enalaprilat-anhydrous and Heart-Failure

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

Topics: Aged; Diuretics; Dobutamine; Enalaprilat; Female; Heart Failure; Hemodynamics; Hospitalization; Humans; Hydrazones; Injections, Intravenous; Male; Milrinone; Natriuretic Agents; Natriuretic Peptide, Brain; Nitroprusside; Pulmonary Wedge Pressure; Pyridazines; Renal Agents; Simendan; Vasodilator Agents

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Enalaprilat; Endothelium, Vascular; Heart Failure; Humans; Renin; Shock, Septic

The prevalence of congestive heart failure (CHF), a debilitating condition associated with impaired quality of life and markedly shortened life expectancy, is increasing. The goals of therapy for CHF are reducing symptoms, improving functional capacity, and slowing the progression of the condition. In most cases, this is best achieved with a combination of diuretic and vasodilator therapy. Angiotensin-converting enzyme (ACE) inhibitors have several advantages over other vasodilatory agents and are becoming widely used for treating CHF. The most recently introduced ACE inhibitor, fosinopril, is at least as effective as enalapril, and its dual and compensatory route of excretion is particularly advantageous in patients with renal insufficiency. Fosinopril may also have particular benefits in the prevention of CHF, as it has beneficial effects on cardiac function that may help delay the onset of overt cardiac failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Clinical Trials as Topic; Enalaprilat; Exercise Tolerance; Fosinopril; Half-Life; Heart Failure; Hemodynamics; Humans; Kidney; Kidney Diseases; Lisinopril; Male

Enalapril is an effective angiotensin-converting enzyme (ACE) inhibitor which produces salutary, beneficial haemodynamic effects in patients with congestive heart failure. Enalapril also produces beneficial neurohumoral changes, as well as improving abnormal coronary haemodynamics and myocardial energetics that are frequently encountered in these patients. Administration of enalapril once or twice daily appears to be quite effective during maintenance therapy in patients with chronic congestive heart failure.

Topics: Aldosterone; Animals; Enalapril; Enalaprilat; Heart Failure; Hemodynamics; Humans; Kidney; Myocardium; Renin

To judge the efficacy of converting enzyme inhibitors in the management of congestive heart failure, it is necessary to interpret this in the context of the factors that stimulate renin release and the subsequent formation of angiotensin and aldosterone. The pharmacologic properties of individual converting enzyme inhibitors must be considered, and the alterations in both renin angiotensin activity and long-term converting enzyme inhibition that interact in complementary or offsetting ways to influence the long-term therapeutic result must be understood.

Topics: Angiotensin-Converting Enzyme Inhibitors; Dipeptides; Enalapril; Enalaprilat; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Humans; Nifedipine; Renin; Renin-Angiotensin System; Vasoconstriction

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

Arterial compliance is determined by structural factors, such as collagen and elastin, and functional factors, such as vasoactive neurohormones. To determine whether angiotensin II contributes to decreased arterial compliance in patients with heart failure, this study tested the hypothesis that administration of an angiotensin-converting enzyme inhibitor improves arterial compliance. Arterial compliance and stiffness were determined by measuring carotid artery diameter, using high-resolution duplex ultrasonography, and blood pressure in 23 patients with heart failure secondary to idiopathic dilated cardiomyopathy. Measurements were made before and after intravenous administration of enalaprilat (1 mg) or vehicle. Arterial compliance was inversely related to both baseline plasma angiotensin II (r = -0.52; P = 0.015) and angiotensin-converting enzyme concentrations (r = -0.45; P = 0.041). During isobaric conditions, enalaprilat increased carotid artery compliance from 3.0 +/- 0.4 to 5.0 +/- 0.4 x 10(-10) N(-1). m(4) (P = 0.001) and decreased the carotid artery stiffness index from 17.5 +/- 1.8 to 10.1 +/- 0.6 units (P = 0.001), whereas the vehicle had no effect. Thus angiotensin II is associated with reduced carotid arterial compliance in patients with congestive heart failure, and angiotensin-converting enzyme inhibition improves arterial elastic properties. This favorable effect on the pulsatile component of afterload may contribute to the improvement in left ventricular performance that occurs in patients with heart failure treated with angiotensin-converting enzyme inhibitors.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Brachial Artery; Carotid Arteries; Compliance; Elasticity; Enalaprilat; Female; Heart Failure; Humans; Male; Manometry; Middle Aged

To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril.. Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalaprilat; Female; Fosinopril; Heart Failure; Humans; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Time Factors

Administration of angiotensin-converting enzyme (ACE) inhibitors to patients with congestive heart failure has been shown to increase parasympathetic tone as indicated by increases in high-frequency heart rate variability. The mechanism for this effect, including its relation to changes in baroreflex activity, blood pressure variability, and suppression of ACE activity, remains undefined. This study was designed to test the relation of these variables, which may govern changes in autonomic activity, to the previously described increase in parasympathetic tone.. Seven patients with heart failure received a 3-hour infusion of the ACE inhibitor enalaprilat. Hemodynamic variables and parameters of heart rate and blood pressure variability, baroreflex gain derived from the interaction of heart rate and blood pressure variability, and serum ACE activity were measured during and after the infusion. Measures of heart rate and blood pressure variability were also compared against a historic control group.. Serum ACE activity was significantly suppressed throughout and after enalaprilat infusion. Hemodynamic measures did not change other than a small decline in right atrial and pulmonary capillary wedge pressures. Parasympathetic tone showed an initial significant increase with a peak at 2 hours but then declined below baseline 8 hours after initiation of enalaprilat infusion. Sympathetically influenced low-frequency heart rate variability was significantly increased above baseline in the enalaprilat treatment group 8 hours after initiation of the infusion. Baroreflex gain showed a significant trend to an increase with the maximum value coinciding with the peak in parasympathetic tone. There was no change in blood pressure variability in the enalaprilat group and no change in baroreflex gain, heart rate variability, or blood pressure variability in the control group.. Parasympathetic tone and baroreflex gain increased with parenteral administration of an ACE inhibitor but subsequently decreased below baseline values despite continued suppression of serum ACE activity. The dissociation between ACE suppression and autonomic response to ACE inhibition indicates that enzyme systems not reflected by plasma ACE activity or independent from the classic pathways of angiotensin formation contribute to the regulation of the autonomic response to ACE inhibition in patients with heart failure. The absence of significant change in hemodynamic variables or in blood pressure variability indicates that these autonomic changes are not an indirect reflex response to ACE inhibitor-induced vasodilation or hemodynamic baroreceptor stimulation.

Topics: Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Autonomic Nervous System; Baroreflex; Blood Pressure; Drug Administration Schedule; Enalaprilat; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Probability; Reference Values

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

The first dose of angiotensin-converting enzyme (ACE) inhibitors may trigger a considerable fall of blood pressure in chronic heart failure. The response may be dose-related. To determine hemodynamic and systemic oxygenation effects of low-dose enalaprilat, we administered intravenous enalaprilat (0.004 mg/kg) as bolus (group B) or continuous 1-hour infusion (group C) in 20 patients with congestive heart failure due to ischemic heart disease with acute decompensation refractory to inotropic, vasodilator and diuretic therapy. Hemodynamic and systemic oxygenation variables were recorded at baseline (+0 min), +30, +60, +120, +180, and +360 min after the start of intervention. Mean arterial pressure (MAP) (p < 0. 001), mean pulmonary artery pressure (MPAP) (p < 0.001), pulmonary artery occlusion pressure (PAOP) (p < 0.001), oxygen extraction ratio (ER) (p < 0.026) decreased regardless of enalaprilat application. Compared to group B, there was in group C prolonged decrease of MAP, MPAP, PAOP, ER and increase of pulmonary artery oxyhemoglobin saturation in regard to baseline values. Cardiac index, heart rate, central venous pressure and oxygen consumption index did not change. A low dose of intravenous enalaprilat (0.004 mg/kg) can be used to safely improve hemodynamics and systemic oxygenation in congestive heart failure due to ischemic heart disease with acute refractory decompensation.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Coronary Disease; Drug Administration Schedule; Drug Therapy, Combination; Enalaprilat; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Oxygen; Pilot Projects

