ramiprilat and Coronary-Disease

We determined the relationship between cardiac angiotensin-converting enzyme (ACE) inhibition and anti-ischemic efficacy of several structurally different ACE inhibitors or their prodrug esters perfused through the isolated rat heart. Seven ACE inhibitors inhibited cardiac ACE to varying degrees due to differences in uptake during perfusion through nonischemic rat hearts. Zofenopril-sulfhydryl and fosinoprilic acid were the most effective of the free inhibitors. Among the prodrugs, zofenopril and S-benzoylcaptopril, hydrolyzed rapidly by cardiac esterase, were more effective than their component ACE-inhibitors, whereas fosinopril, ramipril and enalapril were poorly active. For studies in ischemic rat hearts, vehicle or drug treatment was initiated 10 min before a 25-min period of global ischemia and during a 30-min reperfusion period. Of five unesterified ACE inhibitors studied for anti-ischemic activity, only captopril and zofenopril-sulfhydryl were found to improve postischemic contractile function and reduce cell death in the isolated rat hearts. Fosinoprilic acid, ramiprilat and enalaprilat were not cardioprotective at high perfusion concentrations, despite the fact that nearly complete inhibition of cardiac ACE was achieved with all of the compounds studied. The S-benzoyl prodrugs of zofenopril-sulfhydryl and captopril were at least as potent as their component ACE inhibitors in reducing ischemic-reperfusion damage in the same model. Neither zofenopril nor captopril, however, had any effect on coronary flow before or after ischemia. Thus, it appears that the cardioprotective effects of zofenopril and captopril are independent of cardiac ACE inhibition or, at least, that ACE inhibition alone is not sufficient. Both captopril and zofenopril are sulfhydryl-containing compounds whereas the inactive compounds are not; and, thus, this group appears to be important in mediating their cardioprotective actions.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Coronary Disease; Drug Stability; Enalaprilat; Fosinopril; Heart; In Vitro Techniques; Male; Myocardium; Organophosphorus Compounds; Prodrugs; Proline; Pyrroles; Ramipril; Rats; Rats, Inbred Strains; Sulfhydryl Compounds

The chemiluminescence reaction elicited from luminol in the presence of hydroxyl radicals was concentration-dependently suppressed by captopril, indicating efficacious radical scavenging. As to be expected, ACE inhibitors lacking free sulfhydryl groups (ramipril, enalapril) were inactive. However, the endogenous scavenger and anti-oxidant uric acid proved to be far superior to captopril, when concentrations of both were compared that are realized in vivo. A substantial augmentation of endogenous scavenging ability during therapy with captopril thus seems unlikely. In a model of standardized myocardial hypoxia (isolated working heart of the guinea pig with 30 min low flow perfusion) captopril, ramiprilat and uric acid equally improved post-hypoxic heart function. There was no cardioprotective action of captopril in excess of that accountable for by inhibition of ACE. It seems possible that ACE (kininase II) inhibitors exert cardioprotection via elevated tissue levels of kinins: bradykinin also improved heart performance after low flow perfusion and bradykinin-induced coronary dilatation was markedly enhanced in the presence of ramiprilate, reflecting attenuated degradation by endothelial kininase II.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bridged Bicyclo Compounds; Captopril; Coronary Disease; Dose-Response Relationship, Drug; Enalapril; Guinea Pigs; Hemodynamics; Hydroxides; Hydroxyl Radical; Luminescent Measurements; Myocardial Reperfusion Injury; Pyrroles; Ramipril; Sulfhydryl Reagents; Uric Acid

