enalaprilat-anhydrous and Chronic-Disease

We tested the hypothesis that enalaprilat induces preconditioning (PC)-mimetic actions in patients with stable coronary artery disease.. Angiotensin-converting enzyme (ACE) inhibitors increase the bioavailability of bradykinin, which induces cardiac PC.. Twenty-two patients undergoing coronary angioplasty were randomized to an intracoronary infusion of enalaprilat or placebo, followed 10 min later by a PC protocol.. In control patients, the ST-segment shift was greater during the first inflation than during the second and third inflations, both on the intracoronary electrocardiogram (ECG) (21.0 +/- 2.8 mm vs. 13.0 +/- 2.0 mm and 13.0 +/- 2.0 mm, p < 0.05) and the surface ECG (16.0 +/- 4.0 mm vs. 10.0 +/- 2.0 mm and 9.0 +/- 2.0 mm, p < 0.05). In contrast, enalaprilat-pretreated patients showed no change in ST-segment shift during inflations on either the intracoronary or the surface ECG. During the first inflation, the ST-segment shift was significantly smaller in treated versus control patients. The chest pain score during the first inflation was also significantly smaller in treated patients versus control patients (33.0 +/- 6.0 mm vs. 64.0 +/- 6.0 mm) and did not change in treated patients during the second and third inflations, whereas it decreased significantly in control patients. In a subset of 6 patients, enalaprilat increased coronary blood flow during infusion, but this effect dissipated before the beginning of angioplasty.. Pretreatment with enalaprilat attenuates the manifestations of myocardial ischemia during angioplasty. This is the first in vivo evidence showing that an ACE inhibitor protects human myocardium, possibly via PC-mimetics actions, a novel property that might explain the cardioprotective actions of these drugs.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Chi-Square Distribution; Chronic Disease; Coronary Angiography; Coronary Circulation; Electrocardiography; Enalaprilat; Female; Follow-Up Studies; Humans; Infusions, Intralesional; Ischemic Preconditioning, Myocardial; Male; Middle Aged; Probability; Reference Values; Risk Assessment; Severity of Illness Index; Treatment Outcome; Vascular Patency

Angiotensin-converting enzyme (ACE) inhibitors are established as first-line therapy in chronic heart failure (CHF). However, little is known about the dosage-plasma-level relationship of ACE inhibitors in CHF and its relation to drug-induced adverse effects. We investigated 45 patients (age 55 +/- 10 years) with stable CHF who presented with a maintenance dosage of enalapril of either 5 mg b.i.d. (E10, n = 16), 10 mg b.i.d. (E20, n = 18), or 20 mg b.i.d. (E40, n = 11). This dosage was changed three times to treat all patients with lower, higher, and, finally, the initial dosage for 4 weeks each. Patients were examined clinically, by questionnaire, and by spiroergometry. In addition, neurohormones (atrial and brain natriuretic peptide and norepinephrine), enalaprilat trough levels, and serum potassium and creatinine were measured. Enalaprilat trough levels differed significantly between the three groups at study entry but also varied markedly within each group. In addition to the dose of enalapril, serum creatinine, severity of CHF, basal metabolic rate, and body weight significantly influenced enalaprilat trough levels (R2 =.84, p <.001). Within-patient comparisons revealed that serum creatinine (107 +/- 26 versus 102 +/- 20 micromol/liter) and potassium (3.8 +/- 0.4 versus 3.7 +/- 0. 3mmol/liter) were higher, cough was more common (scored on a scale of 0-8: 1.7 +/- 2.1 versus 1.4 +/- 1.8), and blood pressure was lower (systolic, 112 +/- 14 versus 117 +/- 13 mm Hg; diastolic, 66 +/- 9 versus 69 +/- 11 mm Hg) on the highest than on the lowest enalaprilat trough level (all p <.05). Highly variable enalaprilat trough levels and the fact that adverse effects were more common on high enalaprilat trough levels provide a rationale for individually adjusting ACE-inhibitor dose in case of adverse effects.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Creatinine; Cross-Over Studies; Enalaprilat; Female; Heart Failure; Humans; Male; Middle Aged; Potassium; Spirometry

