Diazoxide concentration-response relation in hypertension.

The pharmacokinetic disposition and antihypertensive response of bolus infusions of diazoxide, 1, 2, or 4 mg/kg over 5, 10, or 20 seconds, were examined in seven patients with chronic stable essential hypertension and mean arterial pressures (MAP) between 122 and 155 mm Hg off therapy. Maximal reductions in MAP were noted 2 minutes after each dose, and a linear correlation was obtained in all patients between dose or plasma diazoxide concentration and maximal change in MAP. Individual concentration-time curves were analyzed to determine the apparent volume of distribution at steady state (Vdss range, 0.178 to 0.250 liter/kg), beta t 1/2 (range, 32 to 62.5 hours), and plasma clearance rate (Clp range, 2.2 to 5.3 ml/kg . hour-1) for the calculation of loading and maintenance doses designed to produce steady-state concentrations within 0.5 hours. These infusions resulted in steady-state reductions in MAP (16% to 30%) which could be predicted from the concentration-response curves of each patient after bolus infusions. With the use of kinetic principles, a diazoxide dose regimen (average load, 7.5 mg/kg at 7.5 mg/min; average maintenance, 10% of loading dose every 6 hours) produced gradual and predictable reductions in MAP in patients with accelerated hypertension, since the response was proportional to plasma diazoxide concentrations.

Cardiovascular effects of enprofylline and theophylline.

The cardiovascular effects of enprofylline (with no adenosine receptor antagonism) and of theophylline (with adenosine receptor antagonism) were compared in six normal subjects in a double-blind trial at steady-state concentrations of theophylline (12.5 +/- 1.6 mg/L) and enprofylline (2.7 +/- 0.3 mg/L). The mean (+/- SD) recumbent heart rate (HR) was higher (P less than 0.04) after enprofylline (70 +/- 14 bpm) than after theophylline (58 +/- 13 bpm) or saline solution (57 +/- 10 bpm). Forearm arterial resistance determined by plethysmography was lowered (P less than 0.01) by theophylline (-37% +/- 14%) and enprofylline (-43% +/- 24%) but not by saline solution (-6% +/- 16%). In the semiupright position, the mean arterial pressure was lower (P less than 0.01) after enprofylline (93 +/- 15 mm Hg) than after theophylline (108 +/- 16 mm Hg). The cardiac index (CI) and left ventricular ejection fraction (LVEF) determined by radionuclide angiocardiography and the left ventricular end-systolic pressure/volume ratio were not different for any regimen. During maximal exercise, HR was higher (P less than 0.01) after both enprofylline (176 bpm) and theophylline (175 bpm) than after saline solution (161 bpm), but the increases in mean arterial pressure (18% to 32%), CI (153% to 167%), and LVEF (34% to 74%) were similar for all three regimens. Both theophylline and enprofylline lowered forearm arterial resistance without an increase in CI, LVEF, or cardiac inotropy, although enprofylline tended to cause a lower blood pressure and higher HR than did theophylline.

Antihypertensive responses to spironolactone in normal renin hypertension.

The antihypertensive effect of spironolactone was studied in 20 patients with essential hypertension and normal stimulated peripheral renin activity (PRA). Single-blind 8-wk treatment periods of placebo, 100, 200, and 400 mg spironolactone were used in consecutive order. Average supine and erect blood pressures were lower than placebo values at the end of each treatment. A prominent orthostatic effect was observed. Changes in blood pressure were not related to changes in body weight, PRA, or blood urea nitrogen. A larger proportion (50%) of patients had a more normal erect diastolic pressure at the end of 400 mg/day than at the end of 100 mg/day (20%), but the response to 400 mg/day could not be predicted from the responses to lower doses. Larger doses of spironolactone were predictably associated with rises in serum potassium, PRA, and aldosterone excretion. Adverse effects were absent during therapy with 100 mg/day but were frequent during 200--400 mg/day. Although there are no apparent advantages in increasing spironolactone from 100 to 200 mg/day in this group of patients with normal renin hypertension, increasing the dose to 400 mg/day resulted in better blood pressure control with more frequent adverse effects.

Pharmacokinetic and pharmacodynamic interactions between nisoldipine and propranolol.