Angiotensin II facilitates sympathetic transmitter release in the heart. Thus, angiotensin converting enzyme inhibitors may be assumed to suppress noradrenaline release in the heart. To test this hypothesis endogenous noradrenaline release was induced either by electrical stimulation of the stellate ganglion or by global ischaemia in rat hearts. Noradrenaline was determined by high performance liquid chromatography in coronary venous overflow. Endogenous angiotensin formation was blocked by the angiotensin converting enzyme inhibitors captopril and ramiprilat and the activity of the endogenous renin-angiotensin system was modulated by variations in nutritional sodium load prior to the experiments. Both angiotensin converting enzyme inhibitors significantly reduced noradrenaline release evoked by nerve stimulation when the animals had been fed a low sodium diet. Following a high sodium diet, however, captopril and ramiprilat had no effect on stimulation-induced noradrenaline release. Global ischaemia (20 min) resulted in noradrenaline overflow from sympathetic nerves, independent of nerve stimulation. This ischaemia-induced noradrenaline release was not influenced by either converting enzyme inhibitor. In conclusion, the results suggest a sodium-dependent endogenous angiotensin formation in the heart which facilitates physiological noradrenaline release and is sensitive to angiotensin converting enzyme inhibitors. In contrast, noradrenaline release in ischaemia is not affected by converting enzyme blockers, due to a different, non-exocytotic release mechanism of noradrenaline during myocardial ischaemia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Coronary Disease; Heart; Male; Norepinephrine; Pyrroles; Ramipril; Rats; Rats, Inbred Strains; Sodium

Local inhibition of angiotensin-converting enzyme (ACE, kininase II) produces both-attenuation of angiotensin II generation and of bradykinin degradation. To delineate the participation of bradykinin in the cardioprotective actions of ACE inhibitors, experiments were performed in rats and dogs with cardiac ischemia-reperfusion injuries. In isolated perfused working rat hearts with regional myocardial ischemia, bradykinin in concentrations as low as 1 x 10(-9) M increases coronary flow and reduces the incidence and duration of reperfusion ventricular fibrillation. In addition, enzyme activities of lactate dehydrogenase and creatine kinase as well as lactate output were decreased in the venous effluent of bradykinin-perfused hearts, which also showed improved cardiodynamic and metabolic parameters. Even concentrations of bradykinin lower than 1 x 10(-10) M, which were without influence on coronary flow, exerted comparable beneficial metabolic effects connected with reduced incidence and duration of ventricular fibrillation. Combined perfusions with threshold concentrations of bradykinin (1 x 10(-12) M) and the ACE inhibitor ramiprilat (2,58 x 10(-9) M), which were ineffective given alone, resulted in a marked cardioprotective effect. Perfusion with angiotensin II (1 x 10(-9) M) aggravated reperfusion arrhythmias and worsened myocardial metabolism. Bradykinin perfusion prevented this deterioration in a concentration-dependent manner. The bradykinin antagonist D-Arg-[Hyp2, Thi5,8, D-Phe7]-bradykinin (1 x 10(-5)) completely abolished the cardioprotective effects of bradykinin or the ACE inhibitor. However, higher concentrations of bradykinin (1 x 10(-7) M) or ramiprilat (2,58 x 10(-5) M) reversed these properties of the bradykinin antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Energy Metabolism; Hemodynamics; Myocardial Reperfusion Injury; Myocardium; Organ Culture Techniques; Pyrroles; Ramipril; Rats; Ventricular Fibrillation