Angiotensin-converting enzyme (ACE) inhibitors are established as first-line therapy in chronic heart failure (CHF). However, conflicting results exist regarding the dose-effect relation of ACE inhibitors.. We investigated 45 patients (age 55 +/- 10 years) with stable CHF who presented with a maintenance dosage of enalapril of either 5 mg given twice daily (E10; n = 16), 10 mg given twice daily (E20; n = 18), or 20 mg given twice daily (E40; n = 11). This dosage was changed 3 times to treat all patients with lower, higher, and the initial dosages for 4 weeks each. Neurohormones (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and norepinephrine) and enalaprilat trough levels were measured, and ergospirometry was performed.. Changes in enalapril dose and enalaprilat level were concordant in 82% of patients, indicating good compliance. After augmentation of enalapril to 40 mg daily, patients in the E10 group showed an increase in maximal oxygen consumption and a decrease in neurohormonal stimulation, whereas the opposite changes were observed after reduction of enalapril to 10 mg daily in patients in the E20 and E40 groups (maximal oxygen consumption: Delta1.1 +/- 2.0 vs -1.0 +/- 1.9 mL. kg(-1). min(-1), P <.01; ANP: Delta-63 +/- 106 vs 19 +/- 54 pg/mL, P <.01; BNP: Delta-62 +/- 104 vs 18 +/- 89 pg/mL, P <.05; norepinephrine: Delta-1.3 +/- 2.9 vs 0.6 +/- 1.8, P <.05). Within-patient comparison showed that neurohormone levels were higher and exercise capacity lower while patients were receiving 10 mg of enalapril per day than when they were receiving 40 mg per day (ANP: 172 +/- 148 vs 139 +/- 122 pg/mL, P <.01; BNP: 193 +/- 244 vs 152 +/- 225 pg/mL, P <.005; norepinephrine: 4.2 +/- 2.2 vs 3.5 +/- 1. 6 nmol/L, P <.05; maximal oxygen consumption 22.0 +/- 4.4 vs 21.3 +/- 4.3 mL. kg(-1). min(-1) P <.05). Similar differences were observed when comparing these variables, and patients had lowest and highest enalaprilat trough levels.. High doses of enalapril resulted in an improvement of exercise capacity and reduction of neurohumoral stimulation, whereas these parameters worsened after reduction of enalapril dose. Thus patients with congestive heart failure may benefit from increasing dosage of ACE inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Enalapril; Enalaprilat; Exercise Test; Exercise Tolerance; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Single-Blind Method

Converting enzyme inhibitors meet most of the criteria required to be used in acute pulmonary edema. However, they could also induce deleterious effects on renal function and electrolytes. The purpose of this study was to evaluate the efficacy and safety of a single intravenous 2-hour infusion of enalaprilat (1 mg) after an acute pulmonary edema.. This was a placebo-controlled, randomized, double-blind study performed in 20 congestive heart failure patients (New York Heart Association class III or IV). Systemic and regional hemodynamic parameters, biological parameters, and blood gases were measured before and repeatedly after the onset of infusion. Compared with placebo, enalaprilat decreased pulmonary capillary wedge pressure (-37% versus -10%, P = .001), diastolic and mean systemic blood pressures (-21% versus 0%, P = .009, and -18% versus -1%, P = .026, respectively), diastolic and mean pulmonary blood pressures (-21% versus -8%, P = .040; -18% versus -9%, P = .046), and brachial and renal resistances (-44% versus -14%, P = .017, and -22% versus -2%, P = .014, respectively); increased brachial and renal blood flows (+77% versus +8%, P = .036, and +12% versus 0%, P = .043, respectively), arterial oxygen tension (+2% versus -16%, P = .041), and arterial oxygen saturation (+1% versus -2%, P = .045); and tended to decrease rate-pressure product (-19% versus -7%, P = .076), increase brachial artery diameter (+13% versus 0%, P = .081), and improve intrapulmonary shunt (-18% versus +16%, P = .080). Enalaprilat did not affect cardiac output or carotid or hepatosplanchnic hemodynamics.. Early administration of enalaprilat is effective and well tolerated in acute pulmonary edema.

Topics: Acute Disease; Aged; Double-Blind Method; Enalaprilat; Female; Gases; Heart Failure; Hemodynamics; Hormones; Humans; Injections, Intravenous; Male; Placebos; Pulmonary Circulation; Pulmonary Edema

Neurohormonal activation may provide a pathophysiological link between acute myocardial infarction and chronic congestive heart failure, and modulation of neurohormonal activity may be an important therapeutic target in these conditions. Plasma neurohormones were studied in 55 patients with acute myocardial infarction. Angiotensin II, noradrenaline and ANP were elevated in the early phase but tended to normalize during the first week in patients without signs of heart failure. In patients with heart failure angiotensin II and noradrenaline remained elevated for 1 month and ANP for 4-6 months. During head-up tilt, angiotensin II and noradrenaline increased most in patients with heart failure. In patients with a first myocardial infarction there was a positive correlation between sustained neurohormonal activity and infarct size. Almost complete suppression of plasma ACE activity was achieved within 30 min in 48 patients treated with intravenous enalaprilat, initiated within 24 h from the onset of infarction. The drug was tolerated in dosages of 1.0-1.2 mg given over 1-2h. Patients with systolic blood pressure between 100 and 110 mmHg incurred a greater risk of hypotension than those with higher blood pressure at baseline. Tolerance was not worse among patients treated with intravenous diuretics, metoprolol or nitroglycerin. A total of 98 patients were randomized to treatment with enalapril or placebo, initiated within 24 h from onset of infarction and continued for 4-6 months. During treatment there were no significant differences in plasma levels of angiotensin II, aldosterone, ANP or catecholamines between groups. Echocardiographic recordings were performed in 28 patients. Among patients on placebo there was a positive correlation between plasma levels of noradrenaline at days 5-7 and the increase in left ventricular volumes during the study period, and an inverse correlation between plasma aldosterone at days 5-7 and the increase in left ventricular ejection fraction during the study. No such correlation was found among patients on enalapril. ANP levels at 1 month correlated inversely with the left ventricular ejection fraction at the same time. Plasma neurohormones were measured in 223 patients with mild or moderately severe chronic heart failure, randomized to treatment with ramipril or placebo for 3 months. There was wide variation in hormone levels. Noradrenaline and aldosterone correlated inversely with exercise duration at baseline. Noradrenaline

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Enalapril; Enalaprilat; Exercise; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Neurosecretory Systems; Norepinephrine; Peptidyl-Dipeptidase A; Ramipril; Ventricular Function, Left

This study was performed to determine whether acute inhibition of angiotensin-converting enzyme restores impaired endothelium-dependent vasorelaxation in patients with chronic heart failure.. Recent reports have demonstrated that endothelium-dependent vasodilation induced by cholinergic stimuli is attenuated in the peripheral vascular bed of patients with chronic heart failure.. We examined the effects of local intraarterial infusion of enalaprilat (0.6 micrograms/min per 100 ml tissue volume) on responses initiated by acetylcholine or sodium nitroprusside in the forearm vascular bed in 8 normal subjects, 12 patients with mild heart failure (New York Heart Association functional classes I and II) and 10 patients with more advanced heart failure (functional classes III and IV). Forearm blood flow was measured by means of venous occlusion plethysmography.. Although enalaprilat alone did not affect basal forearm blood flow, it significantly augmented the increase in forearm blood flow induced by acetylcholine in normal subjects (p < 0.01) and in those with mild heart failure (p < 0.05). However, the effect was not found in patients with more advanced heart failure. Coinfusion of enalaprilat did not enhance sodium nitroprusside-induced vasodilation in any of the groups. To explore the mechanism of the inhibitor's effect, an additional 20 patients with mild heart failure (functional class II) were pretreated with a cyclooxygenase inhibitor, acetylsalicylic acid (n = 10) or an inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (n = 10), followed by administration of acetylcholine with or without enalaprilat. Acetylsalicylic acid reduced the converting enzyme inhibitor's effect, whereas NG-monomethyl-L-arginine failed to block the augmentation of blood flow.. These results suggest that inhibition of angiotensin-converting enzyme potentiates endothelium-dependent vasodilation induced by cholinergic stimuli, presumably through modulation of prostaglandin metabolism, in the peripheral vasculature of patients with mild chronic heart failure.

Topics: Acetylcholine; Arginine; Aspirin; Enalaprilat; Endothelium, Vascular; Female; Forearm; Heart Failure; Hemodynamics; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Nitric Oxide; Nitroprusside; omega-N-Methylarginine; Peptidyl-Dipeptidase A; Plethysmography; Premedication; Vasodilation

To evaluate the acute effects of intravenous enalaprilat infusion in critically ill patients with intractable heart failure after acute myocardial infarction.. Prospective, consecutive sample, before-after trial.. Medical intensive care unit in a university hospital.. Eight consecutive patients with intractable acute heart failure after acute myocardial infarction. All study patients continued receiving inotropic, vasodilating, and diuretic medication at a constant rate. Six patients received steady intermittent mandatory ventilation and two patients were on a continuous positive airway pressure mask during the investigation, all with constant positive end-expiratory pressure. Heart failure was defined as intractable if the pulmonary artery occlusion pressure remained > 20 mm Hg despite this conventional therapy.. Enalaprilat was infused at a rate of 1 mg/hr until the pulmonary artery occlusion pressure decreased by > or = 20%.. Central hemodynamics, oxygenation, and hormonal regulation (plasma renin activity, plasma norepinephrine, epinephrine, endothelin, atrial natriuretic peptide, and vasopressin concentrations, serum angiotensin-converting enzyme activity, and serum concentrations of aldosterone) were assessed at baseline before enalaprilat infusion, and repeatedly during 2 hrs after the infusion. The statistical analysis was performed with analysis of variance for repeated measurements. Enalaprilat infusion (median dose 0.3 mg and infusion time 21 mins) caused significant but short-lasting decreases in pulmonary artery occlusion pressure (p = .007), mean arterial pressure (p = .003), mean pulmonary arterial pressure, and rate pressure product. These findings coincided with inhibition of serum angiotensin-converting enzyme activity, an increase in plasma renin activity, and a decrease in plasma endothelin concentrations (p = .041). Enalaprilat had no significant effects on the other hormones studied. Cardiac output and stroke volume index, venous admixture, oxygen extraction ratio, and mixed venous and arterial oxygen saturations remained unchanged.. Adding enalaprilat to conventional therapy makes it possible to transiently relieve pulmonary congestion while maintaining cardiac function and systemic oxygenation. The decrease in plasma endothelin concentrations may have further clinical implications, because endothelin is known to have potent vasoconstricting effects on the coronary circulation and it may also contribute to the extension of myocardial infarction. Whether these observed benefits can be maintained with repeated bolus injections or with continuous infusion of enalaprilat, remains to be settled.