The pharmacokinetic and pharmacodynamic effects of nisoldipine, a 1,4-dihydropyridine calcium entry blocker, and the lipophilic beta-adrenoceptor blocker propranolol were assessed alone and in combination in 12 healthy men. Oral nisoldipine, 20 mg, or placebo was followed 1 hour later by propranolol, 40 mg, or placebo using a randomized, crossover, double-blind design. Nisoldipine significantly increased the AUC (+43%) and peak plasma drug concentration (Cmax) (+68%) of propranolol resulting in a higher degree of beta-adrenoceptor blockade (as assessed by isoproterenol). Conversely, nisoldipine's AUC (+30%) and Cmax (+57%) were increased with concomitant administration of propranolol. Nisoldipine did not affect blood pressure but caused significant decrease in total peripheral resistance (TPR) and increases in plasma catecholamines and cardiac index. Forearm vascular resistance and blood flow changed more markedly than did TPR and cardiac index. In contrast, propranolol had little effect on forearm hemodynamics despite significant decreases in cardiac index and increases in TPR. The data are compatible with changes in hepatic blood flow, accounting for the pharmacokinetic interaction of nisoldipine and propranolol. Different vascular beds appear to contribute to the effects of nisoldipine vs. propranolol on peripheral resistance.

Acebutolol and hydrochlorothiazide in essential hypertension.

Acebutolol (ABL) and hydrochlorothiazide (HCT) were compared in patients with mild to moderate essential hypertension and low or normal peripheral renin activity. ABL reduced mean supine blood pressure from 151/97 to 140/87 mm Hg and HCT reduced the mean supine blood pressure from 153/98 to 143/92 mm Hg. ABL reduced heart rate from 73 to 67 beats/min; during HCT therapy it rose from 74 to 77 beats/min. Although the same proportion of patients achieved normal diastolic pressures with ABL (11/19) and with HCT (10/19), tension-time indices were lower during ABL than during HCT therapy. The average daily dose was 621 mg of ABL and 168 mg of HCT. Stimulated peripheral renin activity increased with HCT and was the same or lower with ABL. ABL did not induce adverse effects on serum potassium or uric acid. ABL was as effective in lowering blood pressure HCT but induced larger reductions in tension-time index as a result of the lowerered heart rate.

Effect of phenobarbital on the disposition of intravenous theophylline.

The disposition of intravenous doses of theophylline was determined in normal male subjects before and after treatment with phenobarbital 2 wk. Although there was some variation in disposition of the 2 drugs, there were no significant effects of phenobarbital on theophylline kinetics. We conclude that theophylline dosage need not be altered during concomitant administration of phenobarbital.

Amantadine kinetics in healthy young subjects after long-term dosing.

We investigated the disposition of amantadine in 13 healthy, young adults after long-term dosage. Doses of 25, 100, or 150 mg, randomly allocated, were taken at 12-hr intervals in syrup for 31 doses. A 1-compartment open model and complete bioavailability were assumed. Absorption rate was variable with peak concentrations in plasma occurring at 1 to 12 hr. Since the calculated area under the plasma concentration against time curve was proprotional to it, relative bioavailability was independent of dose at steady state. As the dose increased, the apparent volume of distribution decreased. Intra- and intersubject variations in trough plasma drug concentrations at steady state were less than triple for equivalent doses. Elimination of drug from plasma was consistent with a first-order process. Plasma half-lifes (t1/2s) ranged from 10.2 to 31.4 hr and were independent of dose or creatinine clearance. The ratio of renal drug clearance to creatinine clearance ranged from 1.26 to 14.97, suggesting substantial renal tubular secretion. The median ratio of plasma drug clearance to renal drug clearance approached unity.

Duration of cardiac effects of timolol and propranolol.

The duration of the cardiac effects of single intravenous doses of the beta-antagonists, timolol and propranolol, was compared in 6 healthy male subjects. Timolol and propranolol were given in doses of 1 mg and 10 mg, respectively, and at specified times after their administration, beta-blockade was assessed by the reduction of maximal exercise-induced tachycardia and by the inhibition of the chronotropic and inotropic effects of isoproterenol. Inotropic effects were measured by changes in the pre-ejection period of left ventricular systole obtained from systolic time intervals. There was no statistically significant difference in the timolol and propranolol time-courses of beta-blockade. The change in exercise-tachycardia was maximal 5 min after beta-antagonist infusion but dissipated rapidly so that no statistically significant change was observed 9 hr later. The chronotropic and inotropic effects of isoproterenol were almost completely antagonized for 11/2 hr after beta-antagonist infusion, and significant beta-blockade could be demonstrated 9 hr later. There was no difference in the time-course of the negative chronotropic and inotropic effects of either beta-antagonist.