Local inhibition of angiotensin-converting enzyme (ACE, kininase II) produces both attenuation of angiotensin (Ang) II generation and bradykinin (BK) degradation. To delineate the participation of BK in the cardioprotective actions of ACE inhibitors, experiments were performed in rats and dogs with cardiac ischemia-reperfusion injuries. (I) In rat isolated perfused working hearts with regional myocardial ischemia, BK in concentrations as low as 1 X 10(-9) M increased coronary flow (CF) and reduced the incidence and duration of reperfusion ventricular fibrillation (VF). In addition, enzyme activities of lactate dehydrogenase (LDH) and creatine kinase as well as lactate output were decreased in the venous effluent of BK-perfused hearts, which also showed improved cardiodynamic and metabolic parameters. Even concentrations of BK lower than 1 X 10(-10) M, which were without influence on coronary flow, exerted comparable beneficial metabolic effects connected with reduced incidence and duration of VF. Combined perfusions with threshold concentrations of BK (1 X 10(-12) M) and the ACE inhibitor ramiprilat (2.58 X 10(-9) M), which were ineffective given alone, resulted in a marked cardioprotective effect. Perfusion with Ang II (1 X 10(-9) M) aggravated reperfusion arrhythmias and worsened myocardial metabolism. BK perfusion prevented this deterioration in a concentration-dependent manner, whereas the Ang II receptor antagonist saralasin was only marginally effective. The BK antagonist D-Arg-[Hyp2, Thi5,8, D-Phe7]-BK (1 X 10(-5) M) completely abolished the cardioprotective effects of BK or the ACE inhibitor. However, higher concentrations of BK (1 X 10(-7) M) or ramiprilat (2.58 X 10(-5) M) competitively reversed these properties of the BK antagonist. (II) In anesthetized dogs, BK was infused into the coronary artery in a dose of 1 ng/kg/min during occlusion (90 min) and reperfusion (30 min) of the left descending coronary artery (LAD)--a dose without effects on cardiovascular parameters. In line with the findings in isolated ischemic rat hearts, BK infusion reduced LDH activities and lactate concentrations in the coronary sinus blood, whereas myocardial tissue levels of glycogen and energy-rich phosphates were increased in the infarcted area. The cardioprotective effects produced by perfusion with BK or by reduction of BK degradation through local interference with ACE favor a role for BK in ischemia-reperfusion injuries in rats and dogs.

Topics: Anesthesia; Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Bradykinin; Coronary Circulation; Coronary Disease; Dogs; Female; Hemodynamics; In Vitro Techniques; L-Lactate Dehydrogenase; Lactates; Male; Myocardial Reperfusion Injury; Myocardium; Pyrroles; Ramipril; Rats; Rats, Inbred Strains; Saralasin

The effects of the converting enzyme inhibitors ramiprilat and enalaprilat on ischemia-induced release of noradrenaline (NA) were examined in the isolated perfused rat heart, submitted to 30 min of total flow restriction followed by 5 min of reperfusion. Ramiprilat (2.6 nM-2.6 microM) caused a concentration-dependent decrease in the efflux of NA at reperfusion. The maximal effect (about 70% reduction) was observed at a concentration of 26 nM. In contrast, enalaprilat (10 nM-10 microM) caused no reduction in NA efflux until at a high concentration (10 microM, NA efflux reduced by about 20%). Moreover, the prodrugs ramipril and enalapril (added to the perfusion medium) were without any significant effects on ischemia-induced NA release. Both the angiotensin II receptor antagonist saralasin (0.1 microM) and bradykinin (0.1 and 1 nM) caused marked reductions in ischemic NA efflux. However, when indomethacin (10 microM) was added to the perfusion medium, the effects of bradykinin (1 nM) and ramiprilat (26 nM) on NA efflux were abolished. Likewise, in the presence of angiotensin II (0.1 microM) the effect of ramiprilat was no longer evident. The magnitude of cellular injury, expressed as efflux of creatine kinase during reperfusion, was reduced by bradykinin (0.1 and 1 nM) and by ramiprilat (by about 55% at 2.6 microM). It is concluded that ramiprilat, at therapeutically relevant concentrations, attenuates the ischemia-induced mobilization of NA via a reduction in local angiotensin II production and/or bradykinin degradation. The lack of effect of enalaprilat in this model may reflect differences between converting enzyme inhibitors regarding tissue accumulation or the potency of local enzyme inhibition.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Coronary Disease; Creatine Kinase; Heart; In Vitro Techniques; Indomethacin; Male; Myocardium; Norepinephrine; Pyrroles; Ramipril; Rats; Rats, Inbred Strains; Saralasin