 611 +/- 51 nmol O(2)/min per g, P > 0.05). Addition of bradykinin, enalaprilat, and amlodipine decreased oxygen consumption significantly less in SHR than WKY (SHR: bradykinin -13.9 +/- 1.9%, enalaprilat -15.3 +/- 1.6%, amlodipine -11.9 +/- 0.7%; WKY: bradykinin -22.8 +/- 1.0%, enalaprilat -24.1 +/- 2.0%, amlodipine -20.7 +/- 2.3%; P < 0.05), consistent with less NO effect in SHR. Addition of tempol reversed the defects in responsiveness to enalaprilat and amlodipine, suggesting that inactivation of NO by superoxide contributes to decreased NO availability. The response to an NO donor was similar in both groups and was unaffected by the addition of tempol. These results demonstrate that NO availability in the kidney is decreased in SHR, resulting in increased oxygen consumption. This effect is due to enhanced production of superoxide in SHR. By lowering intrarenal oxygen levels, reduced NO may contribute to susceptibility to injury and renal fibrosis. Increasing NO production, decreasing oxidant stress, or both might prevent these changes by improving renal oxygenation.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cyclic N-Oxides; Enalaprilat; Free Radical Scavengers; Hypertension; Kidney; Kidney Cortex; Nitric Oxide Donors; Oxygen Consumption; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; S-Nitroso-N-Acetylpenicillamine; Spin Labels

The aim of the study was to investigate if hypertension affects pancreatic islet blood flow and endocrine function. For this purpose, spontaneously hypertensive rats (SHR) were compared with normotensive control Wistar-Kyoto rats (WKY). Both islet size and islet cell replication in 4-month-old SHR was increased compared with WKY. The (pro)insulin biosynthesis was reduced in islets isolated from SHR, whereas the insulin content was unchanged. A hyperinsulinemic response to glucose in vivo was observed in 4- and 12-month-old SHR. Pancreatic blood flow, measured using a microsphere technique, was lower in SHR than in WKY in rats aged 5 weeks, 4 months or 1 year. Islet blood flow was lower in 4-month-old and 1-year-old SHR. In 4-month-old animals, islet blood flow was unaffected by administration of enalaprilate and prazosin in both strains, but was markedly decreased by the administration of N(G)-methyl-L-arginine. It was concluded that the islets of SHR have a decreased insulin production in vitro and a decreased islet blood perfusion. The reasons for this are likely to be multifactorial. Because SHR maintained an essentially normal glucose tolerance, an adaptation of the beta-cells to the metabolic and hemodynamic changes imposed by hypertension occurred.

Topics: Adrenergic alpha-Antagonists; Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; DNA; Enalaprilat; Enzyme Inhibitors; Hypertension; In Vitro Techniques; Insulin; Islets of Langerhans; omega-N-Methylarginine; Prazosin; Rats; Rats, Inbred SHR; Rats, Inbred WKY

We report an 11-year-old boy with hypertension and chronic intestinal pseudo-obstruction, which renders him totally dependent on parenteral nutrition and prevents the use of oral medications. Here we report the feasibility of utilizing chronic i.v. enalaprilat and transdermal clonidine on a chronic basis to control hypertension. Over the last 10 months, the patient's hypertension has been well controlled by 1.25 mg i.v. enalaprilat every 8 h and a 0.2-mg clonidine patch every 6 days, with no apparent side-effects. There are no reports of i.v. enalaprilat usage exceeding 3 weeks' duration. Therefore we believe that it is possible to effect reasonable management of chronic hypertension with the use of chronic i.v. enalaprilat and transdermal clonidine therapy.

Topics: Administration, Cutaneous; Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Clonidine; Drug Therapy, Combination; Enalaprilat; Feasibility Studies; Humans; Hypertension; Injections, Intravenous; Intestinal Pseudo-Obstruction; Male; Parenteral Nutrition

Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First-dose and steady-state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first-dose and steady-state AUCs, the accumulation of enalaprilat in children ranged from 1.13- to 1.45-fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half-life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.

Topics: Adolescent; Analysis of Variance; Antihypertensive Agents; Area Under Curve; Child; Child, Preschool; Confidence Intervals; Enalapril; Enalaprilat; Female; Humans; Hypertension; Infant; Male

The aim of this study was to assess the sigmoid line of elasticity in the human aorta.. The pressure-diameter relation was measured in the descending aorta in 120 subjects. In an additional group of 6 subjects, transient vena caval occlusion produced 5 sets of pressure-diameter data. We found that the best fit curve of the pooled pressure-diameter data was a third-order polynomial. A polynomial equation was used to calculate the sigmoid line of elasticity in the entire population and after the administration of diltiazem (15 patients) or enalaprilat (10 patients). The sigmoid line of elasticity was significantly different with respect to age (P<0.001), history of hypertension (P<0.004), and hypercholesterolemia (P<0.02). The difference between the transition point and the peak systolic pressure was increased in normal subjects compared with patients (P<0.0001). The sigmoid line shifted leftward and upward with diltiazem, but it remained unchanged with enalaprilat. During an average of 3 years of follow-up, 19 of 88 patients developed stroke (n=4), unstable angina (n=8), acute myocardial infarction (n=4), or acute pulmonary edema (n=3).. This approach provides a quantitative evaluation of the aortic line of elasticity, which can differentiate the intrinsic from the extrinsic aortic elastic properties. Furthermore, it is a powerful and independent risk factor for cardiovascular events.

Topics: Aorta; Blood Pressure; Coronary Disease; Data Interpretation, Statistical; Diltiazem; Elasticity; Enalaprilat; Heart Failure; Humans; Hypertension; Regression Analysis; Risk Factors; Vasodilator Agents

In this study we investigated whether timed administration of drugs that inhibit the renin-angiotensin system can be used to blunt the rise in blood pressure that occurs during the transition from the resting to the active period of the day. For this purpose we compared in spontaneously hypertensive rats (SHR) the antihypertensive efficacy of the angiotensin converting enzyme (ACE) inhibitors captopril (doses: 3, 10, and 30 mg/ kg/6 h) and enalaprilat (0.3 mg/kg/6 h), and the AT1-receptor antagonist losartan (10 mg/kg/6 h) at two different treatment regimens. The antihypertensive drugs were given as a continuous 6-h infusion either during the transition from the dark to light period (DL) or that from the light to dark period (LD) for 5 consecutive days. For all agents, the average 24-h reduction of blood pressure was comparable for the LD or DL treatment regimen. However, the dynamics of the antihypertensive response were markedly different. The increase in blood pressure at awakening could be blunted much more effectively by the LD than DL treatment regimen. Furthermore, as indicated by the trough:peak ratios, blood pressure profiles were flatter with the LD than with the DL regimen. Thus, in SHR, 24-h rhythms of blood pressure can be modulated by timed administration of ACE inhibitors and losartan, such that the early morning rise in blood pressure is suppressed.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Chronotherapy; Enalaprilat; Hypertension; Infusions, Intravenous; Losartan; Male; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System

Nitric oxide and angiotensin II have been shown to attenuate cardiac beta-adrenergic inotropism.. To study sympathetic presynaptic and post-synaptic functions after chronic nitric oxide synthesis blockade with NG-nitro-L-arginine-methyl-ester (L-NAME, for 40 days) in association with renin-angiotensin system blockade (during the last 12 days) in order to evaluate the possible physiological interactions between these systems.. Haemodynamic parameters in conscious rats were assessed. Release of noradrenaline from isolated atria and cardiac beta-adrenergic-adenylyl cyclase pathway in rats of sham-treated and L-NAME-treated groups, with or without losartan or enalaprilat treatment, were assessed.. L-NAME-treated rats developed a time-dependent increase in blood pressure associated with increased plasma adrenaline levels whereas plasma noradrenaline and cardiac catecholamine levels were similar to those in sham-treated rats. Field-stimulated release of noradrenaline, cardiac beta-adrenoceptor density and affinity and isoproterenol-stimulated formation of cyclic AMP were similar in sham and L-NAME-treated rats. However, Gpp(NH)p, NaF and forskolin-stimulated adenylyl cyclase activity were greater in L-NAME rats although Gs and Gi protein levels were similar in sham-treated and L-NAME-treated rats. Losartan and enalaprilat treatments exerted equipotent angiotensin-pressor response blockade and hypotensive effects whereas catecholamine levels were not altered. Interestingly, only losartan treatment acted to reduce the increased Gs-adenylyl cyclase activity in L-NAME rats, without alteration of G protein levels.. The nitric oxide synthase blockade-induced hypertension seems to be associated with increased adrenal-medullary system and renin-angiotensin system activities. The increased Gs-adenylyl cyclase activity after chronic inhibition of formation of nitric oxide suggests that nitric oxide plays a modulatory role in formation of cyclic AMP, to which angiotensin II seems to contribute through an angiotensin II type 1 receptor-mediated mechanism.

