ramiprilat and Heart-Failure

The aim of the present study was primarily to evaluate the haemodynamic effects of the ACE-inhibitor ramipril which is active via its metabolite ramiprilat. Ramipril 1.25, 2.5 and 5 mg and placebo was administered orally to 4 groups of 12 patients with heart failure (NYHA III) in a double-blind randomised, parallel study. Haemodynamics were monitored for 24 h and blood was sampled and urine collected for up to 96 h. In the placebo-treated group the cardiac index (CI) was significantly increased (15.8%) and right atrial pressure decreased (26.6%). Ramipril 1.25 mg had insignificant haemodynamic effects compared to placebo and the 2.5 mg dose had significant effects on some haemodynamic variables. Ramipril 5 mg had pronounced and sustained effects on pulmonary artery pressure, which fell by 43.7%, and pulmonary capillary wedge pressure (PCWP; -59.1%); systemic vascular resistance was also decreased 21%. A significant effect on CI was only seen after 2.5 mg ramipril (+7.4%). The mean maximal degree of ACE inhibition was 73.2, 90.4 and 98.5%, respectively, after the three doses of ramipril. Complete inhibition of ACE-activity was seen at a mean plasma concentration of ramiprilat of 4.7 ng.ml-1. The degree of inhibition declined with a half life of about 75 h. There was a significant relation between the degree of ACE-inhibition and change in PCWP but not with the change in SVR. Ramipril was mainly eliminated in the form of ramiprilat and inactive metabolites.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Double-Blind Method; Heart Failure; Hemodynamics; Humans; Male; Metabolic Clearance Rate; Pulmonary Wedge Pressure; Ramipril; Vascular Resistance

We investigated the role of nitric oxide (NO) in the modulation of renal O2 consumption in dogs with pacing-induced congestive heart failure (CHF). O2 consumption in the renal cortex (C) and medulla (M) of normal dogs and dogs with CHF was measured under control conditions and in the presence of increasing concentrations of three stimulators of NO production, bradykinin, ramiprilat, and amlodipine, or the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Baseline O2 consumption (nmol O2/min per gram) was similar in the CHF group (C: 637+/-65; M: 618+/-83) and the control group (C: 601+/-58, M: 534+/-55). In normal dogs, bradykinin (10(-4) M), ramiprilat (10(-4) M), amlodipine (10(-5) M) and SNAP (10(-4) M) all significantly reduced O2 consumption in the cortex (-31.5+/-3.5%, -33+/-2.5%, -28.4+/-4.9%, -49.3+/-3.1%) and medulla (-26.9+/-2.2%, -31.4+/-2.2%, -23.1+/-1.3%, -48.3+/-4%), respectively. The responses to bradykinin, ramiprilat and amlodipine were significantly attenuated in dogs with CHF (C: -22.2+/-1.8%, -20.1+/-2.6%, -14.2+/-2.5%; M: -20.8+/-1.7%, -17.8+/-1.9%, -15.6+/-2.6%, respectively; p < 0.05). The responses in dogs with CHF were not altered by NO synthase blockade with L-NAME (10(-4) M). In contrast, in normal kidneys treatment with L-NAME significantly attenuated the response to all three stimuli of NO production. Responses to SNAP were not affected either by CHF or L-NAME. These data indicate that the role of NO production in the modulation of tissue O2 consumption in the kidney is impaired after the development of pacing-induced heart failure in dogs.

Topics: Amlodipine; Animals; Bradykinin; Cardiac Pacing, Artificial; Dogs; Female; Heart Failure; Kidney; Nitric Oxide; Nitric Oxide Donors; Oxygen Consumption; Ramipril

Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) regulates renal O(2) consumption. This mechanism is impaired in heart and kidney of dogs with heart failure (CHF). Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, increases eNOS expression in the endothelium. Therefore, we studied whether simvastatin treatment could restore the regulation of renal O(2) consumption by stimulators of NO production in dogs with CHF. Renal O(2) consumption was measured after stimulation of NO production with bradykinin, ramiprilat, or amlodipine or the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Simvastatin delayed the time to euthanasia in dogs with CHF (35 +/- 1.0 vs. 29 +/- 1.2 days; P < 0.01). In normal dogs, bradykinin (10(-4) M), ramiprilat (10(-4) M), amlodipine (10(-5) M), and SNAP (10(-4) M) significantly reduced O(2) consumption in the renal cortex (-31.8 +/- 0.9, -30.3 +/- 1.1, -30.1 +/- 2.0, -46.9 +/- 1.0%) and renal medulla (-29.7 +/- 2.1, -33.0 +/- 2.7, -30.8 +/- 2.2, -46.8 +/- 1.1%). Responses to bradykinin, ramiprilat, and amlodipine were significantly attenuated in CHF but were partially or completely restored by simvastatin. Responses to SNAP were unaffected. These data demonstrate that treatment with simvastatin improves renal production of NO in CHF, restoring the normal regulation of renal O(2) consumption by NO.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Dogs; Endothelium, Vascular; Heart Failure; Hemodynamics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Kidney Cortex; Kidney Medulla; Male; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxygen Consumption; Penicillamine; Ramipril; Simvastatin; Ventricular Function, Left

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

In heart failure atrial natriuretic peptide (ANP) release in response to volume expansion is impaired while the renin-angiotensin system is activated. This study was designed to test the hypothesis that ANP release in heart failure is dependent on an activated angiotensin system.. We studied the ANP and renin-angiotensin systems in a rat model of shunt-induced high-output heart failure, in which we rapidly increased circulating fluid volume with a 5 ml, hyperoncotic infusion, and evaluated the effects of acute inhibition of the angiotensin converting enzyme as well as of the blockade of the angiotensin II type 1 receptors on the ANP release and on renal excretory function.. ANP and angiotensin II plasma concentrations prior to volume expansion were elevated (p < 0.05) in rats with aortocaval shunt compared to controls. The diuretic response to acute volume expansion (18.5 +/- 1.5 vs. 48.2 +/- 2.4 microliters/min, p < 0.001) was markedly blunted. ANP release was attenuated in rats with aortocaval shunt, as was the increase of its second messenger cGMP in plasma and urine. The blunted increase in ANP plasma levels was not due to depleted cardiac stores as cardiac ANP content, as well as ANP synthesis, were increased (p < 0.05). Acute inhibition of the angiotensin converting enzyme as well as blockade of the angiotensin II type 1 receptors restored ANP release in response to volume expansion (p < 0.01). Moreover, acute inhibition of the renin-angiotensin system completely normalized the diuretic response.. Our data suggest that the ANP system is impaired in rats with aortocaval shunt. The activation of the angiotensin system contributes to the impairment of the ANP system. Acute inhibition of the angiotensin II system significantly improved the ability of the ANP system to respond to acute volume expansion. Our findings indicate a hitherto fore unappreciated interaction between both systems and suggest additional mechanisms for the beneficial effects of angiotensin converting enzyme inhibition or angiotensin II type 1 receptor antagonists in heart failure.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Volume; Cyclic GMP; Diuresis; Heart Failure; Male; Myocardium; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; Statistics, Nonparametric; Tetrazoles; Valine; Valsartan

The production of endogenous nitric oxide, which regulates myocardial oxygen consumption, is decreased in heart failure. As with angiotensin-converting enzyme (ACE) inhibitors, amlodipine, a calcium antagonist, increases kinin-mediated nitric oxide production in coronary microvessels. We investigated the possibility of synergy between ACE inhibitors and amlodipine in regulating myocardial oxygen consumption. Left ventricular myocardium was isolated from 6 healthy dog hearts and 5 human hearts with end-stage heart failure at the time of orthotopic heart transplantation. Myocardial oxygen consumption was measured before and after administration of bradykinin, S-nitroso N-acetyl penicillamine (SNAP, a nitric oxide donor), ramiprilat (an ACE inhibitor), amlodipine, and the combination of a sub-threshold dose of ramiprilat (10(-8) md/L) + amlodipine. These experiments were repeated with L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthesis), dichloroisocoumarin (an inhibitor of kinin synthesis), and HOE 140 (a B2 kinin-receptor antagonist). Baseline myocardial oxygen consumption in canine hearts was 182 +/- 21 nmol/g/min. Bradykinin and SNAP caused dose-dependent reductions in myocardial oxygen consumption (p <0.05). Ramiprilat and amlodipine caused a 10 +/- 3.2% and 11 +/- 0.8% reduction in myocardial oxygen consumption, respectively, when used alone (p <0.05). In the presence of a subthreshold dose of ramiprilat, amlodipine caused a larger (15 +/- 1.7%) reduction in myocardial oxygen consumption compared with either drug used alone (p <0.05). In human hearts, baseline myocardial oxygen consumption was 248 +/- 57 nmol/g/min. Amlodipine caused a larger reduction in myocardial oxygen consumption when used with ramiprilat (22 +/- 3.2%) as compared with amlodipine alone (15 +/- 2.6%). The effect of both drugs was attenuated by L-NAME, dichloroisocoumarin, and HOE 140 (p <0.05). In conclusion, ACE inhibitors and amlodipine act synergistically to regulate myocardial oxygen consumption by modulating kinin-mediated nitric oxide release, and this combination of drugs may be useful in the treatment of heart failure.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Calcium Channel Blockers; Child; Coumarins; Dogs; Drug Synergism; Drug Therapy, Combination; Female; Heart Failure; Humans; Isocoumarins; Male; Middle Aged; Myocardial Contraction; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxygen Consumption; Penicillamine; Ramipril; Serine Proteinase Inhibitors