Topics: Acute Disease; Aged; Combined Modality Therapy; Enalaprilat; Female; Finland; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Statistics as Topic; Time Factors

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

Comparison of the first dose responses to low dose constant rate infusions of diacid angiotensin converting enzyme (ACE) inhibitors.. Double blind, randomised, placebo controlled, parallel group prospective study.. General hospital inpatient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of ACE inhibitor treatment.. 36 unselected elderly (aged 60-87 years) patients with symptomatic but stable chronic cardiac failure (New York Heart Association grades II-IV). ACE inhibitor started under double blind conditions with blood pressure monitoring.. Patients were randomly allocated to receive intravenous placebo (saline), enalaprilat (1.5 mg over six hours) or perindoprilat (1 mg over six hours) by constant rate intravenous infusion (5 ml/hour). The protocol allowed for discontinuation of infusion if mean arterial blood pressure fell by 30% from the value before treatment.. Blood pressure and heart rate responses, drug concentration, plasma renin, and ACE activities.. The three groups had similar age, severity of heart failure, diuretic dose before treatment, plasma renin activity, and serum electrolyte state. All patients remained symptom free throughout the study. Infusions were only ended early with active treatment: 5/12 perindoprilat cases, (mean (SD) dose 0.88 (0.18) mg, and 5/12 enalaprilat cases (mean (SD) dose 1.2 (0.4) mg. Both active treatments lowered mean arterial pressure until discontinuation of infusion. Heart rate was not altered. Two patients (one perindoprilat, one enalaprilat) showed transient and symptom free renal impairment.. Slow intravenous infusion of diacid ACE inhibitors may allow safe initiation of treatment in patients with heart failure and with activated renin angiotensin systems. The similar effects of intravenous perindoprilat and enalaprilat on blood pressure contrast with previously reported differences when perindopril and enalapril were given orally.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Enalaprilat; Female; Heart Failure; Heart Rate; Humans; Indoles; Male; Middle Aged; Prospective Studies; Renin

Angiotensin-converting enzyme (ACE) inhibitors improve survival in heart failure and delay progression to clinical heart failure in patients with left ventricular dysfunction after myocardial infarction. Increasing numbers of older patients are being considered for such treatment. However, there are reports of excessive and prolonged decreases in blood pressure (BP) after the first dose of some ACE inhibitors. We have studied the hemodynamics, pharmacokinetics, and neurohumoral responses to the first dose of oral captopril 6.25 mg, enalapril 2.5 mg, perindopril 2.0 mg, intravenous enalaprilat 1.5 mg, and perindoprilat 1.0 mg, compared with oral or intravenous placebo in 6 parallel groups of 12 elderly patients each with moderate-to-severe (New York Heart Association classes II-IV) heart failure. Oral dosing with active drugs led to different temporal responses. After captopril, there was an early short-lived decrease in BP. Enalapril led to a later long-lasting decrease, but perindopril was not different from placebo. Intravenous enalaprilat and intravenous perindoprilat each lowered BP to a similar extent. The doses of drugs used appeared to be comparable because plasma ACE inhibition was similar following perindopril or enalapril and also comparing perindoprilat and enalaprilat. These studies indicate that oral ACE inhibitors have different profiles of acute BP changes after the first dose. The explanation is not clear, but could include physicochemical differences in the interaction between prodrug ester and diacid metabolites leading to differences in tissue distribution and local enzyme inhibition.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Double-Blind Method; Enalapril; Enalaprilat; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Perindopril; Prodrugs

Angiotensin-converting enzyme (ACE) inhibitors prevent the formation of angiotensin II in the circulation and a range of tissues. ACE inhibitors not only are effective, well-tolerated antihypertensive drugs but also improve symptoms and signs in patients with congestive cardiac failure. In addition, they improve long-term survival in these latter patients. Although ACE inhibitors are relatively free of side effects in patients with heart failure, hypotension after the first dose has been reported that may lead to symptomatic renal, cardiac, or cerebral hypoperfusion. Most reports have been uncontrolled and anecdotal. We report a double-blind placebo-controlled study in a parallel group of patients with cardiac failure (New York Heart Association classes II through IV). In total, 72 patients (6 groups of 12) were studied after either placebo, captopril, 6.25 mg, enalapril, 2.5, or perindopril, 2 mg orally, enalaprilat 1.5 mg, or perindoprilat, 1.0 mg intravenously. The blood pressure responses differed between the groups, with a short-lived early fall after captopril and a long-lasting fall after enalapril, whereas perindopril was no different from placebo. There was no significant difference between the two active intravenous regimens. Plasma ACE measurements suggested that the relative doses used were at least comparable. Further studies are in progress to investigate the mechanisms underlying the differential hemodynamic responses and also to explore the clinical relevance to safety and efficacy in the management of heart failure.

Topics: Acetylcholinesterase; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Double-Blind Method; Enalapril; Enalaprilat; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Perindopril

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

To examine the manner in which changes in diastolic performance can contribute to the effect of vasodilation in patients with left ventricular (LV) systolic dysfunction, we examined the effect of acute inhibition of angiotensin converting enzyme with intravenous enalaprilat on early LV diastolic filling. We studied 43 patients with congestive heart failure and depressed LV systolic function (mean ejection fraction +/- SD, 0.24 +/- 0.06), performing radionuclide ventriculography before and after administration of 1.25 mg intravenous enalaprilat. We measured the effect of enalaprilat on the maximum rate of early LV diastolic filling normalized in four different ways and related these changes to both LV and right ventricular (RV) volumes. Enalaprilat induced a small but statistically significant reduction in LV end-systolic volume and increase in LV ejection fraction. For the entire patient group, there was no significant change in LV peak filling rate after enalaprilat administration. For individual patients, however, the effect of enalaprilat on peak filling rate was related to resting RV end-diastolic and end-systolic volumes. In patients with enlarged RV end-diastolic volumes (greater than or equal to 120 ml/m2), mean peak filling rate increased from 1.38 +/- 0.6 to 1.71 +/- 0.6 end-diastolic volumes (EDV)/sec and from 244 +/- 131 to 297 +/- 162 ml/sec/m2 after enalaprilat administration, whereas no change in mean peak filling rate was observed in patients with nondilated RVs. These observations were present regardless of the method of normalizing peak filling rate. Thus, the response of LV peak filling rate to enalaprilat is influenced by the presence of RV dilatation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalaprilat; Heart Failure; Humans; Multicenter Studies as Topic; Myocardial Contraction; Randomized Controlled Trials as Topic; Stroke Volume

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

Serum MK-422 and plasma angiotensin converting enzyme activity were measured during the introduction of enalapril therapy in eight patients with heart failure. In a second study of 16 patients, we recorded exercise tolerance, clinical status and haemodynamics before and after 12 weeks of placebo or enalapril treatment. Increasing doses of enalapril gave step-wise increments in serum MK-422. Plasma converting enzyme activity remained low for at least 24 h after each dose of enalapril (5, 10 and 20 mg). Compared to placebo patients (n = 8), those receiving enalapril (n = 8) tended to improve their exercise performance and clinical status, and showed a fall in right heart pressures after 12 weeks of treatment.