Topics: Adenylyl Cyclases; Animals; Antihypertensive Agents; Enalaprilat; Enzyme Inhibitors; Epinephrine; GTP-Binding Proteins; Heart; Hemodynamics; Hypertension; In Vitro Techniques; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Norepinephrine; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Renin-Angiotensin System; Sympathetic Nervous System

The purpose of this study was to study the effect of the angiotensin-converting enzyme inhibitor, enalaprilat, on blood pressure and splanchnic perfusion after cardiac surgery.. Sixteen patients were studied after coronary artery bypass grafting. After admission to the intensive care unit, a 30-minute baseline measurement of systemic hemodynamics, oxygen transport, and gastric tonometry was performed. In 6 of 10 patients receiving enalaprilat and in each of 6 control patients, regional (splanchnic and leg) blood flows were measured also. After the baseline measurement period, 10 patients received a 0.5 mg bolus of enalaprilat and thereafter an incremental infusion of enalaprilat up to a total dose of 10 mg (mean 8.3; range 4 to 10 mg) was continued to reduce the mean arterial pressure (MAP) to 70 to 80 mm Hg. A 30-minute measurement period was repeated 2 to 3 hours after the first measurement period. In the control group, the second measurement was performed at corresponding time points.. Though MAP decreased in the enalaprilat group (enalaprilat 99 +/- 14 mm Hg v 89 +/- 21 mm Hg, P < .05; control 95 +/- 13 mm Hg v82 +/- 10 mm Hg, P = NS) in only 4 of 10 patients was the targeted MAP reduction achieved. No significant changes were observed either in systemic or regional blood flows. Systemic, pulmonary, and femoral vascular resistance indices decreased significantly in both groups. Gastric-arterial PCO2 difference did not change in either groups. Angiotensin-converting enzyme activity decreased in the enalaprilat group (10.0 +/- 2.3 v 1.3 +/- 0.3 U x l(-1), P < .01), but plasma renin and endothelin-1 concentrations did not change in either group.. The effect of enalaprilat on blood pressure was poor and it had no beneficial effects on splanchnic circulation. Renin-angiotensin activation is not a major factor in hypertension and splanchnic perfusion after cardiac surgery.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Coronary Artery Bypass; Critical Care; Dose-Response Relationship, Drug; Drug Administration Schedule; Enalaprilat; Female; Gastric Mucosa; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Monitoring, Physiologic; Postoperative Complications; Splanchnic Circulation; Vascular Resistance

The pump function during exercise can be disturbed not only in hypertensives with coronary artery disease (CAD), but also in those with a normal angiogram.. In 10 hypertensive patients (group 1; aged 52+/-4 years, 1 men, 9 women) with ST segment depression during exercise and concomitant angina pectoris but normal coronary angiograms (microangiopathy) and without left ventricular hypertrophy (LVMI <110 g/m2), the left ventricular function at rest and during exercise was studied by cardiac catheterization and compared with 10 hypertensives with CAD (group 2; aged 57.6+/-4 years, 7 men, 3 women) and 10 hypertensives without ST segment depression (group 3; aged 51.8+/-5 years, 10 men) before and after intravenous administration of 1.25 mg enalaprilat.. The pulmonary capillary wedge pressure (PCWP) was normal at rest and pathologically increased at 60+/-13 W only in groups 1 and 2 (27.2+/-3 and 32.2+/-8 mm Hg, respectively), but not in group 3 (12.2+/-4 mm Hg; p<0.001). At the identical load level, the PCWP in patients with microangiopathy (group 1) was significantly (p<0.01) reduced after enalaprilat (-21.7%) and even normalized in 5 of 10 patients. This was accompanied by a significant (p>0.01) decrease in ST segment depression (-73.9%) and in the occurrence of angina pectoris, despite the fact that the rate-pressure product as a measure of myocardial oxygen consumption was significantly (p<0.05) increased. Also in patients with CAD enalaprilat had a significant effect on PCWP (p<0.01), ST segment depression (p<0.01), occurrence of angina pectoris (p<0.001), cardiac index (p<0.05), and stroke index (p<0.05) during exercise. In group 3 there were no significant changes in PCWP, cardiac index, and stroke index after enalaprilat either at rest or during exercise.. The functional improvement under the action of enalaprilat suggests that the advantages of the drug may be mediated mainly through an increase in myocardial blood flow and that angiotensin II might be involved in the restricted increase in coronary blood flow during dynamic exercise in hypertensives with coronary microangiopathy.

Topics: Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Coronary Disease; Enalaprilat; Exercise Test; Female; Hemodynamics; Humans; Hypertension; Male; Microcirculation; Middle Aged; Ventricular Dysfunction, Left

The purpose of the study was to evalute the impact of the renin-angiotensin-aldosterone (RAA) system on blood pressure (BP) response in patients with hypertensive emergencies and urgencies treated with intravenous enalaprilat. Thirty-five patients with a systolic BP (SBP) >210 mm Hg and/or diastolic BP (DBP) >110 mm Hg received 5 mg enalaprilat intravenously. The extent of systolic and DBP reduction was correlated with pretreatment concentrations of angiotensin II (ANGII) (SBP: r = -0.47; P = 0.006; DBP: r = -0.55; P = 0.001) and plasma renin activity (PRA) (SBP: r = -0.49; P = 0.003; DBP: r = 0.48; P = 0.007). Non-responders to enalaprilat exhibited significant lower pretreatment levels of PRA, angiotensin-converting enzyme (ACE) and ANG II compared to responders (PRA: 5.5 +/- 3.7 vs 1.1 +/- 2.2 ng/ml/h, P < 0.001; ACE: 12.8 +/- 3.5 vs 8.2 +/- 4.8 U/l, P = 0.003; ANG 11:8.7 +/- 6.2 vs 5.0 +/- 3.8 pg/ml, P = 0.04). In patients with severe hypotension following application of enalaprilat ANG II concentrations were significantly higher compared to patients with mean arterial BP reduction <25% (12.3 +/- 6.7 vs 5.6 +/- 4.0 pg/ml,P = 0.013). These data indicate that PRA and ANG II are the major determinants for BP response to enalaprilat. This relation between BP response and RAA system activity have important clinical implications for the treatment of patients with severe hypertension. Primary therapeutic failure indicates that the RAA system contributes very little to the hypertensive status of the patient. Thus, repetitive application on an ACE inhibitor in primary responders is clinically unhelpful and may result in an unnecessary delay of an effective BP reduction. In contrast, high ANG II concentrations are associated with a considerable risk for severe hypotension after enolanalaprilat application. Therefore, the status of the RAA system determines the efficacy as well as the safety of ACE inhibitor treatment in patients with severe hypertension.

Topics: Adult; Aged; Aged, 80 and over; Aldosterone; Blood Pressure; Emergencies; Enalaprilat; Female; Humans; Hypertension; Hypotension; Injections, Intravenous; Male; Middle Aged; Peptidyl-Dipeptidase A; Prospective Studies; Renin; Renin-Angiotensin System; Treatment Failure

As interactions between the renin-angiotensin and sympathetic nervous systems have been suggested in the pathogenesis of hypertension, we wanted to investigate the effect of chronic renin-angiotensin blockade with losartan and enalaprilat on the sympathetic reactivity to hypotension and on the cardiac beta-adrenergic-coupled adenylyl cyclase pathway in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Both treatments, exerting equipotent shifts of angiotensin-pressure responses, lowered blood pressure and attenuated cardiac hypertrophy similarly in SHR. The nitroprusside-induced hypotension was similar in both strains, but the associated increases in plasma catecholamines and heart rate were higher in SHR. In SHR treated with losartan and enalaprilat, the nitroprusside-induced hypotension was greater and associated with markedly attenuated increases in norepinephrine and heart rate. The binding affinity of cardiac beta-adrenoceptors was significantly lower, and beta2-adrenoceptor subtype was dominant in untreated SHR in contrast to WKY, in which beta1-adrenoceptor subtype was dominant. Enalaprilat treatment increased total beta-adrenoceptor density, whereas both treatments restored the binding affinity and beta1- and beta2-adrenoceptor proportions to normal in SHR. Isoproterenol-, guanylylimidodiphosphate [Gpp(NH)p]-, and forskolin-stimulated adenylyl cyclase reactivity was increased in SHR. Enalaprilat restored adenylyl cyclase reactivity to normal in SHR and reduced the sensitivity (EC50) of Gpp(NH)p-induced cAMP formation in both strains. The present study supports the possibility that functional alterations of the renin-angiotensin and sympathetic systems are involved in hypertension in SHR. The antihypertensive action of losartan and enalaprilat in SHR may be partly mediated through the normalization of sympathetic hyperreactivity and the restoration of beta-adrenergic signaling pathway sensitivity.

