ramiprilat and Myocardial-Ischemia

ACE-inhibitors and AT -receptor antagonists may exert part of their pharmacological actions by interference with angiotensin-and/or bradykinin-mediated prejunctional stimulation of cardiac norepinephrine release. As endogenous formation of angiotensin and bradykinin is increased in ischemia, we investigated the effects of the ACE-inhibitor ramiprilat and the AT -receptor antagonist candesartan on cardiac norepinephrine release in isolated perfused rat hearts, under nonischemic and stop-flow conditions. Exocytotic release of endogenous norepinephrine was induced by electrical field stimulation and measured by HPLC. Paired stimulations were applied in each heart to obtain an intraindividual comparison of the effect of the pharmacological agent on norepinephrine release with the release under baseline conditions. The ACE-inhibitor ramiprilat (0.1-10 nM) and the AT -receptor antagonist candesartan (1-100 nM) were studied during normal flow or in the fourth minute of stop-flow. Under nonischemic conditions, the ACE-inhibitor slightly reduced norepinephrine release at the highest concentration, while the AT -receptor antagonist did not influence norepinephrine release in normoxia. Conversely, both substances significantly increased norepinephrine release during ischemia. Augmentation of norepinephrine release in ischemia by ramiprilat and candesartan was blocked by the bradykinin B -receptor antagonist HOE 140 and, in case of candesartan, by the AT -receptor antagonist PD 123319. The ACE-inhibitor ramiprilat and AT -receptor antagonist candesartan enhance cardiac norepinephrine release selectively in ischemia by stimulating presynaptic bradykinin B -receptors. Regarding the AT -receptor antagonist, AT -receptor activation is also involved in bradykinin-mediated prejunctional stimulation.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Male; Myocardial Ischemia; Myocardium; Norepinephrine; Ramipril; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Tetrazoles

Because part of the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors results from their protective effects on cardiac bradykinin (BK) metabolism, the purpose of this study was to define the metabolism of BK in normal and failing human hearts and to compare the effect of omapatrilat, a vasopeptidase inhibitor (VPI), which simultaneously inhibits both neutral endopeptidase (NEP) and ACE, with that of an ACE inhibitor. Exogenous BK at a nanomolar concentration was incubated alone, in the presence of an ACE inhibitor (ramiprilat, 36 nM), or in the presence of a VPI (omapatrilat, 61 nM) with left ventricular membranes prepared from normal donor hearts (n = 7), and hearts from patients with an ischemic (n = 11) or dilated (n = 12) cardiomyopathy (DCM). The half-lives calculated for BK alone (199 +/- 60, 224 +/- 108, and 283 +/- 122 s; P = NS) exhibited similar values for normal, ischemic, and DCM heart tissues, respectively. Ramiprilat significantly increased the half-life of BK (P <.01), but the effect was similar for the three kinds of tissues (297 +/- 104, 267 +/- 157, and 407 +/- 146 s, respectively; P = NS). The potentiating effect of the VPI omapatrilat on the kinetic parameter of BK (478 +/- 210, 544 +/- 249, and 811 +/- 349 s, respectively) was greater than that of the ACE inhibitor (P <.01). Moreover, omapatrilat had a more important potentiating effect with DCM than normal heart membranes (P <.05). These results show that not only ACE but also and mainly NEP play an important role in the degradation of BK in human heart membranes. Omapatrilat, a VPI, has a greater protective effect on BK metabolism than that of a pure ACE inhibitor. Thus, inhibition of both ACE and NEP with omapatrilat could be more cardioprotective than ACE inhibition alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Cardiomyopathy, Dilated; Cardiovascular Agents; Female; Half-Life; Heart; Humans; Male; Membranes; Middle Aged; Myocardial Ischemia; Myocardium; Neprilysin; Peptidyl-Dipeptidase A; Protease Inhibitors; Pyridines; Ramipril; Thiazepines

We investigated the effect of an infusion of ramiprilat on the development of coronary endothelial dysfunction. In anesthetized dogs, the endothelium-dependent vasodilators acetylcholine (ACh, 5 and 10 microg x min(-1) for 1 min) and serotonin (5-HT, 50 and 100 microg x min(-1) for 1 min) and the endothelium-independent vasodilator nitroglycerin (NTG, 50 and 100 microg x min(-1) for 1 min) were given intracoronarily (i.c.) both prior to and after 60 min of ischemia (I) and 180 min of reperfusion (R) of a coronary artery. During I/R the dogs received i.c. either saline (N = 22) or ramiprilat (40 ng/kg x min(-1), N = 14). At the end of the experiment, a biopsy of the most distal coronary bed was processed for scanning electron microscopy (SEM). Prior to I/R all vasodilators induced a similar dose-related increase in coronary flow in both groups. Following I/R, in controls the responses to ACh and 5-HT were significantly blunted (ACh: -39% and -34%; 5-HT: -48% and -49%); those to NTG were unchanged. Ramiprilat significantly prevented the blunting of the responses to ACh (-5%, and -10%) and 5-HT (-11%, and -19%). SEM of control subepicardial arterioles showed adhesion of leukocytes to the endothelium and crater formation. No craters were seen in the ramiprilat-treated dogs. Thus, an acute infusion of ramiprilat significantly prevents the development of coronary endothelial dysfunction. Additionally, the appearance of crater-like changes on the endothelial surface can be taken as a morphological marker of endothelial dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Coronary Circulation; Coronary Vessels; Dogs; Endothelium, Vascular; Female; Male; Microscopy, Electron, Scanning; Myocardial Ischemia; Myocardial Reperfusion; Ramipril