Topics: Aged; Clinical Trials as Topic; Dipeptides; Double-Blind Method; Enalapril; Enalaprilat; Enzyme Inhibitors; Exercise Test; Heart Failure; Humans; Middle Aged; Peptidyl-Dipeptidase A

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Drug Interactions; Enalaprilat; Fibrinolytic Agents; Heart Failure; Humans; Male; Practice Patterns, Physicians'

Several recent studies suggest an important role for the brain renin-angiotensin system in the pathogenesis of heart failure. Angiotensin-converting enzyme (ACE) activity and binding of angiotensin type 1 (AT1) receptors, which mediate the central effects of ANG II, are increased in heart failure. The present study examined the relationship between brain ACE activity and the autonomic dysregulation characteristic of rats with congestive heart failure. Rats with heart failure (HF) induced by coronary artery ligation and sham-operated control (SHAM) rats were treated with chronic (28 days) third cerebral ventricle [intracerebroventricular (ICV)] or intraperitoneal (IP) infusion of a low dose of the ACE inhibitor enalaprilat (ENL) or vehicle (VEH). VEH-treated HF rats had increased sodium consumption, reduced urine sodium and urine volume, and increased sympathetic nerve activity with impaired baroreflex regulation. These responses were minimized or prevented by ICV ENL started 24 h after coronary ligation. IP ENL at the low dose used in these studies had no beneficial effects on HF rats. Neither IP nor ICV ENL had any substantial effect on the SHAM rats. The findings confirm a critically important contribution of the brain renin-angiotensin system to the pathophysiology of congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autonomic Nervous System; Baroreflex; Brain; Diuresis; Drinking; Enalaprilat; Heart Failure; Injections, Intraperitoneal; Injections, Intraventricular; Male; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Sodium Chloride; Water

We sought to demonstrate non-angiotensin converting enzyme (ACE) dependent angiotensin II (AII) generating pathways in resistance arteries from patients with chronic heart failure (CHF).. Non-ACE dependent AII generation occurs in resistance arteries from normal volunteers. Inhibition of non-ACE dependent AII generation may have therapeutic potential in CHF.. Resistance arteries were dissected from gluteal biopsies from patients with coronary heart disease (CHD) and preserved left ventricular function and from patients with CHF. Using wire myography, concentration response curves to angiotensin I (AI) and AII were constructed in the presence of 1) vehicle, 2) chymostatin [an inhibitor of chymase], 3) enalaprilat, and 4) the combination of chymostatin and enalaprilat.. In resistance arteries from patients with CHD, the vasoconstrictor response to AI was not inhibited by either inhibitor alone (chymostatin [p > or = 0.05] or enalaprilat [p > or = 0.05]) but was significantly inhibited by the combination (p < 0.001). In arteries from patients with CHF, AI responses were inhibited by enalaprilat (p < 0.05) but not by chymostatin alone (p > 0.05). The combination ofchymostatin and enalaprilat markedly inhibited the response to AI (p < 0.001) to a greater degree than enalaprilat alone (p < or = 0.01).. Non-ACE dependent AII generating pathways exist in resistance arteries from patients with both CHF and CHD. In resistance arteries from patients with CHD, inhibition of either the ACE or chymase pathway alone has no effect on AII generation, and both pathways must be blocked before the vasoconstrictor action of AI is inhibited. In CHF, blockade of ACE results in marked inhibition of responses to AI, but this is enhanced by coinhibition of chymase. These studies suggest that full suppression of the renin-angiotensin system cannot be achieved by ACE inhibition alone and provide a rationale for developing future therapeutic strategies.

Topics: Acetylcholine; Aged; Angina Pectoris; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Arteries; Bradykinin; Chymases; Enalaprilat; Female; Heart Failure; Humans; In Vitro Techniques; Losartan; Male; Middle Aged; Oligopeptides; Peptidyl-Dipeptidase A; Serine Endopeptidases; Vascular Resistance; Vasoconstriction

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

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

Increasing evidence suggests that angiotensin-converting enzyme (ACE) inhibitors can increase vascular nitric oxide (NO) production. Recent studies have found that combined inhibition of ACE and neutral endopeptidase (NEP) may have a greater beneficial effect in the treatment of heart failure than inhibition of ACE alone. Amlodipine, a calcium channel antagonist, has also been reported to have a favorable effect in the treatment of patients with cardiac dysfunction. The purpose of this study was to determine whether and the extent to which all of these agents used in the treatment of heart failure stimulate vascular NO production. Heart failure was induced by rapid ventricular pacing in conscious dogs. Coronary microvessels were isolated from normal and failing dog hearts. Nitrite, the stable metabolite of NO, was measured by the Griess reaction. ACE and NEP inhibitors and amlodipine significantly increased nitrite production from coronary microvessels in both normal and failing dog hearts. However, nitrite release was reduced after heart failure. For instance, the highest concentration of enalaprilat, thiorphan, and amlodipine increased nitrite release from 85 +/- 4 to 156 +/- 9, 82 +/- 7 to 139 +/- 8, and 74 +/- 4 to 134 +/-10 pmol/mg (all *p <.01 versus control), respectively, in normal dog hearts. Nitrite release in response to the highest concentration of these two inhibitors and amlodipine was reduced by 41% and 31% and 32% (all #p <.01 versus normal), respectively, in microvessels after heart failure. The increase in nitrite induced by either ACE or NEP inhibitors or amlodipine was entirely abolished by Nw-nitro-L-arginine methyl ester, HOE 140 (a B2-kinin receptor antagonist), and dichloroisocoumarin (a serine protease inhibitor) in both groups. Our results indicate that: 1) there is an impaired endothelial NO production after pacing-induced heart failure; 2) both ACE and NEP are largely responsible for the metabolism of kinins and modulate canine coronary NO production in normal and failing heart; and 3) amlodipine releases NO even after heart failure and this may be partly responsible for the favorable effect of amlodipine in the treatment of heart failure. Thus, the restoration of reduced coronary vascular NO production may contribute to the beneficial effects of these agents in the treatment of heart failure.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin Receptor Antagonists; Coronary Vessels; Cysteine Proteinase Inhibitors; Dogs; Enalaprilat; Glycopeptides; Heart Failure; Kininogens; Kinins; Nitric Oxide; Protease Inhibitors; Ramipril; Receptor, Bradykinin B2; Thiorphan; Vasodilator Agents

This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, i.v.) or enalaprilat (1 mg/kg, i.v.) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50% of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 +/- 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 +/- 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Dogs; Enalaprilat; Female; Heart Failure; Hemodynamics; Imidazoles; Losartan; Male; Renin; Renin-Angiotensin System; Tetrazoles; Vasodilation

To determine the short-term effects of angiotensin-converting enzyme (ACE) inhibition on hemodynamics and circulating levels of norepinephrine, angiotensin, and bradykinin, responses to enalaprilat and perindoprilat were examined at doses of 0.03, 0.3, and 1 mg/kg in permanently instrumented conscious dogs with pacing-induced heart failure (right ventricular pacing, 240-250 beats/min, 3 weeks). All doses of the two inhibitors produced similar decrease in mean aortic pressure and increase in cardiac output. Neither inhibitor affected plasma norepinephrine level. Both compounds induced a similar 60-80% decrease in blood angiotensin II level, a similar two- to eightfold increase in blood angiotensin I level, and a 80-95% decrease in the angiotensin II/angiotensin I ratio. There were also a fourfold to 10-fold increase in blood bradykinin-(1-9) level, a twofold increase in blood bradykinin-(1-7) level, and a 70-85% decrease in bradykinin-(1-7)/bradykinin-(1-9) ratio. In addition, the changes in total peripheral resistance induced by the two ACE inhibitors were weakly but significantly correlated with the changes in blood angiotensin II or blood bradykinin-(1-9). Thus whatever the specificity of enalaprilat and perindoprilat, both inhibitors produced similar acute hemodynamic effects in dogs with heart failure, which was associated with marked decrease in circulating angiotensin II level and increase in bradykinin-(1-9) level. This study, which measures for the first time in heart failure the blood bradykinin level after ACE inhibitors, indicates, in concert with angiotensin II reduction, a role for increased bradykinin-(1-9) level in mediating short-term hemodynamic effects of ACE inhibition in this model of heart failure.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cardiac Output; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Enalaprilat; Heart Failure; Indoles; Norepinephrine; Peptide Fragments; Ventricular Function, Left

Toborinone (OPC-18790), a phosphodiesterase III inhibitor, enhances cardiac contractility and is an arterial dilator. However, its effects on the venous system have not yet been clearly defined. Because toborinone administration reduces left ventricular (LV) end-diastolic pressure, it is probably also a venodilator. Because of the known arterial effects and the hypothesized venous effects, we compared changes in systemic vascular conductance (the inverse of resistance) with changes in venous capacitance.. In 15 anesthetized, splenectomized dogs (10 treatment, 5 control), pressures were measured in the right atrium, aorta, portal vein, and LV. A cuff constrictor was placed around the portal vein. Cardiac output was measured by thermodilution, and splanchnic vascular capacitance was measured by blood-pool scintigraphic methods. Data were collected at baseline, after induction of heart failure (microsphere embolization into the left coronary artery), and then after toborinone boluses of 0.1, 0.2, 0.4, and 0.8 mg/kg. Heart failure was associated with decreased capacitance and conductance (to 87+/-3% and 64+/-4% of baseline values, respectively, P<0.05). After administration of the lower doses of toborinone, capacitance increased more than conductance; however, the effects were more balanced at the higher doses. Compared with nitroglycerin, hydralazine, and enalaprilat (results of an earlier study) in the same model, toborinone increased capacitance to a degree similar to that with nitroglycerin, at higher doses increased conductance similarly to hydralazine, and increased both capacitance and conductance considerably more than did enalaprilat.. Toborinone is a potent balanced venous and arterial dilator in experimental acute heart failure. These marked effects suggest that it may prove to be a clinically important alternative to other vasodilators.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Dogs; Enalaprilat; Female; Heart Failure; Hemodynamics; Hydralazine; Male; Nitroglycerin; Phosphodiesterase Inhibitors; Quinolones; Vascular Capacitance; Vasodilator Agents