Topics: Adenylyl Cyclases; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Enalaprilat; Hypertension; Hypertrophy, Left Ventricular; Imidazoles; Losartan; Male; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, beta; Reflex; Renin-Angiotensin System; Sympathetic Nervous System; Tetrazoles

Endothelin-1 (ET-1) may play a role in hypertension. ET-1 receptor antagonism by bosentan lowers blood pressure in hypertension. We evaluated whether the effect of bosentan is still observed under ACE inhibitors (ACEI).. Thirty anesthetized and 18 conscious hypertensive dogs were studied randomly. Anesthetized dogs were divided into 4 groups: group 1 received cumulative doses of bosentan (bolus+30-minute infusion: 0.1 mg/kg+/-0.23 mg/kg per hour to 3 mg/kg+/-7 mg/kg per hour); group 2, the same dose-responses after 1 mg/kg enalaprilat; group 3, the vehicle after enalaprilat; and group 4, the dose responses to bosentan followed by enalaprilat. The conscious dogs were divided into 3 groups: group 5 received 2 cumulative doses of bosentan; group 6, the vehicle; and group 7, enalaprilat alone. In groups 1 and 2, bosentan produced dose-related decreases (P=.0001) in left ventricular systolic pressure and mean aortic pressure (AOP). In group 1, bosentan decreased mean AOP by 22%. In group 2, enalaprilat decreased mean AOP by 25% (from 173+/-26 to 130+/-25 mm Hg; P<.005); an additional 18% decrease was obtained with bosentan, the mean AOP reaching 98+/-21 mm Hg (P<.01). In group 3, the effect of enalaprilat alone was a 22% decrease in mean AOP (P<.005). The additive effect of the bosentan-ACEI association was also observed in group 4. In group 5, bosentan reduced mean AOP by 20% (P<.005), whereas mean AOP remained unchanged in group 6. The effect of ACEI alone (group 7) was similar to that of bosentan.. Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Dogs; Dose-Response Relationship, Drug; Enalaprilat; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Sulfonamides; Vascular Resistance

1. Heterozygous, male, hypertensive, transgenic ((mRen-2)27) rats (350-450 g) were instrumented for the measurement of regional or cardiac haemodynamics (n = 16, in both groups). Animals were given continuous i.v. infusions of the angiotensin-converting enzyme inhibitor, enalaprilat, or the dual metallopeptidase inhibitor, MDL 100,240 (both at 3 mg kg-1, 3 mg kg-1 h-1; n = 8 for regional and cardiac haemodynamics), for 32 h. Twenty four hours after the onset of infusion of enalaprilat or MDL 100,240, the bradykinin (B2)-receptor antagonist, Hoe 140 (1 mg kg-1, i.v.), was given and measurements were continued for a further 8 h, to assess any possible involvement of bradykinin. 2. Over the first 8 h of infusion, both enalaprilat and MDL 100,240 had significant antihypertensive effects, accompanied by similar regional vasodilatations. However, the blood pressure lowering effect of MDL 100,240 (-54 +/- 9 mmHg) was greater than that of enalaprilat (-38 +/- 4 mmHg), because the former caused a significantly greater reduction in cardiac index. 3. Between 8-24 h after the onset of infusion, there was a reduction in the effect of enalaprilat on blood pressure, because cardiac index rose, with no further increase in total peripheral conductance. In contrast, the antihypertensive effect of MDL 100,240 persisted, in spite of a recovery in cardiac index, because there was further vasodilatation, particularly in the mesenteric and hindquarters vascular beds. 4. There were no apparent haemodynamic changes associated with the injection of Hoe 140, and over the following 8 h, the difference between the haemodynamic effects of enalaprilat and MDL 100,240 persisted; there was little evidence of suppression of the effects of either drug. 5. These results are more consistent with the antihypertensive effects of enalaprilat or MDL 100,240 in transgenic ((mRen-2)27) rats being due to suppression of angiotensin II production, than due to inhibition of bradykinin degradation. The additional effects of MDL 100,240 may be accounted for by inhibition of the degradation of natriuretic peptides reducing cardiac output, initially, and decreasing vascular tone, subsequently. Alternatively, the additional increase in vascular conductance following treatment with MDL 100,240 may represent an autoregulatory response to the reduced pressure.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Benzazepines; Bradykinin; Enalaprilat; Hemodynamics; Hypertension; Male; Metalloendopeptidases; Protease Inhibitors; Pyridines; Rats

Hypertensive crises are a commonly observed problem in an emergency department. The aim of the study was to evaluate the efficacy and safety of different antihypertensive agents in the treatment of patients with hypertensive crises. 168 patients (mean age: 52 +/- 12 years) admitted to the emergency department with a hypertensive urgency (systolic (SBP) blood pressure > 210 mm Hg and/or diastolic (DBP) blood pressure > 110 mm Hg) or a hypertensive emergency (DBP > 100 mm Hg and evidence of end-organ damage) were included into the study protocol. Blood pressure (BP) was measured every 5 min automatically using a noninvasive BP measurement unit. After a resting period of 30 min the patients received the following drugs: 5 mg enalaprilat intravenous (n = 43) or 25 mg urapidil intravenous (n = 48) or 10 mg nifedipine-capsule sublingual (n = 47) or 2 x 5 mg nifedipine-spray sublingual (n = 30). The aim of treatment was to reduce SBP below 180 mm Hg and DBP below 95 mm Hg within 45 min after start of treatment. When evaluating the response rates the highest rate was observed in the urapidil group (96%). The response rate of enalaprilat and both preparations of nifedipine were similar (70-72%). The rate of major side effects was higher in the urapidil compared to the other drugs (4% vs 2% in the nifedipine-group or 0% in the enalaprilat-group). All four drugs are suitable in the treatment of patients with hypertensive crisis in the emergency department. Urapidil should be used as a first choice drug in critically ill patients with hypertensive crisis due to its higher response rate.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Emergency Medical Services; Enalaprilat; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Piperazines; Treatment Outcome

These experiments compare the effects of a neutral endopeptidase inhibitor, retrothiorphan, 1-[(1-mercaptomethyl-2-phenyl)ethyl]amino-1-oxopropanoic acid, a converting enzyme inhibitor, enalaprilat, and the combination of the two inhibitors on changes in blood pressure and renal function induced by exogenous and endogenous bradykinin in deoxycorticosterone acetate (DOCA)-salt rats. Enalaprilat potentiated the exogenous bradykinin-induced hypotensive responses while retrothiorphan potentiated the effects on urinary cyclic-GMP (cGMP) and bradykinin. The combination potentiated the exogenous bradykinin-induced hypotensive effects and the bradykinin-induced urinary excretion of cGMP, bradykinin and prostaglandin. The bradykinin B2 receptor antagonist, Hoe 140, had no effect on the enalaprilat- and retrothiorphan-induced changes in blood pressure and renal function. In conclusion, while angiotensin-converting enzyme and neutral endopeptidase are involved in the vascular and renal catabolism of exogenous bradykinin, the effects of the peptidase inhibitors do not appear to depend on the protection of endogenous bradykinin under acute conditions in DOCA-salt rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cyclic GMP; Enalaprilat; Hypertension; Kidney; Male; Neprilysin; Rats; Rats, Wistar; Thiorphan

Topics: Antihypertensive Agents; Brain Diseases; Enalaprilat; Humans; Hypertension; Piperazines

To study the effects of ACEI captopril (Cap) and enalaprilat (Ena) on intracellular Ca2+ concentration ([Ca2+]i) in cardiac myocytes isolated from SHR and WKY rats.. Using fluorescent probe Fura 2-AM combined with computer image processing technique to measure [Ca2+]i.. Resting [Ca2+]i was higher in SHR cardiac myocytes (174 +/- 5 nmol.L-1) than that in WKY rat myocytes (148 +/- 15 nmol.L-1, P < 0.01). Cap and Ena decreased the resting [Ca2+]i in SHR myocytes (161 +/- 11 and 166 +/- 7 nmol.L-1, respectively, P < 0.05) but not in WKY rat myocytes (P > 0.05). Both drugs inhibited [Ca2+]i increment induced by KCI, NE, or Ang II in SHR and WKY rat myocytes except on KCI-induced [Ca2+]i increment in WKY rat myocytes (P > 0.05).. Cap and Ena had direct effects on pathological voltage-operated calcium channel in cardiac myocytes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium; Calcium Channels; Captopril; Cells, Cultured; Enalaprilat; Hypertension; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The treatment of chronic hypertension in patients unable to take oral medications is challenging. Little information on the comparative safety and efficacy of i.v. alternatives is available. Hydralazine, methyldopate, enalaprilat, and nicardipine appear to be the best options for patients temporarily requiring i.v. medications for controlling chronic hypertension. Therapy should be selected on the basis of the individual patient's needs and diseases, the potential for adverse events, the monitoring required, drug costs, and the expected duration of therapy. The choices may be limited, but understanding the proper use of i.v. antihypertensives should enhance blood pressure control and patient care.