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 contribution of nonangiotensinergic effects of converting enzyme inhibitors to their hemodynamic effects in patients with chronic heart failure is not clear. A comparison of the effects of renin and converting enzyme inhibition should help to clarify this issue.. Thirty-six patients with chronic heart failure (New York Heart Association class II or III) were randomly assigned to receive double-blind either intravenous placebo, the renin inhibitor remikiren, or the converting enzyme inhibitor enalaprilat followed by coinfusion of a second placebo infusion, the addition of remikiren to enalaprilat, or the addition of enalaprilat to remikiren, respectively. Systemic hemodynamics (Swan-Ganz and radial artery catheters) were measured before (rest and submaximal recumbent bicycle ergometry), during (rest), and at the end (rest and exercise) of each 45-minute single- or combination-infusion period. Placebo did not change hemodynamics or renin activity. Effective inhibition of the renin-angiotensin system by remikiren and enalaprilat was indicated by increases of plasma immunoreactive renin together with rapid and complete inhibition of renin activity after remikiren and an increase after enalaprilat (all P < or = .05). Remikiren and enalaprilat rapidly and to a similar extent reduced resting blood pressure through a reduction of systemic vascular resistance, and these changes were significantly correlated to baseline plasma renin activity. Both compounds also decreased pulmonary artery, pulmonary capillary wedge, and right atrial pressures to a similar extent (P < .05). During exercise, pulmonary capillary wedge and right atrial pressures were equally reduced and stroke volume index was increased with remikiren and enalaprilat (P < .05) for both). The combination of converting enzyme with renin inhibition or vice versa did not cause additional hemodynamic changes.. Specific renin inhibition in patients with chronic heart failure produces short-term hemodynamic effects that are almost indistinguishable from those of converting enzyme inhibition. This finding and the lack of additional effects of converting enzyme inhibition added to renin inhibition suggest that nonangiotensinergic effects of converting enzyme inhibitors do not play a significant role in their short-term hemodynamic effects in patients with chronic heart failure.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiac Output, Low; Chronic Disease; Double-Blind Method; Drug Therapy, Combination; Enalaprilat; Female; Hemodynamics; Humans; Imidazoles; Male; Middle Aged; Renin

This study was designed to determine the effects of intravenous angiotensin II infusions and the short-term effects of enalaprilat on venous plasma norepinephrine and norepinephrine spillover in patients with stable chronic congestive heart failure.. Angiotensin II has been shown experimentally to stimulate norepinephrine release. Such effects, if present in humans with congestive heart failure, could be of pathophysiologic and pharmacologic importance.. In study 1, 60-min angiotensin II (5 ng/kg per min) infusions were administered in eight patients with chronic New York Heart Association functional class II and III congestive heart failure. Heart rate, arterial pressure, forearm venous plasma norepinephrine, norepinephrine clearance (estimated from the clearance of tritiated norepinephrine) and norepinephrine spillover were measured after 30 min in the supine position and after 15 min each of head-up and head-down tilt. All patients were studied in a double-blind manner on two occasions with vehicle control infusions. In study 2, 14 patients comparable to those in the first study had similar measurements made in the supine position before and 30 and 60 min after the administration of enalaprilat (1 mg intravenously). Eight patients received a double-blind vehicle control.. In study 1, there were no effects of angiotensin II on heart rate, plasma norepinephrine, norepinephrine clearance or norepinephrine spillover compared with the vehicle control when the patient was in the supine position. Mean arterial pressure increased from 85 +/- 13 to 95 +/- 10 mm Hg with angiotensin II. During upright tilt, plasma norepinephrine and norepinephrine spillover increased comparably with angiotensin II and the vehicle control. During head-down tilt, plasma norepinephrine decreased with both angiotensin II and the vehicle control. Norepinephrine spillover remained elevated relative to control values on both study days during head-down tilt. In study 2, both enalaprilat and vehicle control administration were associated with a slight decrease in mean arterial pressure (5 +/- 2 vs. 3 +/- 4 mm Hg, p = NS), but no changes were seen in plasma norepinephrine. Norepinephrine clearance and spillover decreased comparably with time after both enalaprilat and vehicle control.. Neither the infusion of angiotensin II nor the acute administration of enalaprilat significantly alters the activity of the sympathetic nervous system as reflected by plasma norepinephrine or systemic venous norepinephrine spillover in patients with chronic congestive heart failure. These data weaken the hypothesis that angiotensin II is an important regulator of sympathetic activity in congestive heart failure.