The goal of this study was to determine if the hemodynamic effects of the combined administration of an angiotensin converting enzyme (ACE) inhibitor and angiotensin II type 1 (AT1) receptor antagonist are greater than those produced by either of these agents administered individually during heart failure.. Ten farm pigs were chronically instrumented with aortic, left atrial and right atrial catheters, a left ventricular (LV) pressure gauge, LV dimension crystals, coronary occluders, an ascending aortic flow probe and pacing leads. Heart failure was induced by serial myocardial infarctions followed by repeated rapid ventricular pacing.. Heart failure was manifested by significant (p < 0.01) decreases in LV dP/dt (-38 +/- 5%, from 2943 +/- 107 mmHg/s) and cardiac output (-27 +/- 4%, from 4.1 +/- 0.2 l/min) and increases in left atrial pressure (+18 +/- 1 mmHg, from 4 +/- 1 mmHg) and total peripheral resistance (TPR)(+40 +/- 8%, from 23 +/- 2 mmHg/l/min). The effects of an ACE inhibitor (enalaprilat) and an AT1 receptor antagonist (L-158,809), administered in maximally effective doses, either individually or concomitantly, were examined on different days in conscious pigs with heart failure. There were no differences in any of the baseline hemodynamic measurements among the groups studied. Thirty minutes after administration, enalaprilat (4 mg/kg i.v.) increased (p < 0.05) cardiac output by 8 +/- 2% and reduced (p < 0.05) mean arterial pressure and TPR by 5 +/- 1 and 12 +/- 1%, respectively, while the changes in LV dP/dt (0 +/- 2%), LV fractional shortening (+4 +/- 3%) and heart rate (+1 +/- 1%) were not statistically significant. Similarly, L-158,809 (4 mg/kg, i.v.) increased cardiac output by 9 +/- 2% and reduced mean arterial pressure and TPR by 4 +/- 1 and 11 +/- 3%, respectively, while the changes in LV dP/dt (+3 +/- 3%), LV fractional shortening (+3 +/- 1%) and heart rate (0 +/- 1%) were not significant. However, enalaprilat (1 mg/kg, i.v.) and L-158,809 (1 mg/kg, i.v.), administered concomitantly, reduced TPR by 21 +/- 3%, an effect greater (p < 0.05) than when either of these agents was administered individually at a dose of 4 mg/kg, i.v. The changes in mean arterial pressure (-9 +/- 2%), cardiac output (+15 +/- 4%) and LV fractional shortening (+11 +/- 3%) also tended to be greater with concomitant administration. In addition, in a sequential dosing protocol, when L-158,809 (1 mg/kg, i.v.) was administered 30 min after enalaprilat (1 mg/kg, i.v.), TPR was reduced by 20 +/- 4% compared to only a 6 +/- 3% reduction (p < 0.05) when the enalaprilat was followed 30 min later by a second dose of enalaprilat (1 mg/kg, i.v.). The changes in mean arterial pressure and cardiac output for the combined treatment group also tended to be greater than those for the group given two sequential doses of enalaprilat.. In conscious pigs with heart failure, the combined vasodilatory effects of an ACE inhibitor and AT1 receptor antagonist are greater than those produced when only one of these agents is administered, suggesting that independent mechanisms of ACE inhibition and AT1 receptor antagonism could be partly responsible for the improved vascular dynamics during heart failure.

Topics: Analysis of Variance; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enalaprilat; Female; Heart Failure; Hemodynamics; Imidazoles; Male; Swine; Tetrazoles

Impaired baroreflex function is a characteristic feature of congestive heart failure (CHF), although the mechanism is obscure. This study examined the hypothesis that activation of the renin-angiotensin system contributes to baroreflex dysfunction in CHF. The acute effects of an angiotensin converting enzyme inhibitor, enalaprilat, on baroreflex-mediated changes in heart rate (HR), total and renal noradrenaline (NA) spillover rates were examined in conscious rabbits with doxorubicin-induced cardiomyopathic CHF. Studies were performed under resting conditions and in response to changes in mean arterial pressure (MAP) induced by sodium nitroprusside and phenylephrine infusions. Seven saline-treated (normal group) and 11 doxorubicin-treated rabbits (1 mg/kg administered intravenously twice weekly) were studied after 4 and 6 weeks' treatment. Five CHF rabbits received saline (C group) and 6 enalaprilat infusion (ACEI group) during each study period. After 4 weeks of doxorubicin, baroreflex-HR responses were normal, whereas baroreflex-NA spillover responses were enhanced. Enalaprilat infusion shifted the HR-MAP curve downwards to the left but had no effect on the NA spillover-MAP curves. After 6 weeks of doxorubicin, when CHF was established, baroreflex-HR and NA spillover curves were depressed. At this stage, enalaprilat had little effect on the HR-MAP curve but restored towards normal the NA spillover-MAP curves. The results suggest that the endogenous renin-angiotensin system contributes to attenuated baroreflex responses when CHF is established.

Topics: Adrenergic alpha-Agonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Baroreflex; Blood Pressure; Doxorubicin; Enalaprilat; Heart Failure; Heart Rate; Nitroprusside; Norepinephrine; Phenylephrine; Rabbits; Regional Blood Flow; Renal Circulation; Renin-Angiotensin System

This study sought to determine the effects of enalaprilat on reflex control of sympathetic nerve activity.. Angiotensin-converting enzyme inhibitors decrease mortality in patients with congestive heart failure. Their efficacy appears to be related importantly to antiadrenergic effects, the mechanism for which has not been determined. Because baroreflexes tonically inhibit sympathetic outflow, and baroreflexes are blunted in heart failure, we hypothesized that these agents reduce sympathetic activity by augmenting baroreflexes.. We assessed baroreflex control of sympathetic nerve activity and heart rate in patients with congestive heart failure and in control subjects before and after enalaprilat (0.02 mg/kg body weight intravenously). Arterial baroreflexes were perturbed by bolus administration of sodium nitroprusside and phenylephrine. Cardiopulmonary baroreflexes were perturbed by lower body negative pressure and head-down tilt. Muscle sympathetic nerve activity was recorded by microneurography.. Enalaprilat decreased systolic blood pressure in patients with heart failure and control subjects. Sympathetic nerve activity increased in control subjects but decreased in patients with heart failure after enalaprilat despite reductions in central venous pressure in this group. Baroreflex control of sympathetic nerve activity was unchanged by enalaprilat in control subjects. In patients with heart failure, both arterial and cardiopulmonary baroreflex control of sympathetic nerve activity was enhanced by enalaprilat. Baroreflex control of heart rate was unchanged by enalaprilat in either group.. Enalaprilat augments both arterial and cardiopulmonary baroreflex control of sympathetic activity in heart failure. These augmented inhibitory influences are associated with a reduction in sympathetic outflow and may contribute to the beneficial effects of angiotensin-converting enzyme inhibitors in heart failure.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Baroreflex; Case-Control Studies; Enalaprilat; Heart Failure; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Sympathetic Nervous System

This study examined the effect of low dose aspirin on cardiorenal and neurohumoral function and on the acute hemodynamic response to enalaprilat in a canine model of heart failure.. Low dose aspirin is frequently prescribed for patients with systolic dysfunction who also benefit from angiotensin-converting enzyme inhibition. Although high doses of potent cyclo-oxygenase inhibitors cause fluid retention and vaso-constriction and antagonize the effects of angiotensin-converting enzyme inhibitors, the effects of low dose aspirin in heart failure are unknown.. A model of heart failure was produced in 11 mongrel dogs by rapid ventricular pacing (250 beats/min for 12 to 14 days). Five dogs received 325 mg aspirin/day for the final 4 days of pacing before the acute experiment; six control dogs received no aspirin. Cardiorenal and neurohumoral function was measured during chloralose anesthesia. Hemodynamic and renal responses to enalaprilat were assessed.. Both groups demonstrated severe heart failure with decreased cardiac output; increased atrial pressures and systemic resistance; activation of plasma renin activity, aldosterone and atrial natriuretic factor; and sodium retention. Low dose aspirin had no detrimental effect on cardiorenal or neurohumoral function. Mean arterial pressure, pulmonary capillary wedge pressure and systemic vascular resistance decreased to a similar degree with enalaprilat in both groups. There was no difference between the groups with respect to renal response to enalaprilat.. The present study demonstrates that low dose aspirin has no adverse effect on hemodynamic, neurohumoral or renal function in heart failure. Furthermore, aspirin has no adverse effect on the acute response to enalaprilat. These findings suggest that there is no contraindication to concomitant treatment with low dose aspirin and angiotensin-converting enzyme inhibitors in humans with heart failure.