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Calcium Channel Blockers; Enalaprilat; Furosemide; Humans; Hydralazine; Hypertension; Injections, Intravenous; Labetalol; Methyldopa; Nitroglycerin; Nitroprusside; Vasodilator Agents

Neutral endopeptidase inhibitors (NEPI) potentiate the hypotensive effect of converting enzyme inhibitors (CEI) in conscious spontaneously hypertensive rats (SHR) but the mechanism of this potentiation remains unknown. The present study assesses the hemodynamic effects of a CEI (enalaprilat 1 mg/kg; n = 9), a NEPI (retrothiorphan 25 mg/kg + 25 mg/kg/h; n = 9) and the combination (CEI+NEPI; n = 9) versus a control group (n = 9) in anesthetized spontaneously hypertensive rats. CEI alone induced a significant hypotensive effect due to a decrease (-35.1%) in total peripheral resistance (TPR), with no significant increase in cardiac output (CO). NEPI alone had a slight hypotensive effect due to a small decrease in CO. CEI+NEPI decreased the mean arterial pressure to the same extent (-26.7%) as the CEI-induced hypotensive effect, decreased TPR (-44.4%) and induced an increase in CO (+38.2%) with an increase in heart rate. In summary, NEPI combined with CEI induces large decreases in blood pressure and in TPR which do not significantly differ from the CEI-induced effects. It also induces increases in heart rate and in cardiac output in anesthetized SHR.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Drug Therapy, Combination; Enalaprilat; Heart Rate; Hemodynamics; Hypertension; Kinetics; Neprilysin; Rats; Rats, Inbred SHR; Thiorphan; Time Factors

We investigated the dose-dependent cardiovascular effects of enalaprilat at different dosing times in two animal models of hypertension. Blood pressure (BP) and heart rate (HR) were measured telemetrically in 5 spontaneously hypertensive rats (SHR) and in 5 transgenic hypertensive rats (TGR) after intraperitoneal (i.p.) injection of enalaprilat either at 700 h or at 1900 h. In SHR, dosing of enalaprilat at the beginning of the resting period, i.e., at 700 h, significantly reduced BP but did not influence HR. After dosing at 1900 h, BP was unchanged, whereas HR increased, which might have resulted from reflexly increased sympathetic tone. In TGR, enalaprilat at either dosing time decreased BP dose dependently and to a higher extent than in SHR, but the effects were more pronounced after morning than after evening dosing. These findings demonstrate that in two animal models of hypertension the antihypertensive effects of enalaprilat depended on the time of drug dosing.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Blood Pressure; Circadian Rhythm; Dose-Response Relationship, Drug; Enalaprilat; Heart Rate; Hypertension; Injections, Intraperitoneal; Male; Motor Activity; Rats; Rats, Inbred SHR

Recently, in vivo and in vitro studies have implicated nitric oxide as a mediator of the vascular effects of angiotensin-converting enzyme inhibitors (ACEIs). In the present study we hypothesized that N-acetyl-L-cysteine (NAC), by increasing the availability of reduced sulfhydryl groups, would enhance the antihypertensive response to the ACEIs captopril and enalaprilat by a mechanism dependent on nitric oxide. The experiments were performed on instrumented, indomethacin-pretreated, awake spontaneously hypertensive rats (SHRs). Thirty minutes after a bolus of captopril (10 mg/kg iv) was administered, blood pressure decreased from 167 +/- 5 to 147 +/- 6 mmHg (n = 8). The pretreatment with the donor of thiol groups NAC (300 mg/kg iv) potentiated the depressor response to captopril because blood pressure decreased from 172 +/- 3 to 139 +/- 4 mmHg (n = 6). At the dose of 60 micrograms/kg iv, the ACEI enalaprilat did not acutely modify the blood pressure of SHRs (from 172 +/- 5 to 167 +/- 4 mmHg; n = 6). However, when the SHRs were pretreated with NAC, the same dose of enalaprilat significantly reduced blood pressure from 176 +/- 5 to 151 +/- 5 mmHg (n = 6). This potentiation of the depressor response to ACEIs, due to NAC, was not observed when SHRs were pretreated with the nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 50 micrograms.kg-1.min-1 iv). The results of this study suggest that NAC, a donor of sulfhydryl groups, potentiates the antihypertensive response to captopril and enalaprilat in SHR by a nitric oxide-dependent mechanism.

Topics: Acetylcysteine; Animals; Blood Pressure; Captopril; Drug Synergism; Enalaprilat; Hypertension; Male; Rats; Rats, Inbred SHR

To investigate the involvement of the sympathoinhibitory effect of imidapril and enalapril in their antihypertensive effect at a clinically reasonable dose, we studied whether some responses induced by the stimulation of the sympathetic nervous system (SNS) were affected by intravenous administration of imidaprilat and enalaprilat in curarized pithed spontaneously hypertensive rats. Imidaprilat and enalaprilat (both at 100 micrograms/kg, i.v.), which are active metabolites of imidapril and enalapril, respectively, suppressed the pressor responses to electrical stimulation (ES) of the spinal cord (T1-L7) and exogenous noradrenaline (NA). The pressor responses to NA were significantly suppressed after either alpha 1- or alpha 2-adrenoceptors were blocked. Furthermore, imidaprilat (100 micrograms/kg, i.v.) suppressed these reduced responses. When the reduced basal blood pressure was restored by vasopressin infusion, imidaprilat and enalaprilat (both at 100 micrograms/kg, i.v.) did not suppress the responses to ES and exogenous alpha-adrenoceptor agonists. They affected neither basal plasma concentrations of NA and adrenaline nor ES-induced increase of these catecholamines. These results suggest that the suppressive effects of imidaprilat and enalaprilat on the pressor responses to ES and alpha-adrenoceptors agonists are apparently observed in pithed SHR because of a reduction of vascular tone and that imidapril and enalapril do not lower the blood pressure through suppressing SNS.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Chromatography, High Pressure Liquid; Decerebrate State; Electric Stimulation; Enalapril; Enalaprilat; Epinephrine; Hypertension; Imidazoles; Imidazolidines; Male; Norepinephrine; Rats; Rats, Inbred SHR; Spinal Cord; Sympathetic Nervous System; Vasopressins

The effects of captopril on the response of cytosolic free Ca2+ concentration in cultured vascular smooth muscle cells of aortas from Wistar-Kyoto and spontaneously hypertensive rats to angiotensin II (Ang II) and bradykinin were studied using fura 2. Incubation with captopril for longer than 10 minutes caused a decreased response of cytosolic free Ca2+ to Ang II and bradykinin. Maximal effects of captopril were observed after a 40-minute incubation. The inhibitory effect of captopril was abolished in Ca(2+)-free medium, suggesting that captopril acts by blocking Ca2+ influx. Similar effects were observed with enalaprilat. Isometric contraction of aortic strips induced by Ang II in normotensive rats was reduced from 6.5 +/- 2.5 to 1.8 +/- 0.6 mN by a 40-minute incubation with 1 mumol/L captopril (P = .016). Enalaprilat similarly decreased the Ang II-induced contraction. Besides the inhibition of the angiotensin converting enzyme, direct effects of Ang II converting enzyme inhibitors on vascular contraction and Ca2+ influx in vascular smooth muscle cells may be of therapeutic relevance.

Topics: Analysis of Variance; Angiotensin II; Animals; Aorta, Thoracic; Bradykinin; Calcium; Calcium Channels; Captopril; Cells, Cultured; Culture Techniques; Dose-Response Relationship, Drug; Drug Interactions; Egtazic Acid; Enalaprilat; Hypertension; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nifedipine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Time Factors; Vasoconstriction

This study was designed to test whether previous work, which showed that the angiotensin converting enzyme (ACE) inhibitor enalaprilat potentiated the alpha 1-adrenoceptor antagonist activity of doxazosin in isolated rat tail arteries, could be extended to demonstrate a synergistic hypotensive effect of these two drugs.. Groups of untreated or chronically deoxycorticosterone acetate (DOCA)-salt-treated female Sprague-Dawley rats were used. Rats were anaesthetized with Inactin (barbiturate); drugs were administered via a jugular venous catheter; blood pressure was monitored via a carotid arterial catheter.. In previously untreated rats, pretreatment with enalaprilat shifted the dose-response curve for the hypotensive effect of doxazosin to the left, indicating synergism. In rats dosed with DOCA-salt (which suppresses renin and angiotensin II production): (1) there was no synergism between the hypotensive actions of enalaprilat and doxazosin; (2) doxazosin was more potent than in untreated rats; and (3) enalaprilat lowered blood pressure, suggesting a hypotensive mechanism separate from ACE inhibition.. In the absence of angiotensin II (resulting from enalaprilat administration or from chronic DOCA-salt), doxazosin had a greater hypotensive action than in the presence of angiotensin II. This is consistent with the concept that angiotensin II modulates alpha 1-adrenoceptor activity.