Comparison of cardiac effects of timolol and propranolol.

The cardiac effects of the beta-adrenergic blocking agent, timolol, were compared to those of propranolol after intravenous administration in 6 healthy male subjects. The effects of timolol and propranolol on maximal exercise-induced tachycardia were measured. Timolol was about ten times as potent as propranolol in antagonizing exercise-induced tachycardia. Dose-response curves to intravenous infusions of isoproterenol were obtained after three doses of each beta-antagonist. Changes in myocardial contractility were assessed by cardiac systolic time intervals and were compared to the simultaneous changes in heart rate elicited by isoproterenol. For the 6 subjects, the mean potency ratios of timolol to propranolol as an antagonist of the chronotropic and inotropic effects of isoproterenol were 13.8 (+/-0.8) and 12.7 (+/-1.0), respectively. Neither timolol nor propranolol acted more selectively on beta-receptors affecting heart rate than on those influencing contractility.

Pharmacokinetic and pharmacodynamic interactions during multiple-dose administration of nisoldipine and propranolol.

OBJECTIVES: The pharmacokinetic and pharmacodynamic interactions after 7 days of oral treatment with nisoldipine (10 mg twice daily) and propranolol (80 mg twice daily) were investigated in a partially randomized, placebo-controlled crossover study of 12 healthy volunteers. METHODS: At the end of each treatment period, pharmacokinetic parameters were measured, along with blood pressure, heart rate, cardiac function, systemic hemodynamics, plasma catecholamines, forearm blood flow, and apparent hepatic blood flow (estimated by the clearance of indocyanine green dye). RESULTS: After 7 days of treatment with nisoldipine and propranolol, neither drug altered the other's bioavailability or elimination parameters, and propranolol did not change the area under the plasma concentration-time curve of nisoldipine's metabolite, N-9425. Nisoldipine alone increased apparent hepatic blood flow and forearm blood flow compared with the other treatment groups but, with the addition of propranolol, both of these parameters were similar to those in the placebo group. Changes in the other hemodynamic parameters were consistent with the known effects of these drugs, and no differences in plasma catecholamine levels were detected. CONCLUSIONS: In contrast to the findings with single-dose treatment, administration of the combination of nisoldipine and propranolol for 7 days is not associated with any measurable kinetic interactions, although significant hemodynamic interactions do occur.

Theophylline kinetics in acute pulmonary edema.

Nine patients with acute cardiogenic pulmonary edema were given theophylline intravenously, and its disposition was observed over the next 24 hr. Compared to that in 19 normal subjects, these patients had prolonged plasma half-lifes (mean, 22.9 from 6.7 hr) and decreased plasma clearances of theophylline (mean, 0.041 from 0.062 L [kg-1] hr-1). The intersubject variation in these parameters was 20-fold in patients with pulmonary edema and 4-fold in normal subjects. Since the peak plasma concentrations attained and the apparent volumes of distribution were not different in the two groups, a suitable initial dose can be calculated. A loading dose of 4.5 to 5 mg/kg theophylline (6 mg/kg aminophylline) given over 20 min appears safe. Because of the great variability in the plasma clearance of this drug in patients with heart failure, plasma concentrations and toxicity would be unpredictable after repeated doses or constant infusions.

Prophylactic amantadine dose and plasma concentration-effect relationships in healthy adults.

Amantadine dose, plasma concentration, prophylactic and adverse effect relationships for prevention of influenza A virus infection in healthy young adult subjects were investigated in a double-blind, placebo-controlled study. Seventy-four subjects with hemagglutination inhibition antibody titers less than or equal to 16 against an attenuated influenza A virus AF9/Montreal/3/72 (H3N2) were randomly allocated to groups taking 0 (placebo), 25, 100, or 150 mg amantadine syrup prophylactically twice a day for 31 doses. Eighteen other subjects were randomly allocated to control groups for investigation of drug toxicity (150 mg) or concurrent other virus infection (placebo). Steady-state trough plasma concentrations were 110 +/- 39, 302 +/- 80, and 572 +/- 207 ng/ml (X +/- SD) for the three amantadine doses and increased out of proportion to dose. Prophylaxis groups were challenged intranasally with virus after the fifth dose at steady state; control subjects received saline solution. No subject became ill. Input virus was recovered 48 or 72 hr after challenge from nose or throat swabs of nine of 21 subjects taking placebo, one of 18 subjects taking 100 mg amantadine, three of 18 subjects taking 25 mg amantadine, and six of 17 subjects taking 150 mg amantadine. There were no differences in seroconversion rates or adverse symptoms. Our data do not support a change in the recommended amantadine prophylactic dose for influenza A virus infection in healthy young adults. We defined trough steady-state plasma concentrations associated with the recommended amantadine dose of 100 mg twice a day that should be mimicked in devising dose schedules for populations with differing amantadine kinetics.