Topics: Aldosterone; Animals; Aspirin; Atrial Natriuretic Factor; Disease Models, Animal; Dogs; Drug Administration Schedule; Drug Interactions; Enalaprilat; Heart Failure; Hemodynamics; Kidney; Renin; Ventricular Dysfunction

Vasodilator drugs have variable effects on veins and arteries. However, direct measurements of their effects on the splanchnic veins, perhaps the most important volume reservoir, have not been reported. We assessed the effect of acute heart failure and the subsequent administration of hydralazine, enalaprilat, and nitroglycerin on the splanchnic venous pressure-volume relation in intact dogs.. Experimental acute ischemic heart failure was induced in 19 splenectomized dogs by microsphere embolization of the left main coronary artery. Embolization was repeated until left ventricular end-diastolic pressure (LVEDP) reached 20 mm Hg and cardiac output decreased by 50%. The splanchnic vascular pressure-volume relation was determined by radionuclide plethysmography during the control stage, after acute heart failure had been established, and after administration of a vasodilator (hydralazine, enalaprilat, or nitroglycerin) at a dose sufficient to reduce mean aortic pressure by approximately 20%. Induction of acute heart failure was associated with a decrease in the splanchnic vascular volume from 100% to 86 +/- 2% and an increase in LVEDP from 6 +/- 1 to 21 +/- 1 mm Hg (P < .001). There was a parallel leftward shift of the splanchnic vascular pressure-volume curve. After the administration of hydralazine, enalaprilat, and nitroglycerin, the splanchnic vascular volumes increased from 86% to 88 +/- 3%, 96 +/- 3%, and 113 +/- 3%, respectively (P = NS, P < .01, and P < .001, respectively, versus heart failure). After drug administration, the LVEDPs were 18 +/- 2, 16 +/- 1, and 13 +/- 1 mm Hg (P = NS, P < .05, and P < .001, respectively, versus heart failure).. Acute heart failure was associated with a parallel leftward shift of the splanchnic venous pressure-volume relation (venoconstriction). Splanchnic (systemic) venoconstriction may in part explain the increased LVEDP during acute heart failure by displacement of blood to the central compartment. Subsequently administered enalaprilat and, to a greater degree, nitroglycerin produced splanchnic venodilation, thereby lowering LVEDP. Hydralazine had no significant effect on the splanchnic veins and only a modest effect on LVEDP. In this model, splanchnic capacitance changes appear to modulate change in left ventricular preload.

Topics: Animals; Dogs; Enalaprilat; Heart Failure; Hydralazine; Mesenteric Veins; Nitroglycerin; Plethysmography; Radionuclide Imaging; Splanchnic Circulation; Venous Pressure; Ventricular Dysfunction, Left; Ventricular Function, Left

Neutral endopeptidase inhibition (NEP-I) and angiotensin converting enzyme inhibition (ACE-I) act synergistically to produce acute beneficial hemodynamic effects in models of heart failure. Blockade of the formation of angiotensin II (Ang II) acting together with potentiation of the natriuretic peptides, bradykinin and other vasoactive peptides may mediate the interaction of dual enzyme inhibition. In this study, the potential roles of Ang II repression and bradykinin potentiation were evaluated in conscious cardiomyopathic hamsters with compensated heart failure. The Ang II AT1 receptor antagonist, SR 47436 (BMS-186295), was administered at 30 mumol/kg, i.v. followed by i.v. infusion at 1 mumol/kg/min in combination with NEP-I (SQ-28603 at 30 mumol/kg i.v.). Cardiac preload (left ventricular end diastolic pressure) and afterload (left ventricular systolic pressure) decreased significantly more after the combination of Ang II blockade and NEP-I than after either treatment alone. This indicated that repression of Ang II contributes importantly to the NEP-I/ACE-I interaction. Bradykinin B2 receptor antagonism by Hoe 140 at 100 micrograms/kg, i.v. significantly blunted the decrease in left ventricular end diastolic pressure but not the decrease in left ventricular systolic pressure after dual NEP-I/ACE-I (SQ-28603 and enalaprilat each at 30 mumol/kg, i.v.). This suggests that bradykinin potentiation contributes to the preload-reducing, but not the afterload-reducing, acute effects of NEP-I/ACE-I. Hence, both Ang II repression and bradykinin potentiation are factors contributing to the synergistic hemodynamic effects of combined NEP-I and ACE-I in hamsters with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alanine; Angiotensin II; Animals; Biphenyl Compounds; Blood Pressure; Blood Volume; Bradykinin; Cricetinae; Drug Synergism; Enalaprilat; Heart Failure; Irbesartan; Male; Neprilysin; Tetrazoles; Vasodilation; Ventricular Function, Left

Chronic congestive heart failure (CHF) was induced in rabbits with doxorubicin in order to evaluate: (1) haemodynamic and regional blood flow responses to propofol anaesthesia; (2) modification of these cardiovascular responses with background intravenous infusions of enalaprilat or dopexamine.. Rabbits received either doxorubicin, 2 mg.kg-1 weekly intravenously for seven weeks (CHF, n = 6), or saline (controls, n = 6). Doppler flow probes were implanted on the ascending aorta, left renal artery, and lower abdominal aorta. In three separate studies propofol was infused for 40 min periods at 0.6 and then 1.2 mg.kg-1.min-1 after background infusions of either saline, enalaprilat (0.2 mg.kg-1 + 0.003 mg.kg-1.min-1), or dopexamine (0.008 mg.kg-1.min-1).. In normal rabbits propofol (1.2 mg.kg-1.min-1) reduced mean arterial pressure from awake control by 33(SEM 3)%, cardiac output by 24(4)%, and hindlimb blood flow (HBF) by 10(2)%, but did not change renal blood flow. In rabbits with CHF, although resting mean blood pressure was lower, propofol did not alter blood pressure or hindlimb blood flow, but renal blood flow was reduced by 37(6)%.. Both enalaprilat and dopexamine increased renal blood flow in the control and CHF groups. Enalaprilat caused marked hypotension during anaesthesia in the CHF group. Dopexamine increased mean arterial pressure, heart rate, and hindlimb blood flow during anaesthesia in controls, but not in CHF.

Topics: Anesthesia; Animals; Blood Pressure; Cardiac Output; Dopamine; Doxorubicin; Enalaprilat; Heart Failure; Heart Rate; Hemodynamics; Hindlimb; Kidney; Propofol; Rabbits; Regional Blood Flow; Vasodilator Agents

Enalapril and enalaprilat concentrations were measured after enalapril maleate (0.05 to 0.3 mg/kg) was administered orally to 12 pediatric patients (age range, 10 days to 6 1/2 years) with congestive heart failure caused by congenital heart disease and compared with those obtained from seven normal adults (age range, 21 to 39 years). When normalized to the oral 1 mg/m2 dose of enalapril maleate, the mean +/- SD area under the serum concentration-time curve (AUC) of enalaprilat, a pharmacologically active angiotensin-converting enzyme inhibitor, did not differ significantly between the pediatric group aged > 20 days and adult group (83.1 +/- 47.0 versus 64.6 +/- 17.8 ng.hr/ml per 1 mg/m2). When normalized to the oral 0.1 mg/kg dose, the mean AUC was significantly (p < 0.05) smaller in this pediatric group than in the adult group (138.4 +/- 69.2 versus 245.7 +/- 61.8 ng.hr/ml per 0.1 mg/kg). The AUC observed in three younger (age < 20 days) subjects tended to be much greater compared with infants aged > 20 days. The mean AUC ratio of enalaprilat to enalapril was significantly (p < 0.05) lower in the older pediatric subgroup (2.0 +/- 1.0) than in the adult group (3.4 +/- 1.6), whereas the mean ratios were comparable between the two subdivided pediatric groups. The results suggest that the oral enalapril dose would be better determined on a body surface area rather than on a body weight basis in pediatric patients with congestive heart failure aged > 20 days. The oral dosage should be much reduced in infants with congestive heart failure aged < 20 days compared with those aged > 20 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Biotransformation; Child; Child, Preschool; Dose-Response Relationship, Drug; Enalapril; Enalaprilat; Female; Heart Defects, Congenital; Heart Failure; Humans; Infant; Infant, Newborn; Male

In this study, the acute haemodynamic effects of angiotensin converting enzyme (ACE) inhibition with intravenous enalaprilat alone or in combination with preload restoration were determined in patients with severe heart failure complicating acute myocardial infarction. Ten patients with raised pulmonary arterial wedge pressure (PAWP > or = 18 mmHg) were first studied during constant conventional vasodilation with diuretic and inotropic medication, by monitoring central haemodynamics and arterial blood gases. The same variables were measured before enalaprilat infusion, after preload reduction with enalaprilat (1 mg.h-1, rate doubled every 30 min until PAWP decreased > or = 25% or up to total cumulative dose of 10 mg) and after preload restoration with fluid loading (4% albumin given 15 ml.min-1 to restore PAWP to baseline) during continuous low dose enalaprilat infusion. Enalaprilat alone (median dose 0.9 mg) reduced significantly the PAWP (from 25 to 17 mmHg; P = 0.004), the mean arterial pressure (from 87 to 83 mmHg; P = 0.008), the mean pulmonary arterial pressure and the right atrial pressure. The cardiac index, stroke volume index and systemic vascular resistance index remained unchanged. Preload restoration during continuous enalaprilat infusion (median dose of 4% albumin 230 ml, and enalaprilat 0.2 mg) did not further enhance left ventricular function; rather, there was a nearly significant decrease in myocardial perfusion pressure. Arterial oxygenation remained unchanged throughout the study. In conclusion, adding intravenous enalaprilat to conventional therapy makes it possible to relieve pulmonary congestion while maintaining the cardiac function and arterial oxygenation. Preload restoration during continuous ACE inhibition offers no further advantages, and may have adverse effects, since the myocardial perfusion pressure may fall.