Topics: Anesthesia; Animals; Antihypertensive Agents; Desoxycorticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Doxazosin; Drug Evaluation, Preclinical; Drug Interactions; Enalaprilat; Female; Hypertension; Prazosin; Rats; Rats, Inbred Strains; Thiopental

We investigated the processing enzymes involved in the formation of circulating angiotensin-(1-7) after intravenous administration of angiotensin I to conscious spontaneously hypertensive and Wistar-Kyoto rats. Immunoreactive products, including angiotensin I, angiotensin II, and angiotensin-(1-7), were measured in arterial blood by three specific radioimmunoassays. Angiotensin I infusion (2 nmol) induced a rapid increase in immunoreactive angiotensin II and angiotensin-(1-7). Pretreatment with the angiotensin converting enzyme inhibitor enalaprilat (2 mg/kg) eliminated angiotensin II formation and augmented circulating levels of angiotensin I and angiotensin-(1-7) in spontaneously hypertensive and Wistar-Kyoto rats. The elevated levels of angiotensin-(1-7) in enalaprilat-treated rats were blocked by concurrent treatment with the neutral endopeptidase (EC 3.4.24.11) inhibitor SCH 39,370 (15 mg/kg) in both strains. Administration of SCH 39,370 alone decreased angiotensin-(1-7) levels in spontaneously hypertensive rats, whereas angiotensin II levels increased in both strains (p less than 0.01). Comparisons of the metabolism of angiotensin I in the two rat strains showed increased formation of angiotensin-(1-7) in spontaneously hypertensive rats not given any of the enzyme inhibitors. In addition, levels of angiotensin I were higher after administration of SCH 39,370 in hypertensive rats. These novel findings reveal that neutral endopeptidase EC 3.4.24.11 participates in the conversion of angiotensin I to angiotensin-(1-7) and in the metabolism of angiotensin II in the circulation of both spontaneously hypertensive and Wistar-Kyoto rats. Our results suggest that neutral endopeptidase EC 3.4.24.11 is a major enzymatic constituent of the circulating renin-angiotensin system.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalaprilat; Endopeptidases; Hypertension; Male; Neprilysin; Osmolar Concentration; Peptide Fragments; Prolyl Oligopeptidases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serine Endopeptidases; Time Factors

Earlier studies on the cardiovascular effects of intracerebroventricular (i.c.v.) administration of angiotensin converting enzyme (ACE) inhibitors implicate angiotensin II (AII) present in the central nervous system in the pathogenesis of hypertension. We have now examined whether central AII contributes to the maintenance of established hypertension in adult stroke-prone spontaneously hypertensive rats (SHRSP). The ACE inhibitor, enalaprilat, was infused i.c.v. for two weeks at a rate of 5 micrograms/h via osmotic minipumps. Control rats were either untreated or infused with saline. Mean arterial pressure (MAP), measured via an indwelling catheter, fell within 24 h in the enalaprilat-treated rats and remained at least 30 mmHg lower than in controls. This difference persisted after intravenous (i.v.) administration of a vasopressin (AVP) antagonist but was eliminated by subsequent ganglion blockade with i.v. pentolinium. Without prior administration of the AVP antagonist, however, the reductions of MAP after pentolinium were smaller. The reduction was still attenuated in treated rats compared with controls but there was a significant difference in the residual MAP. Circulating catecholamine levels were reduced by central ACE inhibition. However, pressor responsiveness to i.v. phenylephrine was unaffected. The results suggest that, in SHRSP, central ACE inhibition lowers blood pressure by reducing sympathetic outflow, implying that central AII has a tonic sympathoexcitatory effect in this strain.

Topics: Animals; Blood Pressure; Cerebrovascular Disorders; Disease Models, Animal; Enalaprilat; Epinephrine; Hypertension; Injections, Intraventricular; Male; Norepinephrine; Pentolinium Tartrate; Rats; Rats, Mutant Strains

Both circulating and local renin-angiotensin systems (RAS) may contribute to cardiovascular homeostasis under normal and pathophysiologic conditions. They may also play a role in the effects of angiotensin-converting enzyme (ACE) inhibitors. In the present study, we compared systemic and regional hemodynamic effects of nonhypotensive doses of captopril and enalaprilate in normal rats, spontaneously hypertensive rats (SHR), and rats with heart failure due to myocardial infarction (MI). Enalaprilate (0.1 mg/kg) or captopril (3 mg/kg) was injected intravenously (i.v.) in conscious rats equipped with miniature Doppler flow probes on renal and mesenteric artery and abdominal aorta or an electromagnetic flow probe on the ascending aorta to measure cardiac output (CO). This resulted in a shift of the angiotensin-I (ANG I) dose-pressor curve (ED50 of ANG I after saline 0.21 +/- 0.33 micrograms, enalaprilate 1.45 +/- 0.26 micrograms, captopril 2.38 +/- 0.73 micrograms; mean +/- SEM; n = 6-12). In the systemic hemodynamic groups, no significant changes in mean arterial pressure (MAP), CO, or total peripheral resistance (TPR) were observed. In the regional hemodynamic groups, enalaprilate caused a slight (-8 +/- 1 mm Hg) reduction in MAP in normal rats. Resistance in the hindquarters was not affected by ACE inhibitors, whereas only enalaprilate reduced mesenteric resistance in MI rats. In contrast, renal resistance was reduced and renal blood flow (RBF) increased after captopril in normal and MI rats and after enalaprilate in MI rats. Effects were greatest in MI rats (RBF: saline -0.05 +/- 1.9%, enalaprilate 10.3 +/- 2.4%, captopril 10.1 +/- 2.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Cardiac Output; Enalaprilat; Heart Failure; Hemodynamics; Hypertension; Injections, Intravenous; Male; Myocardial Infarction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Vascular Resistance

Topics: Enalaprilat; Humans; Hypertension; Injections, Intravenous; Teprotide

Topics: Adult; Enalapril; Enalaprilat; Female; Humans; Hypertension; Milk, Human

Topics: Enalaprilat; Humans; Hypertension; Infant, Newborn; Kidney Diseases, Cystic; Male

The antihypertensive effects of the renin inhibitor enalkiren were compared with those of the angiotensin-converting enzyme inhibitor enalaprilat in 17 hypertensive patients (14 white, 3 black; mean age 57 years), whose renin systems had been stimulated by diuretic pretreatment. Patients were studied on 3 separate in-hospital days. On the first study day patients received placebo alone. On day 2 they received intravenous bolus doses of enalkiren (0.03 to 1.0 mg/kg), and on day 3, intravenous bolus doses of enalaprilat (0.625 to 1.25 mg). Each agent reduced systolic (p less than 0.01) and diastolic (p less than 0.01) blood pressure (BP) from baseline levels. The acute decrease in systolic BP of 18.5 +/- 0.4 mm Hg during enalkiren tended to be greater (p less than 0.01) than the decrease of 12.6 +/- 0.7 mm Hg during enalaprilat. Decreases in diastolic BP during enalkiren (11.9 +/- 0.4 mm Hg) were also slightly greater (p less than 0.1) than those during enalaprilat (9.2 +/- 0.4 mm Hg). Based on prestudy plasma renin activity (PRA), patients were divided into "high" renin (PRA greater than 3.5 ng angiotensin l/ml/hr; n = 6) and "low/normal" renin (less than 3.5 ng angiotensin l/ml/hr; n = 11) groups. Reductions in diastolic BP in the "high" renin group during enalkiren (30 +/- 5/20 +/- 3 mm Hg) tended to be greater (p less than 0.07) than those during enalaprilat (23 +/- 7/14 +/- 1 mm Hg); differences were not significant in the "low/normal" group (12 +/- 2/7 +/- 2 and 7 +/- 2/8 +/- 1 mm Hg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Pressure; Dipeptides; Enalaprilat; Female; Humans; Hypertension; Injections, Intravenous; Male; Middle Aged; Renin; Time Factors