Short-term effects of calcium antagonists on hemodynamics and cyclosporine pharmacokinetics in heart-transplant and kidney-transplant patients.

Effects of two calcium antagonists on hemodynamics and on cyclosporine pharmacokinetics were studied in eight transplant patients (four heart-transplant and four kidney-transplant patients) by use of a single-blind, randomized, crossover, and placebo-controlled design. Patients received, at least 1 week apart, either 90 mg diltiazem, 20 mg nifedipine (in tablet form), or placebo, given 1 hour before cyclosporine. Cyclosporine and its main metabolite (metabolite 17) were measured in plasma (separated at 25 degrees C) by use of HPLC. Both calcium antagonists tended to increase absorption rate and elimination rate, but none of the pharmacokinetic parameters of cyclosporine were significantly altered. Moreover, the area under the curve of plasma concentrations of metabolite 17 did not change. On the other hand, both nifedipine and diltiazem significantly altered the hemodynamics, but to a different extent in the two groups of patients. The heart-transplant patients showed larger decreases in systolic and diastolic blood pressure than the kidney-transplant patients after administration of both nifedipine and diltiazem, but they showed smaller increases in cardiac index and heart rate with nifedipine. In contrast, diltiazem caused small decreases in heart rate and cardiac index in heart-transplant patients and small increases in heart rate and cardiac index in kidney-transplant patients. We conclude that a single dose of either nifedipine or diltiazem does not affect, to a clinically significant extent, the pharmacokinetics of cyclosporine. In addition, heart-transplant patients show different hemodynamic responses to these two calcium antagonists than the responses shown by kidney-transplant patients, probably because of cardiac denervation.

Anti-arrhythmic effects of prazosin and propranolol during coronary artery occlusion and re-perfusion in dogs and pigs.

Open-chest dogs and pigs anaesthetized with pentobarbitone were used to evaluate the anti-arrhythmic effect of prazosin and propranolol during a 30 min period of occlusion of the left anterior descending coronary artery followed by 15 min of re-perfusion. In dogs, both prazosin and propranolol reduced the incidence of ventricular premature depolarizations and ventricular tachycardia during the occlusion period. During the 45 min period of occlusion and re-perfusion, the incidence of ventricular fibrillation was significantly reduced in the prazosin-treated and propranolol-treated dogs. In pigs prazosin reduced the incidence of ventricular premature depolarizations during occlusion and propranolol reduced the incidence of both ventricular premature depolarizations and ventricular tachycardia during occlusion, but the incidence of ventricular fibrillation was not significantly reduced in the prazosin- and propranolol-treated pigs. Prazosin reduced arterial pressure and propranolol lowered heart rate in both dogs and pigs, but a comparison of mean arterial pressure and heart rate in animals surviving and those not surviving the 30 min of coronary artery occlusion and 15 min of re-perfusion showed no significant difference.

Metronidazole kinetics in dialysis patients.