Topics: Aged; Enalaprilat; Female; Heart; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Pulmonary Circulation; Pulmonary Wedge Pressure

The hemodynamic response 1 hour after 1.25 mg of intravenous (IV) enalaprilat was examined in 20 patients (mean age 75 years) with severe congestive heart failure (CHF) and mitral regurgitation (MR), secondary to ischemic heart disease (NYHA Class IV). Patients were classified into two groups based upon the magnitude of MR as derived from Doppler color flow imaging: Group I (n = 13) had severe MR and Group II (n = 7) had moderate MR. Acute therapy significantly reduced systemic vascular resistance index in both groups and provided effective afterload reduction. Although cardiac and stroke volume indices increased in both groups, an improved forward flow was significant only for Group I (cardiac index 2.2 +/- 0.5 to 2.7 +/- 0.5 l/min/m2, p < 0.02). The magnitude of MR, acutely reduced in all patients, was similarly significant only for Group I (56 +/- 10% to 31 +/- 12%, p < 0.01). The reduction of both pulmonary capillary wedge pressure and mean arterial pressure was significant for both groups. This study supports the use of IV enalaprilat, a parenteral angiotensin-converting enzyme (ACE) inhibitor, as an effective and rapidly acting vasodilator in the management of selected patients with chronic heart failure and MR who require immediate hemodynamic improvement.

Topics: Aged; Echocardiography, Doppler; Enalaprilat; Female; Heart Failure; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Mitral Valve Insufficiency

1. The acute effect of an angiotensin converting enzyme inhibitor (ACEI), enalaprilat, on baroreflex-mediated changes in renal and total NA spillover rate in conscious rabbits with doxorubicin-induced cardiomyopathic congestive heart failure (CHF) were investigated under resting conditions and in response to changes in arterial pressure induced by sodium nitroprusside and phenylephrine infusions. 2. Six saline-treated (N group) and 11 doxorubicin-treated rabbits (1 mg/kg administered i.v. twice weekly) were studied after 4 and 6 weeks treatment. Five CHF rabbits received saline (C group) and six enalaprilat infusion (ACEI group). 3. After 4 weeks of doxorubicin, mean arterial pressure (MAP)-renal noradrenaline (NA) spillover and MAP-total NA spillover curves did not change during enalaprilat infusion. 4. After 6 weeks, the C group showed blunted MAP-renal NA spillover and MAP-total NA spillover curves. In the ACEI group, however, both curves returned toward those seen in the N group (slope of MAP-renal NA curve: from 0.27 to 1.80 ng/min per mmHg, MAP-total NA curve: from 1.61 to 3.59 ng/min per mmHg). 5. Results of this study indicate that enalaprilat enhances baroreflex control of renal and total NA spillover in rabbits with CHF and further support the view that activation of the renin-angiotensin system contributes significantly to the attenuated baroreflex responses in CHF.

Topics: Animals; Blood Pressure; Doxorubicin; Enalaprilat; Heart Failure; Kidney; Male; Nitroprusside; Norepinephrine; Phenylephrine; Pressoreceptors; Rabbits

The hemodynamic effects of acute intravenous administration of nitroprusside, dobutamine, enalaprilat, and digoxin was investigated in a canine model of chronic heart failure (CHF) produced by multiple sequential intracoronary microembolizations. Dobutamine (4 micrograms/kg/min) increased cardiac output (2.4 +/- 0.1 vs. 4.0 +/- 0.4 l/min; p < .001) and LV ejection fraction (LVEF; 26 +/- 1 vs. 30 +/- 4%; p < .01), and decreased systemic vascular resistance (SVR; 3620 +/- 170 vs. 2470 +/- 190 dynes sec cm-5; p < .001). Nitroprusside (3 micrograms/kg/min) acted as a venodilator; it decreased pulmonary artery wedge pressure (16 +/- 1 vs. 13 +/- 1 mmHg; p < .01) and SVR (3730 +/- 440 vs. 3210 +/- 280 dynes sec cm-5; NS) but had no effect on cardiac output. Enalaprilat (1.875 mg) produced a significant increase of cardiac output (3.0 +/- 0.5 vs. 3.8 +/- 0.5 l/min; p < .001) and LVEF (22 +/- 1 vs. 30 +/- 1%; p < .01), and decreased SVR (3280 +/- 400 vs. 2450 +/- 250 dynes sec cm-5; p < .01). Intravenous digoxin at a cumulative dose of 0.75 mg increased LVEF (23 +/- 2 vs. 31 +/- 2%; p < .01) but had no effect on SVR. These data indicate that this canine model of CHF responds to acute pharmacologic intervention in a manner comparable to that seen in patients with CHF. Accordingly, this model may be a useful tool for the preclinical evaluation of new drugs targeted toward the treatment of CHF and for investigating the mechanisms of action of drugs currently used for the treatment of this disease state.

Topics: Animals; Blood Pressure; Cardiac Output; Digoxin; Disease Models, Animal; Dobutamine; Dogs; Enalaprilat; Heart Failure; Heart Rate; Hemodynamics; Nitroprusside; Stroke Volume; Vascular Resistance; Ventricular Function, Left

The short-term hemodynamic effects of intravenous enalaprilat were assessed in 26 infants and children, aged 6 months to 15 years, with intracardiac shunts undergoing cardiac catheterization. Pulmonary and systemic pressure, flow, and resistance indices were measured by the direct Fick method before and 30 min after enalaprilat at 0.06 mg/kg. Aortic and pulmonary artery pressure decreased 15 and 20%, respectively, by 10 min, with little further change at 30 min. The heart rate did not change significantly and there was no reduction in systemic flow. In those with a large ventricular septal defect and normal or near-normal pulmonary resistance (less than 3.5 u.m2, n = 8), the mean pulmonary-systemic flow ratio decreased from 2.9 +/- 0.3 to 2.4 +/- 0.3 (p less than 0.05) and the mean left-to-right shunt from 7.4 +/- 0.8 to 5.9 +/- 0.7 L/min/m2 (p less than 0.02). Those with an elevated pulmonary vascular resistance (greater than 5 u.m2, n = 8) showed a varied response. Two children, both with Down's syndrome, an atrioventricular canal defect, and reversible pulmonary hypertension (as assessed by an infusion of isoproterenol), had no decrease in pulmonary vascular resistance with enalaprilat. There were no adverse effects. Converting enzyme inhibitors may benefit "heart failure" associated with large ventricular septal defects and normal or mildly elevated pulmonary resistance.

Topics: Adolescent; Blood Flow Velocity; Child; Child, Preschool; Enalaprilat; Female; Heart Failure; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Male; Pulmonary Circulation; Pulmonary Wedge Pressure; Renin; Vascular Resistance

Topics: Administration, Oral; Enalapril; Enalaprilat; Female; Heart Failure; Heart Septal Defects, Ventricular; Hemodynamics; Humans; Infant; Injections, Intravenous; Male

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

Circulatory responses to isoflurane and halothane anesthesia were studied in eight rabbits with biventricular cardiomyopathy induced by doxorubicin (Adriamycin, 14 mg/kg IV over 7 wk) and in eight controls (saline injections). In preliminary operations pulsed-Doppler flow probes were placed on the ascending aorta, left renal artery, and lower abdominal aorta. Each group was studied after 4, 6, and 7 wk of treatment. The development of congestive heart failure (CHF) was associated with decreases in mean arterial pressure and cardiac output (CO) of 14% and 16%, respectively, (P less than 0.05) and an increase in heart rate. In controls, each anesthetic agent produced dose-related decreases in mean arterial pressure and increases in heart rate, but not significant changes in CO. Renal blood flow was reduced to a similar degree by 1.3 MAC halothane (24% decrease) and 1.3 MAC isoflurane (21% decrease); hindlimb blood flow was reduced only by halothane. As CHF developed there was an attenuation of the heart rate response to anesthesia. Halothane, but not isoflurane, significantly reduced CO in more advanced stages of CHF. The changes in renal blood flow and hindlimb blood flow with each anesthetic in the CHF group were similar to those observed in controls and did not vary with week of treatment. Administration of the angiotensin-converting enzyme inhibitor enalaprilat (0.2 mg/kg IV) reversed the CO and renal blood flow effects of halothane except after 7 wk of treatment in the CHF group, when the combination of halothane and enalaprilat resulted in severe circulatory depression.