Early antihypertensive treatment with beta1 blockers and diuretics has proved to delay progression in diabetic nephropathy. Application of angiotensin converting enzyme inhibitors (ACE-I) may also be relevant. To elucidate possible differences in acute renal response to ACE-I and beta-blockers, kidney function was investigated before and after enalaprilat (10 mg) and metoprolol (10 mg) i.v. in 8 microalbuminuric insulin-dependent diabetic patients on no antihypertensive therapy (Study A). Glomerular filtration rate (clearance of 125I-iothalamate) was unchanged with both agents. ACE-I gave rise to efferent renal vasodilation: renal resistance and filtration fraction fell, renal plasma flow (RPF; 131I-hippuran) tended to rise (2p = 0.07) and blood pressure and urinary albumin excretion rate (UAE; radioimmunoassay) were reduced. In contrast, metoprolol caused a decline in RPF, an increase in renal resistance and filtration fraction, and no change in blood pressure or UAE. In 10 diabetic, nephropathic patients undergoing treatment with metoprolol and thiazide (Study B), the acute response to enalaprilat corresponded closely to that observed in Study A, including a decrease in UAE and blood pressure. Over 6 months the addition of enalapril (20 mg/d) to metoprolol and thiazide produced a more pronounced UAE-reduction, although no significant decrease in blood pressure was observed. The present findings support that ACE-I may process specific renoprotective effects. A combination therapy with beta1 blockers, ACE-I, and diuretics is suggested.

Topics: Adult; Albuminuria; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Enalaprilat; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Metoprolol; Middle Aged; Natriuresis; Renal Circulation; Vascular Resistance

The angiotensin-converting enzyme inhibitor enalapril is available for intravenous administration in the form of enalaprilat. Intravenous enalaprilat is indicated for the management of hypertension when oral therapy is not feasible. However, there are no reports of intravenous enalaprilat therapy exceeding one week in duration. We report the case of a critically ill, 39-year-old woman who received intravenous enalaprilat for the management of hypertension for a period of 21 days. The patient's blood pressure and heart rate were controlled adequately on a regimen of enalaprilat 1.25 mg iv piggyback q6h without any apparent adverse effects.

Topics: Adult; Drug Administration Schedule; Enalaprilat; Female; Humans; Hypertension; Infusions, Intravenous; Sepsis

The purpose of this study was to compare the acute hypotensive efficacy of different types of inhibitor of the renin-angiotensin system. A renin inhibitor (RI), CGP 44,099 A, a converting enzyme inhibitor (CEI), enalaprilat, a peptidic angiotensin II (Ang II) antagonist, [Sar1, Ile8]Ang II (P-Ang IIA), and a nonpeptidic Ang II antagonist devoid of agonistic properties, 2-butyl-4-chloro-1- ([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl)-5- (hydroxymethyl)imidazol (NP-Ang IIA), were administered intravenously to sodium-depleted rats (SDRs), renal hypertensive rats (two-kidney, one-clip) (RHRs), and spontaneously hypertensive rats (SHRs). The four compounds were all effective in lowering blood pressure (BP) in SDRs and RHRs. The maximum hypotensive response observed within 30 min of administration was similar for all four compounds (approximately 30 mm Hg in SDRs and 60 mm Hg in RHRs). In SHRs, the P-Ang IIA induced a pressor response whereas the RI, CEI, and NP-Ang IIA lowered BP to a similar extent (approximately 15 mm Hg). Pretreatment with the CEI completely prevented the hypotensive response to RI in SHRs, and vice versa. These observations indicate that the principal mechanism by which converting enzyme inhibitors lower BP after acute administration in these rat models is by inhibition of the formation of Ang II. The pressor response to the P-Ang IIA in SHRs is probably a consequence of its partial agonistic properties. Renin inhibitors and nonpeptidic Ang II antagonists, devoid of agonistic properties, promise to be effective antihypertensive agents similar to the CEIs.

Topics: 1-Sarcosine-8-Isoleucine Angiotensin II; Analysis of Variance; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Enalaprilat; Hypertension; Hypertension, Renal; Imidazoles; Losartan; Oligopeptides; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Renin; Time Factors

The pressure-natriuresis relationships in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were characterized with or without intrarenal renin-angiotensin system (RAS) blockade. The pressure-natriuresis relationship in SHR was shifted toward higher pressure in comparison to WKY. The inhibition of intrarenal RAS by MK-422 (0.3 ug/kg/min) in SHR enabled to excrete more sodium at the same pressure (P less than 0.05), whereas no significant changes were observed in WKY. In SHR, during administration of Thi5,8, D-Phe7-bradykinin (50 micrograms/kg/min), the natriuretic responses to MK-422 were maintained. Intrarenal infusion of Sar1, Ile8-angiotensin (70 ng/kg/min) into SHR increased sodium excretion accompanied by an increase in renal plasma flow. Intrarenally administered angiotensin I (10 ng/kg/min) into WKY showed antinatriuretic effects with minimal changes in renal hemodynamics. These results indicate that alteration of intrarenal RAS in SHR might contribute to reset the pressure-natriuresis relationship.

Topics: Angiotensins; Animals; Blood Pressure; Enalaprilat; Hypertension; Male; Natriuresis; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System

Topics: Blood Pressure; Creatinine; Diuresis; Enalaprilat; Gestational Age; Humans; Hypertension; Infant, Newborn; Infant, Premature, Diseases; Injections, Intravenous; Water-Electrolyte Balance

When a 35-year-old man with essential hypertension was treated with antibiotics for brucellosis his blood pressure rose significantly. While all other treatment was kept constant rifampicin was discontinued. On rechallenge rifampicin did not alter serum concentrations of enalapril or the area under the curve (AUC) between 0 and 7 h, but it did reduce the AUC of the active metabolite enalaprilat by 31%. These observations suggest that there may be an interaction between rifampicin and enalapril, causing reduced hypotensive efficacy of enalapril. The mechanism of such an interaction merits further study, but it could be due to enhanced renal clearance of enalaprilat.

Topics: Adult; Blood Pressure; Brucellosis; Drug Interactions; Enalapril; Enalaprilat; Humans; Hypertension; Male; Rifampin; Time Factors

The purpose of this study was to assess the role of kinins in the acute antihypertensive effect of the converting enzyme inhibitor (CEI) enalaprilat in rats with severe hypertension induced by aortic ligation between both renal arteries. For this study, we used a bradykinin analogue, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg-TFA, with in vivo antagonistic properties. Hypertensive rats were infused intra-aortically for 15 minutes with either saline (30 microliters/min) or the kinin antagonist (40 micrograms/kg/min). Five minutes after the infusion was begun, a bolus injection of enalaprilat (60 micrograms/kg) was given. The blood pressure of the saline-infused animals decreased 48 +/- 6 mm Hg (from 180 +/- 7 to 132 +/- 7 mm Hg), while that of the rats treated with the antagonist decreased only 21 +/- 4 mm Hg (from 175 +/- 3 to 154 +/- 3 mm Hg). The difference between both decrements was significant (p less than 0.01). In another group of hypertensive animals (n = 9), we measured kinin concentration in plasma from arterial blood before and after administration of CEI (41 +/- 10 vs 68 +/- 20 pg/ml, respectively; NS). These results are consistent with the hypothesis that kinins play a role in the acute antihypertensive effect of CEIs in rats with severe hypertension. However, since arterial blood kinin concentrations were not increased significantly after CEI administration, the effect of the CEI may be due to an increase in tissue kinins, which could act as autacoids regulating vascular resistance.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Enalapril; Enalaprilat; Hypertension; Kinins; Male; Oligopeptides; Rats; Rats, Inbred Strains; Receptors, Bradykinin; Receptors, Neurotransmitter

During chronic chlorthalidone treatment of patients with essential hypertension, distal tubular sodium reabsorption is continuously inhibited. At the same time, sodium balance is maintained by an increase of the proximal tubular sodium reabsorption. In the present study, we investigated whether this increase is caused by a stimulated renin-angiotensin system (RAS). For this purpose, the renal effects of converting enzyme inhibition (CEI) were evaluated in 12 patients with essential hypertension who remained hypertensive despite chronic chlorthalidone treatment. After 6 weeks of chlorthalidone, an intravenous injection of 10 mg enalaprilic acid decreased the mean arterial pressure (MAP) from 110 to 102 mm Hg. The effective renal plasma flow (ERPF) increased. However, glomerular filtration rate (GFR) and the fractional excretions of sodium, lithium and free water did not change significantly. After 2 additional weeks of chlorthalidone combined with enalapril 20 mg b.i.d., MAP fell to 90 mm Hg, ERPF remained elevated and plasma aldosterone concentration decreased. As in the acute study, no significant changes were detected in the GFR and the fractional excretions of sodium, lithium or free water. Extracellular fluid volume was not diminished during these 2 weeks. Fractional proximal sodium reabsorption during chronic chlorthalidone therapy was higher when calculated from free water clearance (91%) than from the lithium clearance (71%), but neither of the two were affected by acute or chronic CEI. The results of this study suggest that during chronic diuretic treatment, maintenance of sodium balance by increased proximal reabsorption is not dependent on the stimulated RAS, or alternatively, that this function of the RAS is exactly counterbalanced by another effect of CEI, possibly by the fall in blood pressure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Chlorthalidone; Chronic Disease; Diuresis; Diuretics; Drug Therapy, Combination; Enalapril; Enalaprilat; Glomerular Filtration Rate; Humans; Hypertension; Kidney Tubules, Distal; Kidney Tubules, Proximal; Renal Circulation; Renin-Angiotensin System; Sodium