Five volunteers with normal renal function (NOR) and eight patients with renal insufficiency (REN) were given a single dose of 500 mg metronidazole (MET) intravenously over 26 minutes. Serial venous plasma samples were taken at certain intervals for 30 hours. Four of the eight REN patients were also given the drug at the start of hemodialysis and four simultaneous inflow-outflow samples were taken over 4 hours of dialysis. Plasma MET, the acetic acid metabolite (MTAC), and the hydroxymethyl metabolite (MTOH) were determined by high-pressure liquid chromatography assay. Plasma MET over time curves were analyzed with a nonlinear curve-fitting computer program (ASAAM-27) which employed a two-compartment open model. Plasma MET concentrations were similar in the NOR and REN groups. The volumes of distribution for MET--both V1 and Vdss--were similar in the two groups. Moreover, renal insufficiency did not affect the beta half-life (6.5 hours) or the plasma clearance (10.1 L/hr) of MET. Metabolite concentrations peaked at about 12 hours in both groups, but peak MTAC was five times higher in the REN group and peak MTOH twofold higher. Plasma clearance of MET by dialysis averaged 4.0 L/hr at 30 minutes, but thereafter ranged from 2.9 to 4.2 L/hr. Clearance of MTAC ranged from 5.8 to 7.8 L/hr and that of MTOH 2.7 to 5.6 L/hr. We concluded that renal failure does not alter MET disposition but is associated with significant accumulation of the metabolites of MET, possibly requiring a dose reduction. Moreover, an 8-hour hemodialysis eliminates approximately 50% of an administered dose of MET.

Biologic activity of metronidazole in plasma and urine of volunteers with normal or impaired renal function.

In this study, we have compared a bioassay procedure with high-pressure liquid chromatography (HPLC) for the determination of metronidazole levels in serum and urine. Plasma and urine of volunteers with normal or impaired renal function were obtained at various intervals after a single intravenous dose of 500 mg metronidazole. In plasma of normal volunteers 30 hours after dosing, the bioassay gave results comparable to the total values of the parent compound plus metabolites. In patients with renal failure, the course of the plasma regression curve of metronidazole as measured by the bioassay procedure was intermediate between the values of metronidazole alone and the total values of parent compound plus metabolites. Recovery of metronidazole activity in urine, as determined by this bioassay method, was somewhat less than one half (in normal volunteers) to one quarter (in patients with renal failure) of metronidazole plus metabolites as measured by HPLC. These discrepancies might be explained by the lower antibacterial activity of the hydroxy (congruent to 40%) and acetic acid (congruent to 2%) metabolites as compared with that of the parent compound in the test system used.

Diuretic treatment in essential hypertension.

In North America, diuretics remain the most common first-line drug therapy for essential hypertension based on efficacy, safety and cost. The promotion of step-care programmes has firmly established their dominant use on this continent whereas in Europe, particularly in Scandinavia and Great Britain, beta-adrenoceptor blocking agents are more frequently chosen as first-line therapy. On both continents, combined therapy with a diuretic and a beta-blocker is probably the most common second step for patients with blood pressures uncontrolled on a single agent alone and diuretics remain useful, if not essential, to prevent sodium retention commonly observed with other antihypertensive agents. Although the forced loss of sodium and water may be responsible for their initial antihypertensive effect, the mechanism underlying their long-term effect is unknown but probably involves some alteration of vascular smooth muscle reactivity. More recently, concern has been expressed about their long-term safety as larger populations are being exposed to diuretic agents for a significant proportion of their life-span. These concerns include haemodynamic and biochemical consequences of diuretic therapy - excessive tachycardia at rest and with minimal exercise, postural hypotension, hypokalaemia and arrhythmias, muscle cramps or fatigue, glucose intolerance, hyperuricaemia and altered circulating lipids as markers or promotors of atherosclerosis and its complications. At present, there is insufficient evidence to alter the present recommendation of diuretic agents as first-line drug therapy in the treatment of hypertension.

Acute effect of rapid ventricular pacing and volume loading on total vascular capacitance.

OBJECTIVE: Rapid right ventricular pacing (RRVP) at 250 beats/min plus a saline volume load produces acute heart failure manifested by a limited increase in cardiac output in response to the volume load and increased right atrial, pulmonary artery and capillary wedge pressures. The effects on vascular capacitance are unknown. DESIGN: Three groups of six anesthetized splenectomized dogs were subjected to RRVP alone at 250 beats/min for 40 mins volume loading alone with intravenous 0.9% sodium chloride 40 mL/kg over 10 mins or volume loading followed by RRVP for 15 mins. Vascular capacitance, unstressed volume and compliance were determined from pressure-volume curves using transient circulatory arrests induced by acetylcholine before and 40 mins after starting the interventions. RESULTS: Neither RRVP nor volume loading alone produced acute heart failure or altered total vascular compliance. Fifteen minutes of RRVP after the volume load induced heart failure, reduced compliance (3.4 +/- 0.5 to 2.5 +/- 0.3 mL/mmHg/kg, P < 0.05), increased central blood volume (7.7 +/- 0.7 to 10.6 +/- 0.5 mL/kg, P < 0.01) and reduced the unstressed vascular volume to 57 +/- 10 mL/kg, compared with 77 +/- 9 mL/kg (P < 0.01) after the volume load alone. Stressed blood volume was increased similarly with either volume loading alone (20.1 +/- 2.0 to 30.0 +/- 1.7 mL/kg, P < 0.01) or volume loading plus RRVP (23.5 +/- 3.8 to 30.2 +/- 4.9 mL/kg, P < 0.01). The reduction in unstressed volume rather than an increase in stressed volume was the major peripheral change associated with acute heart failure induced by volume loading plus RRVP. CONCLUSION: RRVP reduced vascular capacitance by a reduction in unstressed volume. Acute volume loading of this smaller vascular compartment resulted in redistribution centrally and acute heart failure.

