saralasin and Coronary-Disease

Dose-response curves of angiotensin I (AI, 1.0-1000.0 pmol) and angiotensin II (AII, 1.25-1250.00 pmol) were obtained in isolated rat hearts subjected to control conditions, mild hypoxia (PO2 = 145 mm Hg), reoxygenation, ischemic (perfusion pressure = 35 mm Hg) and reperfusion. Both AI and AII caused dose-dependent coronary flow (CF) of 26 +/- 3 and 27 +/- 2%, respectively. The effects of both AI and AII were substantially attenuated during hypoxia, but were fully restored upon reoxygenation. During ischemia, the effect of AII was unaltered while the effect of AI was enhanced compared to the control (P less than 0.05). This enhancement was reversible on reperfusion. Cardiac conversion of AI, calculated from ED50 values for AI and AII, was significantly increased during ischemia (P less than 0.05). Infusion of saralasin (0.5-5.0 micrograms/min) did not increase CF in any of the groups. We conclude that (1) the coronary vasoconstrictive effect of AII is preserved in ischemia but attenuated in hypoxia and (2) cardiac conversion of AI to AII is enhanced in hearts injured by ischemia.

Topics: Angiotensin I; Angiotensin II; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Heart; Hypoxia; In Vitro Techniques; Male; Rats; Rats, Inbred Strains; Saralasin; Vasoconstriction

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

Vasopressin, the renin-angiotensin system and atrial natriuretic factor (ANF) interact in regulating blood pressure. While the vasoconstrictor effect of vasopressin and the renin-angiotensin system is well documented, the direct vascular effect of ANF is unclear. We studied in anaesthetized dogs the coronary vascular effects of agonists and antagonists of vasopressin and the renin-angiotensin system under control and ischaemic conditions, respectively. In addition, the action of ANF and its relationship to the renin-angiotensin system was analysed. A coronary artery was cannulated and perfused by a bypass system from the femoral arteries of the same animal. Coronary vasoconstriction by vasopressin was potentiated when myocardial ischaemia was induced by lowering coronary perfusion pressure while coronary constriction by angiotension I and II was mitigated. A vasopressin receptor blocker slightly reduced coronary blood flow at high doses (intrinsic activity) while the angiotensin II receptor blocker increased coronary flow in myocardial ischaemia. ANF effects were ambiguous at lower doses (1 ng (kg)-1 i.c.) with coronary constriction in 79% of dogs. At higher doses (1 microgram kg-1) ANF consistently induced coronary dilation. The angiotensin II receptor blocker saralasin significantly reduced this coronary dilator effect of ANF. Thus, in conclusion, a vasoconstrictor effect of endogenous vasopressin could not be shown by this study. In contrast, endogenous angiotensin II might participate in control of coronary blood flow during myocardial ischaemia. The coronary dilator effect of ANF at least in part appears to be due to interference with the renin-angiotensin system.

Topics: Angiotensin II; Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Pressure; Captopril; Coronary Circulation; Coronary Disease; Dogs; Renin-Angiotensin System; Saralasin; Vasoconstriction; Vasopressins

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

In order to establish the possible existence of a cardiac converting enzyme and its role in the pathophysiology of the myocardial ischemia, the direct cardiac effects of IEC and AI or AII were studied on the isolated rat heart perfused through the left atria. Three series of seven hypertensive rats (SHR) were used. The reduction of the aortic flow (QAO) due to ischemia (produced by a left coronary artery ligation of 10 mn) was brought into line with the reduction of the coronary flow (QCORO) and the weight of the heart. This reduction was 2.06 +/- 1.8 for the control, 1.96 +/- 1.27 when captopril (CAP) (10(-5) M) was added to the perfusion liquid and 1 +/- 0.42 when perindopril (PER) (1.2 x 10(-5) M) was added to the perfusion liquid (p less than 0.05 vs CAP). Four series of 10 rat hearts (Sprague Dawley) were used to study the changes on the working heart caused by short perfusions of AI or AII (10(-7) M) in the presence of IEC or saralasin (SAR 10(-7) M). AII caused a reduction of the QCORO of 2.1 +/- 0.26 ml/mn, an increase of the QAO of 2.5 +/- 0.9 ml/mn and an increase of the heart rate (HR) of 9 +/- 3.24 beats/mn. In the presence of CAP or PER the effects of AII were the same, however in the presence of SAR these effects were prevented. AI caused a reduction of the QCOR of 2.5 +/- 0.4 ml/mn, an increase of the QAO of 2.5 +/- 0.8 ml/mn and an increase of the HR of 18 +/- 4 beats/mn.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Captopril; Coronary Circulation; Coronary Disease; Heart; Heart Rate; Indoles; Male; Myocardium; Peptidyl-Dipeptidase A; Perindopril; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Saralasin