Topics: Adult; Aged; Analysis of Variance; Angiotensin II; Blood Pressure; Chronic Disease; Double-Blind Method; Enalaprilat; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Norepinephrine; Sympathetic Nervous System

The acute hypotensive response to oral and parenteral enalapril (E) and lisinopril (LI) was assessed in 24 patients with chronic congestive heart failure in two open, randomized, balanced, crossover studies. In the E study, 12 patients received each of three treatments: a single oral dose of 10 mg E, a single intravenous bolus of 5 mg E, and a single intravenous bolus of 5 mg enalaprilat (ET). In the LI study, 12 patients received each of two treatments: a single oral dose of 10 mg LI and a single intravenous bolus of 5 mg LI. Intraarterial blood pressure was measured continuously. Significant decreases from baseline in mean arterial pressure (MAP) were observed in all cases, starting at 15 min. The maximal hypotensive effect (MAP; mean +/- SD) was greatest and the nadir earliest for intravenous ET (-30 +/- 7 mm Hg at 75 min) compared with oral E (-25 +/- 10 mm Hg at 210 min) and intravenous E (-19 +/- 10 mm Hg at 195 min). Oral E and intravenous E had similar onsets of action. The maximal reduction following oral LI (-19 +/- 13 mm Hg at 210 min) was similar to oral E and intravenous E. The effect of intravenous LI (-25 +/- 9 mm Hg at 105 min) was similar to that of intravenous ET. Among the parenteral treatments, E produced the most gradual and least pronounced reduction in blood pressure, and may be best suited for use in the acute situation to minimize the risk of abrupt hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Blood Pressure; Chronic Disease; Enalapril; Enalaprilat; Female; Heart Failure; Humans; Hypotension; Injections, Intravenous; Lisinopril; Male; Middle Aged

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

This study was designed to analyze the pathophysiological role of the endogenous endothelin (ET) system and the therapeutic approach to congestive heart failure (CHF) with ET(A)/ET(B) receptor antagonists in a canine CHF model. After 3 weeks of rapid right ventricular pacing (240 beats/min), concentrations of immunoreactive ET-1 in dogs increased approximately 2-fold in plasma and in the left and right ventricles but not in the lung. There were no meaningful changes in the density and affinity of total ET receptors, or in the ratio of ET(A) to ET(B) receptors. To clarify the functional role of endogenous ET, we examined the effects of acute injection of J-104132 (1 and 3 mg/kg i.v.), an ET(A)/ET(B) receptor antagonist, on cardiovascular and renal function in dogs with CHF. Compared with vehicle, J-104132 at both doses significantly decreased pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and mean arterial pressure (MAP), and increased cardiac output (CO) and renal blood flow. J-104132 had no effects on heart rate and cardiac contractility. In addition, we examined whether J-104132 has an additive effect in the presence of enalaprilat. J-104132 (1 mg/kg i.v.) administered after enalaprilat (0.05 mg/kg i.v.) induced further decreases in MAP, PCWP and PAP, and further increases in CO, resulting in further decreases in total peripheral resistance. These results indicate that the endogenous ET system is exaggerated in CHF and has a detrimental effect on cardiac function. Therefore, J-104132 given alone or as combination therapy may play a beneficial role in the treatment of CHF in humans.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Pacing, Artificial; Chronic Disease; Dogs; Echocardiography; Enalaprilat; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Hemodynamics; Pyridines; Receptors, Endothelin; Tissue Distribution; Ventricular Function