Captopril and angiotensin II receptor antagonist therapy in a pacing model of heart failure.

Twenty-four splenectomized dogs were subjected to rapid right ventricular pacing (RRVP) at 250 beats/min for five weeks. During the final three weeks, four groups six dogs were untreated or treated with captopril alone, with the angiotensin II type 1 (AT1) receptor antagonist L158,809 alone or with the two drugs combined by constant intravenous infusion. Hemodynamic studies were carried out during light anesthesia at baseline, and after two and five weeks of pacing. Total vascular capacitance and stressed blood volume were calculated from the mean circulatory filling pressure during transient circulatory arrest after acetylcholine administration at three different circulating volumes. Central blood volume and cardiac output were measured by thermodilution. Severe heart failure was present in the untreated group after five weeks of RRVP, characterized by low cardiac output and total vascular capacitance, high right atrial and pulmonary capillary wedge and mean circulatory filling pressure, plus increased stressed and central blood volumes. While L158,809 had not effect, captopril alone or combined with L158,809 ameliorated the reduction in total vascular capacitance, and reduced right atrial and mean circulatory pressure and stressed blood volumes. Combined therapy reduced pulmonary capillary wedge pressure. Thus, angiotensin-converting enzyme inhibition with captopril was effective in this model of chronic low output heart failure, whereas AT1 receptor antagonism was not.

Effect of perindopril in pacing-induced canine models of acute and chronic heart failure.

OBJECTIVE: To examine the effects of perindopril, a nonsulfhydryl-containing angiotensin-converting enzyme inhibitor, on total vascular capacitance and hemodynamics in acute and chronic dog models of heart failure. METHODS: Acute heart failure was induced in anesthetized, splenectomized dogs by a volume load (dextran 70, 20 mL/kg) during rapid right ventricular pacing (RRVP) at 250 beats/min. Pretreatment with perindopril (0.3 mg/kg daily for six days, n = 7) was compared with no treatment (n = 7). Total vascular capacitance and compliance were measured from plots of mean circulatory filling pressure during acetylcholine-induced circulatory arrests at different blood volumes. Chronic heart failure was induced by continuous RRVP in splenectomized dogs treated with perindopril (0.3 mg/kg daily, n = 8), which were compared with untreated dogs (n = 8). Hemodynamics and total vascular capacitance and compliance were measured at baseline and after 33 days of RRVP. RESULTS: Perindopril treatment did not significantly modify the increased pulmonary capillary wedge and mean circulatory filling pressures, reduced total vascular compliance or total vascular capacitance associated with the volume load and acute RRVP. During chronic RRVP, perindopril reduced weight gain and the development of ascites, reduced right atrial pressure (6.3 +/- 1.3 versus 10.3 +/- 1.2 mmHg), mean circulatory filling pressure (9.3 +/- 1.0 versus 14.7 +/- 1.2 mmHg), stressed blood volume (22 +/- 3 versus 33 +/- 4 mL/kg) and central blood volume (10 +/- 1 versus 14 +/- 1 mL/kg) while increasing cardiac output (122 +/- 9 versus 98 +/- 7 mL/kg). However, the reduction in total vascular capacitance was not attenuated and pulmonary capillary wedge pressure was not lowered significantly (18.5 +/- 1.5 versus 21.4 +/- 1.3 mmHg). CONCLUSION: Perindopril failed to modify hemodynamics in the pacing-induced canine model of acute heart failure but had beneficial effects in the model of chronic heart failure.