Thirteen patients with chronic congestive heart failure of NYHA class II-III received multiple doses (14 days) of ramipril (5 mg once daily); the concentrations of ramipril and ramiprilat in plasma, as well as ramipril, ramiprilat, glucuronides, diketopiperazine, and diketopiperazine acid in urine were measured at various times for 14 days. One patient dropped out after the first day due to hypotension and another who accidentally received another ACE inhibitor additionally was excluded, so that 11 patients completed the study. Ramipril and ramiprilat in plasma were determined by radioimmunoassay, and ramipril and its metabolites in urine were measured by gas chromatography in the laboratories of Hoechst AG. Peak concentrations of the active substance ramiprilat were reached after about 4 h and amounted to 22.3 +/- 11.1 ng/ml after the first dose, and a peak concentration of 26.6 +/- 10.0 ng/ml was observed 2.5 +/- 1.4 h on average after administration on day 14. Practically no accumulation was observed for ramiprilat; the AUD (0-24 h) values increased from 191.3 +/- 83.1 ng.h/ml for the first study day to 238.3 +/- 98.0 ng.h/ml for day 14. As expected, only very small fractions of the dose were excreted with urine as unchanged ramipril and ramipril glucuronide. Ramiprilat is excreted with urine to a larger extent than is rampiril--on average 6.6 +/- 3.0% on the first day and 12.2 +/- 3.8% on day 14. The total amount excreted increased by 34% on average, and was mainly due to an increased ramiprilat excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Drug Administration Schedule; Heart Failure; Humans; Middle Aged; Radioimmunoassay; Ramipril

To investigate the pharmacokinetics and pharmacodynamics of a new angiotensin converting enzyme (ACE) inhibitor, ramipril (HOE 498), in patients with cardiac insufficiency (NYHA III-IV), we performed an open trial with a follow-up of 10 days. Twenty-seven patients (18 females, 9 males), mean aged 62 years (46-83) with severe heart failure, were included. After a single oral dose of 5 mg ramipril, the plasma and urine levels of ramipril, ramiprilat, ACE plasma activity, standard laboratory values, blood pressure and pulse rate were evaluated. The maximal plasma level of ramipril was 57.0 +/- 26.8 ng/ml after 1.4 h; t1/2 was 2.4 +/- 1.2 h. The peak level of ramiprilat was 27.9 +/- 24 ng/ml after 4.6 h; t1/2 for the active compound was 6 +/- 4.2 h. The total recovery of ramipril and metabolites in urine was on average 39 +/- 17.5% within 96 h. Ninety-five percent inhibition of ACE activity was observed in all patients and 80% inhibition lasted 24 h. Systolic and diastolic blood pressure decreased without changes in heart rate. Five patients had mild side effects: hypotension, diarrhea, and dizziness. In conclusion, in patients with severe heart failure, plasma levels of drug and active metabolite were higher and remained measurable longer, with more sustained inhibition of ACE activity than reported in healthy volunteers. This indicates that titration should start with lower doses (1.25-2.5 mg) and that doses above 5 mg may rarely be necessary.

Topics: Administration, Oral; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Female; Heart Failure; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Pyrroles; Ramipril