In arteries and veins smoking is associated with impaired nitric oxide-mediated relaxation to endothelium-dependent agonists such as bradykinin. We investigated whether acute local angiotensin-converting enzyme (ACE) inhibition, achieved by enalaprilat, could influence bradykinin-induced vasodilation in veins of smokers.. We studied 7 smokers and 7 nonsmokers with the hand vein technique. After preconstriction with phenylephrine was performed, endothelium-dependent and independent relaxations were assessed by infusing bradykinin (1 to 278 ng/min) and sodium nitroprusside (0.0001 to 3166 ng/min), respectively. Dose-response curves were constructed before and during enalaprilat coinfusion (1 microg/min for 40 minutes).. Smokers had impaired venodilation to bradykinin compared with nonsmokers (P < .01). Apparent maximal relaxation induced by bradykinin was 78%+/-9% in the control group and 48%+/-9% in smokers (mean +/- SD). ACE inhibition shifted the bradykinin dose-response curve to the left in both groups (P < .001) and was associated with a minimal increase in apparent maximal venodilation in nonsmokers (78%+/-9% to 83%+/-18%). In contrast, in smokers ACE inhibition augmented the magnitude of apparent maximal venodilation to values comparable to those observed in the control group (48%+/-9% to 102%+/-21%). In both groups the response to sodium nitroprusside was not affected by enalaprilat.. This study shows that acute local ACE inhibition restores bradykinin-induced relaxation in smokers to values found in nonsmokers. This observation suggests that increased vascular metabolism of bradykinin exists in veins of smokers and that the vascular renin-angiotensin system may play a key role in smoking-induced endothelial dysfunction.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Chronic Disease; Dose-Response Relationship, Drug; Enalaprilat; Endothelium, Vascular; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Nitroprusside; omega-N-Methylarginine; Smoking; Vasodilation; Vasodilator Agents; Veins

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

Systemic and coronary hemodynamic, metabolic and humoral effects of a new intravenous angiotensin-converting enzyme inhibitor, enalaprilat, were evaluated in 14 patients with chronic heart failure. Onset of hemodynamic action occurred within 15 minutes and persisted for 6 hours. At the time of peak effect, there was a significant reduction in mean arterial pressure (-21%) and pulmonary capillary wedge pressure (-33%). Systemic vascular resistance decreased by 32% and stroke volume index increased by 20%. These systemic hemodynamic changes indicate improved left ventricular function. There was a substantial sustained reduction in rate-pressure product initially without a change in coronary sinus blood flow or myocardial oxygen consumption. There was also reduced myocardial oxygen extraction and augmented coronary sinus oxygen saturation at 30 minutes and 1 hour. In three patients, abnormal myocardial lactate extraction, present before enalaprilat, changed to uptake after enalaprilat, indicating amelioration of myocardial ischemia that was not clinically manifest. Systemic catecholamine levels and myocardial catecholamine balance did not change. Plasma renin activity increased and plasma aldosterone decreased. These findings suggest that enalaprilat produces inhibition of the angiotensin-converting enzyme and consequent beneficial systemic hemodynamic changes in heart failure. In some patients with heart failure, silent myocardial ischemia at rest can occur and can be alleviated with enalaprilat. Decreased myocardial oxygen extraction, increased coronary sinus oxygen saturation and lack of expected decrease in coronary sinus blood flow despite reduced rate-pressure product suggest transient coronary vasodilation by enalaprilat.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Catecholamines; Chronic Disease; Coronary Circulation; Enalapril; Enalaprilat; Female; Heart Failure; Hemodynamics; Humans; Infusions, Parenteral; Male; Middle Aged; Myocardium; Renin-Angiotensin System

The renin-angiotensin system is activated in the majority of patients with chronic congestive heart failure. This may be part of the pathophysiology of the disease, a secondary phenomenon, or the result of intense diuretic therapy. Irrespective of the mechanism of renin-angiotensin activation, converting enzyme inhibitors are an effective form of therapy as well as a means to evaluate pathophysiologic mechanisms of congestive heart failure. Because of the activation of the renin-angiotensin system, angiotensin-mediated vasoconstriction and aldosterone-mediated sodium retention can be suppressed and, in some individuals, completely blocked by converting enzyme inhibitors. Improved forward cardiac flow and reduction of pulmonary congestion occur with reversal of vasoconstriction, so that relief of edema, due to enhanced sodium and water excretion, will occur. While it is easy to identify a close correlation between markers of renin-angiotensin activity and the initial response to converting enzyme inhibitors, it is more difficult to identify this response long-term. This may be due to changes in dietary sodium intake, intensity of diuretic therapy, or alteration in renal blood flow and function. Clinically, however, the response to converting enzyme inhibitors is favorable in the majority of people.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Enalapril; Enalaprilat; Enzyme Activation; Heart Failure; Heart Rate; Hemodynamics; Humans; Renin-Angiotensin System; Saralasin; Sodium; Vasoconstriction