The relationship between serum concentrations of the angiotensin converting enzyme inhibitor, enalaprilat, and its antihypertensive action was investigated using integrated pharmacokinetic-dynamic modelling techniques. The model was parameterized in terms of slope "m", describing the sensitivity to the fall of blood pressure, and an intercept term "i". A linear pharmacodynamic model: E = m. ce(t) + i, adequately characterized the concentration-effect relationship in most of the young (aged 22-30 years) and elderly normotensive subjects (aged 65-73 years). However, no age-related differences were seen, indicating that angiotensin II vasoconstrictor action is unaltered by senescence.

Topics: Adult; Age Factors; Aged; Antihypertensive Agents; Blood Pressure; Enalapril; Enalaprilat; Female; Humans; Hypertension; Injections, Intravenous; Kinetics; Male; Models, Biological

The hemodynamic effects of enalaprilat (MK-422) and lisinopril (MK-521) were compared with the calcium channel blocker felodipine in dogs with ischemic left ventricular (LV) failure. The combination of nitrendipine plus enalapril was also examined in ischemic failure and in rats with spontaneous hypertension. In anesthetized dogs coronary embolization with 50 micron plastic microspheres reduced cardiac output and LV dP/dt max by approximately 40%, and LV end-diastolic pressure increased to greater than 13 mm Hg. Enalaprilat and lisinopril reduced mean arterial pressure by a maximum of 20 mm Hg and total peripheral resistance by approximately 30%. Left ventricular dP/dt:LVP, which was substantially decreased by embolization, was slightly increased by both angiotensin converting enzyme (ACE) inhibitors. The calcium entry blockers felodipine and nitrendipine qualitatively produced many of the same hemodynamic effects as the ACE inhibitors, but, in addition, they markedly reduced coronary resistance, increased myocardial blood flow, and did not alter cardiac contractility (LV dP/dt max). In spontaneously hypertensive rats single doses of nitrendipine (1.25 to 5.0 mg/kg per os) and enalapril (0.3 and 3.0 mg/kg per os) reduced mean arterial pressure, but differences were observed in the onset (enalapril 2 h versus nitrendipine 0.5 h), the duration of action, and magnitude of effect. In terms of blood pressure lowering, nitrendipine, 5.0 mg/kg per os, was clearly additive to 3.0 mg/kg per os of enalapril, but other combinations (enalapril, 3 mg/kg per os plus 0.625 mg/kg of nitrendipine or enalapril, 0.3 mg/kg per os plus 0.625 mg/kg nitrendipine) were not.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Dogs; Drug Therapy, Combination; Enalapril; Enalaprilat; Felodipine; Heart; Heart Failure; Hypertension; Lisinopril; Male; Nifedipine; Nitrendipine; Rats; Rats, Inbred SHR

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.

Topics: Administration, Oral; Adult; Angiotensin II; Body Weight; Enalapril; Enalaprilat; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Middle Aged; Natriuresis; Potassium; Renal Circulation; Renin; Sodium; Vasodilation

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biological Availability; Enalapril; Enalaprilat; Enzyme Inhibitors; Esterification; Humans; Hypertension; Kinetics; Liver; Oligopeptides; Peptidyl-Dipeptidase A; Teprotide

Enalaprilat (MK-422), an intravenously administered angiotensin-converting enzyme inhibitor, which is the parent compound of the oral angiotensin-converting enzyme inhibitor enalapril (MK-421), was studied in 11 patients with asymptomatic accelerated hypertension. Each patient received an initial intravenous dose of 1 mg, followed at one-hour intervals by enalaprilat 10 mg, furosemide 40 mg, and enalaprilat 40 mg. Six of 11 patients responded with a drop in mean arterial pressure greater than 15 mm Hg to diastolic levels below 110 mm Hg; there were four partial responders and one nonresponder. Pretreatment renins were not predictive of blood pressure response. No patient had any adverse reaction to the drug; there were no significant changes in posttreatment laboratory values. We conclude that enalaprilat is an effective, well-tolerated agent for the treatment of uncomplicated accelerated hypertension and its use does not imperil nonresponding uncomplicated patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Emergencies; Enalapril; Enalaprilat; Female; Humans; Hypertension; Male; Middle Aged; Renin

Thirteen subjects with essential hypertension controlled on oral enalapril (20 mg/day) therapy were entered into a protocol to assess serially 24-hour blood pressure, the renin-angiotensin-aldosterone system, angiotensin-converting enzyme activity, and plasma and urine enalaprilat drug levels, following both chronic oral administration of enalapril and its replacement with intravenous enalaprilat. Results indicate that systolic and diastolic blood pressures remain well controlled following cessation of oral enalapril and replacement with intravenous enalaprilat. Enalaprilat drug levels, following oral enalapril and intravenous enalaprilat, remained above the therapeutic levels required for angiotensin-converting enzyme inhibition. However, therapeutic enalaprilat levels can probably be achieved with one fourth of the total cumulative dose of enalapril, administered as enalaprilat at 6-hour intervals. Intravenous enalaprilat stimulated plasma renin activity and decreased immunoreactive plasma angiotensin II and plasma aldosterone concentrations. However, immunoreactive plasma angiotensin II concentrations were not suppressed below pretreatment values, suggesting that chronic enalapril/acute enalaprilat therapy controls blood pressure through a nonangiotensin-mediated antihypertension mechanism.

Topics: Administration, Oral; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Enalapril; Enalaprilat; Humans; Hypertension; Injections, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Renin

To investigate the renal actions of the converting enzyme inhibitor enalaprilic acid, incremental doses of this drug were infused into the renal artery of hypertensive patients just before renal angiography. One group (n = 6) received doses of 0.1, 0.3 and 1 microgram/kg per min, while in another group (n = 7) doses of 1, 3 and 10 micrograms/kg per min were given. Each dose was infused for 10 min, at the end of which renal blood flow was assessed by means of xenon-washout. At the same time, blood was sampled from the renal artery and vein for determination of converting enzyme, renin and angiotensin II. Enalaprilic acid caused a dose-related suppression of converting enzyme activity, which was maximal at a dose of 1 microgram/kg per min; arterial levels fell more steeply than venous ones. Angiotensin II disappeared in parallel with the drop in converting enzyme. Renal blood flow, on the other hand, began to increase only when 3 micrograms/kg per min was given, and no further changes occurred with the highest dose. Intra-arterial blood pressure fell only when the highest dose was given. Renin secretion tended to increase, but changes were not statistically significant. It is concluded that systemic suppression of converting enzyme is needed for renal vasodilatation to occur. However, the renal vascular response comes well before blood pressure falls.

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalaprilat; Female; Humans; Hypertension; Kidney; Male; Renal Circulation

The effect of enalaprilat (MK-422), a newly synthesized, intravenous, nonsulfhydryl, angiotensin-converting enzyme inhibitor, was studied in seven patients with either severe or malignant hypertension. All subjects initially received a 1 mg bolus injection of enalaprilat followed in 30 minutes by 10 mg. Five subjects received an additional 40 mg. Mean (+/- SE) pretreatment blood pressure for the group was 226 +/- 9/141 +/- 7 mm Hg. Five minutes after the 1 mg enalaprilat dose, blood pressure decreased to 211 +/- 10/131 +/- 9 mm Hg and further fell to 201 +/- 14/123 +/- 11 mm Hg at 30 minutes. The maximal reduction in blood pressure to 169 +/- 14/112 +/- 10 mm Hg occurred 30 minutes after the 10 mg dose. No further blood pressure reduction was observed in those subjects who received the additional 40 mg dose. Within the entire group, five subjects exhibited sustained blood pressure reduction. No adverse side effects or symptomatic hypotension occurred in any subject.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dipeptides; Emergencies; Enalaprilat; Female; Heart Rate; Humans; Hypertension; Injections, Intravenous; Male; Middle Aged

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.