Topics: Animals; Doxorubicin; Drug Interactions; Enalaprilat; Halothane; Heart Failure; Hemodynamics; Isoflurane; Rabbits; Renal Circulation; Renin

Topics: Blood Circulation; Blood Pressure; Cardiac Catheterization; Enalaprilat; Heart Failure; Hemodynamics; Humans; Infant; Vascular Resistance

Topics: Blood Pressure; Echocardiography; Enalaprilat; Esophagus; Gastrectomy; Heart Failure; Heart Rate; Humans; Injections, Intravenous; Male; Middle Aged; Radiography; Surgical Procedures, Operative

Intravenous enalaprilic acid (2.5 mg) was given to 11 patients with stable cardiac failure (NYHA functional class II-IV). Reductions in mean right atrial, pulmonary artery and pulmonary capillary wedge pressure of 25%, 18% and 30% respectively (P less than 0.01), were observed. Cardiac output rose by 13% (NS) and mean blood pressure fell by 20% (P less than 0.01) with a decrease in systemic vascular resistance of 24% (P less than 0.01). Heart rate was unaltered. The haemodynamic effects correlated with control plasma renin activity (r = 0.78, P less than 0.01). Marked hypotension occurred in several subjects but no other side-effects were noted. The rapid onset of action and mixed venous and arteriolar dilating activity of intravenous enalaprilic acid may be an advantage in some clinical situations where parenteral vasodilating therapy is required.

Topics: Aged; Enalapril; Enalaprilat; Female; Heart Failure; Heart Ventricles; Hemodynamics; Humans; Hypotension; Injections, Intravenous; Male; Middle Aged; Pilot Projects; Vasodilator Agents

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

Anesthetized dogs in acute left ventricular failure were treated with the ACE-inhibitor enalaprilat (MK-422). ACE-inhibition produced a fall in the mean blood pressure and a redistribution of cardiac output to the brain, right ventricle, upper gastrointestinal tract, and the inner and middle part of the renal cortex. The flow to the spleen, adrenals, skin, muscle, fat, lower gastrointestinal tract, and outer renal cortex did not change significantly. The differential sensitivity of the tissues to ACE-inhibition is most likely due to differences in sensitivity to circulating angiotensin II.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Circulation; Dogs; Enalapril; Enalaprilat; Heart Failure; Hemodynamics

A model of congestive heart failure (CHF) was produced in rats approximately 76 days following surgical occlusion of the left coronary artery. In rats with healed myocardial infarction (MI size = 45% LV), hemodynamic variables were predictably elevated (LVEDP greater than 20 mm Hg) or depressed LV dP/dtmax (5200 mm Hg/sec). The hemodynamic response (MAP, HR, LVEDP, and dP/dtmax) to intravenous infusion of Mil (54 to 347 micrograms/kg) was measured on two occasions, separated by a 7-12 day period of oral treatment (2 mg/kg/day). Enalaprilat was tested in a similar design with the infusion phase (70 micrograms/kg, total dose) separated by oral enalapril (Enal), 1 mg/kg/day. The hemodynamic response to Mil was also examined in rats treated with the ACE inhibitor. At low doses, Mil modestly elevated HR (+17 beats/min) and dose-dependently increased (P less than 0.05) LV contractility by approximately 25%. Higher doses of Mil reduced preload (LVEDP) and afterload (MAP). Oral Mil produced little hemodynamic improvement except modest elevation (+9%) in LV contractility. There was no evidence of tachyphylaxis to i.v. Mil. In contrast, enalaprilat reduced MAP and preload without altering HR or contractility, effects observed after oral treatment. In the presence of the ACE inhibitor, Mil's hemodynamic actions were not enhanced. These experiments demonstrate that ACE inhibition improves ventricular performance by reducing preload and afterload. In this model, Mil improves performance by a direct inotropic mechanism as well as a reduction in afterload.

Topics: Animals; Antihypertensive Agents; Drug Therapy, Combination; Enalapril; Enalaprilat; Heart Failure; Hemodynamics; Milrinone; Myocardial Contraction; Myocardial Infarction; Pyridones; Rats; Vasodilator Agents

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

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

Renal blood flow was serially measured as the left renal vein blood flow using the continuous thermodilution technique during acute angiotensin converting enzyme inhibition in 20 patients with stable congestive heart failure. Eleven patients received captopril orally, and the remaining nine patients received enalaprilat intravenously. During the control period, left renal vein blood flow and cardiac output did not correlate closely (r = 0.57). Following administration of captopril or enalaprilat, stroke volume index increased from 20 +/- 7 to 25 +/- 8 ml/M2 (p less than 0.001), while pulmonary capillary wedge pressure decreased from 26 +/- 8 to 19 +/- 8 mm Hg (p less than 0.001). Left renal vein blood flow increased in all patients despite a consistent reduction in systemic arterial pressure. At peak effect, left renal vein blood flow increased from 295 +/- 86 to 443 +/- 122 ml/min (p less than 0.001), while mean systemic arterial pressure fell from 81 +/- 13 to 71 +/- 14 mm Hg (p less than 0.001). Thus, in patients with stable congestive heart failure, acute angiotensin converting enzyme inhibition, although decreasing substantially systemic arterial pressure, consistently enhances renal blood flow.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Enalapril; Enalaprilat; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Renal Circulation; Thermodilution

Acute left ventricular failure was induced in anesthetized dogs by left coronary embolization. Treatment with the converting enzyme inhibitor enalaprilat (MK-422) was then given. Hemodynamic registrations confirmed the development of left ventricular failure. Plasma concentrations of angiotensin II and aldosterone rose significantly. Treatment with enalaprilat was accompanied by significant reductions in heart preload and afterload and in plasma hormone concentrations.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Dogs; Enalapril; Enalaprilat; Heart Failure; Hemodynamics

Renal and systemic hemodynamics were measured during titration of dopamine and serially after intravenous administration of enalaprilat in nine patients with chronic severe congestive heart failure. During titration of dopamine, renal blood flow increased by 99%, from 304 +/- 120 to 604 +/- 234 ml/min (p less than .01) at a dose of dopamine of 2.1 micrograms/kg/min, which produced only a 21% increase in cardiac index, from 1.96 +/- 0.36 to 2.38 +/- 0.35 liters/min/m2 (p less than .05). Cardiac index was increased maximally at a dose of 4.0 micrograms/kg/min dopamine; however, renal blood flow was not further augmented. In contrast, after intravenous administration of enalaprilat, peak improvement of renal blood flow and cardiac index occurred concomitantly. Renal blood flow increased by 35%, from 316 +/- 97 to 427 +/- 107 ml/min (p less than .05), and cardiac index increased by 18%, from 1.99 +/- 0.40 to 2.35 +/- 0.40 liters/min/m2 (p less than .05). At similar increases in cardiac index, dopamine produced a greater increase in renal blood flow than enalaprilat: 604 +/- 234 vs 427 +/- 107 ml/min (p less than .05). Mean systemic arterial pressure, however, was greater with dopamine than with enalaprilat (78.1 +/- 16.7 vs 70.2 +/- 17.2 mm Hg; p less than .05) at peak effect. Thus, although both drugs appear to be potent renal vasodilators in patients with severe congestive heart failure, dopamine may be more effective in augmenting renal blood flow.

Topics: Adult; Aged; Cardiac Output; Dipeptides; Dopamine; Enalaprilat; Female; Heart Failure; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Renal Circulation; Renin

The effects of enalaprilat (MK-422), an angiotensin converting enzyme inhibitor, were compared to those of SCRIP, a renin inhibitor, in experimentally induced left ventricular failure. In anesthetized dogs, acute left ventricular failure was induced by repeated embolization, via the left main coronary artery, with 50 microns plastic microspheres. Embolization significantly increased left ventricular enddiastolic pressure from 6 +/- 1 to 14 +/- 1 (p less than 0.05) mm Hg and decreased both left ventricular maximal dP/dt (3,135 +/- 338 to 1,636 +/- 126 mm Hg/second, p less than 0.05) and cardiac output (3.0 +/- 0.3 to 1.6 +/- 0.1 liters per minute, p less than 0.05). Embolization also significantly reduced heart rate and mean arterial pressure. These parameters remained stable after induction of heart failure. Forty-five minutes after embolization, 16 dogs received enalaprilat (100 microns/kg intravenously) and six dogs received SCRIP (100 microns/kg intravenously followed by 10 microns/kg per minute). Both agents caused similar reductions in left ventricular end-diastolic pressure (21 percent versus 26 percent) and total peripheral resistance (25 percent versus 32 percent) and rise in peak positive cardiac contractility, as measured by (dP/dt)/P, (12 percent versus 11 percent). The data suggest that inhibition of angiotensin II formation by two agents, each or which acts at a different point in the cascade, results in similar beneficial hemodynamic effects in dogs with acute left ventricular failure. In addition, angiotensin converting enzyme inhibition failed to further increase sodium excretion and glomerular filtration rate caused by embolization. In summary, inhibition of angiotensin II production by two different inhibitors of the renin system causes an improvement in left ventricular performance in a model of acute experimental left ventricular failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiac Output; Coronary Vessels; Dipeptides; Dogs; Embolism; Enalaprilat; Female; Heart Failure; Heart Rate; Hemodynamics; Injections, Intravenous; Kidney; Male; Oligopeptides; Renin-Angiotensin System

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