Topics: Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Dose-Response Relationship, Drug; Enalapril; Enalaprilat; Female; Furosemide; Heart Rate; Humans; Hypertension; Male; Middle Aged; Renin

The effects of MK 422 (enalaprilic acid) on renal function and electrolyte excretion were assessed in 14 patients with essential hypertension on a sodium intake of 100 mmol/day. Injection of MK 422 led to a prompt fall in blood pressure (p less than 0.01). Effective renal plasma flow increased by 9 +/- 4% (p less than 0.01) within 1 hour, an increase that persisted for a least 5 hours. Glomerular filtration rate did not change, so filtration fraction decreased by 6 +/- 2% (p less than 0.01). Sodium excretion increased with a maximum of 61 +/- 17% (p less than 0.01) after 5 hours, and potassium excretion fell (p less than 0.01). The log of the initial plasma renin activity correlated with the changes in blood pressure (r = 0.59, p less than 0.05) in effective renal plasma flow (r = 0.59, p less than 0.05) and in sodium excretion (r = 0.65, p less than 0.01). All the renal effects of MK 422 could be reversed by infusion with angiotensin II.

Topics: Blood Pressure; Electrolytes; Enalapril; Enalaprilat; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Sodium

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.

Topics: Angiotensin I; Angiotensins; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Dipeptides; Drug Evaluation, Preclinical; Enalapril; Enalaprilat; Hypertension; Male; Pressoreceptors; Proline; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Thirst; Time Factors

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.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Captopril; Dipeptides; Drug Interactions; Enalapril; Enalaprilat; Humans; Hypertension; Liver; Renin; Time Factors

Intracerebroventricular (i.c.v.) administration of captopril attenuates the development of hypertension in spontaneously hypertensive rats (SHR). To determine whether these effects are related to inhibition of angiotensin-converting enzyme we assessed the effects of chronic i.c.v. administration of MK-422 (a converting enzyme inhibitor chemically unrelated to captopril) on arterial pressure and vascular reactivity in young (seven-week-old) male SHR. MK-422 (0.2 or 1.0 microgram/h, osmotic mini pump) was infused into the lateral ventrical for 4 weeks. Control SHR received artificial CSF i.c.v., or 0.2 microgram/h MK-422 i.v. Vascular reactivity to phenylephrine, vasopressin and direct sympathetic nerve stimulation was assessed in renal and mesenteric vascular beds using miniaturized pulsed Doppler flow probes. MK-422 attenuated the development of hypertension. Arterial pressure at 4 weeks of treatment was: SHR-i.c.v. MK-422 (0.1 microgram/h): 137 +/- 3.4; (1.0 microgram/h): 138 +/- 2.9; SHR i.v. MK-422 176 +/- 4.5 and SHR control: 168 +/- 4.9 mmHg (P less than 0.01). SHR-i.c.v. MK-422 showed significantly attenuated increases in mesenteric vascular reactivity in response to vasoconstrictors, nerves and sympathetic nervous stimulation. Dose and frequency response curves were characterized by a shift to the right and a significant decrease in the slopes. In conclusion, both captopril and MK-422 prevent the development of hypertension in SHR, presumably by blocking angiotensin-converting enzyme, suggesting that the brain renin-angiotensin system contributes to the pathogenesis of hypertension in that model.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Captopril; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electric Stimulation; Enalapril; Enalaprilat; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Sympathetic Nervous System; Time Factors; Vascular Resistance

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.

Topics: Antihypertensive Agents; Blood Pressure; Dipeptides; Enalapril; Enalaprilat; Enzyme Induction; Humans; Hypertension; Oligopeptides; Peptidyl-Dipeptidase A; Teprotide

Ten years of experience with three different converting enzyme inhibitors (CEI; teprotide, captopril and enalapril) in over 300 hypertensive patients reveals that CEI act largely to block renin-angiotensin mediated vasoconstriction. Thus, their effectiveness or lack of it is predicted by the baseline plasma renin measurement. Accordingly, responses to these pharmacological agents can be used to identify and quantify renin-mediated vasoconstriction in the spectrum of hypertensive diseases. The converse is also generally true. Patients failing to respond to CEI exhibit low renin values and their increased peripheral resistance appears related to other mechanisms, possibly involving a subtle increase in total body sodium. Thus, low renin states such as low-renin essential hypertension, primary aldosteronism, and anephric man exhibit little or no response to CEI. The relationship between the renin system activity and effectiveness of CEI reflects a specific interference with a particular pathogenic mechanism which is further supported by the fact that two other types of renin system inhibitors (beta-blockers and saralasin) are similarly effective or ineffective according to the operant renin profile also by studies in patients with congestive heart failure without hypertension in whom the same relationships can be demonstrated. Like hypertensives, heart failure patients exhibit a broad spectrum of renin activity values, and their pretreatment renin levels predict the responses to CEI. We have also found that plasma renin values in heart failure are dependent on sodium intake. When salt is administered, renin falls and patients then become unresponsive to CEI.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arterioles; Captopril; Enalapril; Enalaprilat; Heart Failure; Humans; Hypertension; Kinetics; Male; Nifedipine; Renin; Renin-Angiotensin System; Sodium; Teprotide; Vascular Resistance

In hypertensive patients the time courses for the rise in serum MK-422 level, and fall in both angiotensin converting enzyme (ACE) activity and blood pressure after 10 mg of enalapril were very similar. A close relationship between serum MK-422 levels and percentage ACE inhibition could be demonstrated and the acute fall in blood pressure showed a good correlation with either measurement. With chronic administration, serum MK-422 levels increased linearly with the dose of enalapril. As in the acute study, close relationships between the serum MK-422 level and ACE inhibition, and between either measurement and the fall in blood pressure, could be demonstrated after chronic enalapril administration. However, when compared to the acute response, the ACE inhibition dose-response line was shifted to the right after chronic enalapril therapy suggesting that enalapril may lead to ACE induction in humans. This did not appear to influence significantly the blood pressure lowering effect of enalapril or the relationship between ACE inhibition and the hypotensive effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biotransformation; Blood Pressure; Enalapril; Enalaprilat; Female; Humans; Hypertension; Kinetics; Male; Peptidyl-Dipeptidase A

Twenty years ago it was demonstrated that angiotensin II (Ang II) acts on the brain, which results in an elevation of blood pressure. Ten years later, reninlike activity was discovered in the brain of the rat and dog, which gave rise to the concept of an endogenous brain renin-angiotensin system. In the periphery, the kidney, liver, and lungs work in unison to produce Ang II. Evidence for brain renin, substrate, converting enzyme, and angiotensins is reviewed. New data indicate that the enzyme system for the synthesis of Ang II within the brain may in fact be contained in the cell. All the components for a renin-angiotensin system have now been found in neuroblastoma/glioma cell lines and Ang II is present in primary cell culture of rat brain neurons. The significance of angiotensin in the brain for hypertension is that it may be a stimulus for vasopressin release and sympathetic activation, which can maintain high blood pressure. In the spontaneously hypertensive rat, there is evidence of increased brain angiotensin. Also, experiments with angiotensin-converting enzyme inhibitors show that blockade of brain angiotensin production leads to a long-lasting lowering of blood pressure. The activity of the inhibitors in part appears to be directly on the brain.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Brain; Cells, Cultured; Dipeptides; Enalaprilat; Humans; Hypertension; Peptidyl-Dipeptidase A; Rats; Renin

The new angiotensin converting enzyme inhibitor enalapril maleate was given in single oral doses of 2.5, 5, and 10 mg to 11 hospitalized patients with uncomplicated essential hypertension who were on a 150-mEq sodium diet. All doses of enalapril induced reduction of mean seated diastolic blood pressure (SDBP). The magnitude of the initial SDBP reduction was not dose related, but the duration of effect was longer (greater than 12 hr) after the 5 and 10 mg. After dosing, mean plasma angiotensin converting enzyme activity (ACE) and aldosterone concentration (PAC) fell, while plasma renin activity (PRA) rose. Serum concentrations of the active diacid from of enalapril increased linearly with dosage; ACE was inhibited maximally at concentrations above 10 ng/ml. During repeated dosing in the outpatient trial there was attenuation of the antihypertensive effect (12 to 24 hr after dosing) in eight of 10 patients. Despite dose increases only two patients achieved SDBP control (less than or equal to 90 mm Hg). In the five patients in whom 50 mg/day hydrochlorothiazide was added near the end of the trail mean SDBP was further reduced. Enalapril was well tolerated. Further studies of the drug, especially in combination with diuretic, are needed.

Topics: Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Dipeptides; Dose-Response Relationship, Drug; Enalapril; Enalaprilat; Female; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Pulse; Renin