Cardioprotective effects of the angiotensin-converting enzyme inhibitors captopril and ramiprilat were studied in two in vivo canine models of myocardial ischemic injury: 90 min of regional ischemia with 18 h reperfusion (protocol I) and 6 h of continuous ischemia without reperfusion (protocol II). In protocol I, neither ramiprilat (50 micrograms/kg) nor captopril (5 mg/kg + 0.25 mg/kg/h) reduced infarct size after 18 h of reperfusion (vs. controls). In protocol II, drugs were administered directly into both left anterior descending coronary artery and left circumflex branch. Compared to controls, continuous intracoronary administration of ramiprilat (40 ng/kg/min) or captopril (400 ng/kg/min) did not reduce infarct size. Thus neither captopril nor ramiprilat protected the heart from injury under conditions of ischemia with reperfusion or ischemia without reperfusion.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Dogs; Evaluation Studies as Topic; Heart Rate; Hemodynamics; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Ramipril

After transient episodes of ischemia, benefits of thrombolytic or angioplastic therapy may be limited by reperfusion injury. Angiotensin-converting enzyme inhibitors protect the heart against ischemia/reperfusion injury, an effect mediated by kinins. We examined whether the protective effect of the angiotensin-converting enzyme inhibitor ramiprilat on myocardial ischemia/reperfusion is due to kinin stimulation of prostaglandin and/or nitric oxide release. The left anterior descending coronary artery of Lewis inbred rats was occluded for 30 minutes, followed by 120 minutes of reperfusion. Immediately before reperfusion rats were treated with vehicle, ramiprilat, or the angiotensin II type 1 receptor antagonist losartan. We tested whether pretreatment with the kinin receptor antagonist Hoe 140, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, or the cyclooxygenase inhibitor indomethacin blocked the effect of ramiprilat on infarct size and reperfusion arrhythmias. In controls, infarct size as a percentage of the area at risk was 79 +/- 3%; ramiprilat reduced this to 49 +/- 4% (P < .001), but losartan had little effect (74 +/- 6%, P = NS). Pretreatment with Hoe 140, NG-nitro-L-arginine methyl ester, or indomethacin abolished the beneficial effect of ramiprilat. Compared with the 30-minute ischemia/120-minute reperfusion group, nonreperfused hearts with 30 minutes of ischemia had significantly smaller infarct size as a percentage of the area at risk, whereas in the 150-minute ischemia group it was significantly larger. This suggests that reperfusion caused a significant part of the myocardial injury, but it also suggests that compared with prolonged ischemia, reperfusion salvaged some of the myocardium. Ventricular arrhythmias mirrored the changes in infarct size. Thus, angiotensin-converting enzyme inhibitors protect the myocardium against ischemia/reperfusion injury and arrhythmias; these beneficial effects are mediated primarily by a kinin-prostaglandin-nitric oxide pathway, not inhibition of angiotensin II formation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Arrhythmias, Cardiac; Bradykinin; Bradykinin Receptor Antagonists; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Hemodynamics; Indomethacin; Male; Myocardial Infarction; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Ramipril; Rats; Rats, Inbred Lew; Reperfusion Injury

We studied the effects of angiotensin-converting enzyme (ACE)/kininase II inhibition selectively in the ischemic zone on reperfusion arrhythmias, and the role of bradykinin versus angiotensin II (produced locally in this zone) in modulating the severity of such arrhythmias. Isolated rat hearts (n = 12 per group) were subjected to independent perfusion of left and right coronary beds. The left coronary bed received the ACE/kininase II inhibitor ramiprilat, alone or in combination with either HOE140 (bradykinin B2 receptor antagonist) or angiotensin II, before induction of regional ischemia (10 min) by discontinuation of flow to the bed. Ramiprilat (1, 10, or 100 nM) did not significantly alter the incidence of reperfusion-induced ventricular tachycardia (VT) or fibrillation (VF), but reduced the incidence of sustained VF from 83% in controls to 75, 50, and 25% (p < 0.05). The protective effects of 100 nM ramiprilat were abolished by coinfusion of HOE140 (10 or 100 nM) but not affected by coinfusion of angiotensin II (1 nM). HOE140 (10 nM), when infused alone into the left coronary bed before 7-min ischemia, increased the incidence of sustained VF from 42 to 100% (p < 0.05). Although HOE140 caused vasoconstriction in the left coronary bed when given alone or in combination with ramiprilat, its proarrhythmic effects were not due to a reduction of flow to the bed. We conclude that selective inhibition of ACE/kininase II in the ischemic zone moderately attenuates reperfusion arrhythmias and that enhanced bradykinin availability rather than reduced angiotensin II in synthesis contributes to such an effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Bradykinin; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Ramipril; Rats; Rats, Wistar

Tissue edema is a facet of ischemia/reperfusion injury in many organs, polymorphonuclear leukocytes (PMN) presumably playing a contributory role. We studied the intracoronary adhesion of PMN and its effect on vascular permeability during reperfusion in isolated guinea-pig hearts. After a global ischemia of 15 min duration. PMN (10(7)) were infused into the coronary system during the first minute of reperfusion. PMN adhesion was measured as difference of applied PMN and those recovered in the effluent perfusate. Coronary permeability was assessed by measuring the rate of transudate formation (TF) on the epicardial surface, before as well as 5, 15 and 30 min after ischemia. Experiments were also performed in the presence of the NO-synthase inhibitor nitro-L-arginine (10 microM) and the ACE-inhibitor ramiprilat (2 microM), the latter known to enhance endogenous nitric oxide formation. Furthermore, the radical scavenger uric acid (0.5 mM) was applied either before and during ischemia or starting after PMN application. Ischemia/reperfusion increased coronary PMN adherence from 23 +/- 1% (basal) to 33 +/- 2%. Whereas ischemia alone did not influence TF (about 100 microliters/min during reperfusion), postischemic PMN infusion led to progressive TF. With nitro-L-arginine, PMN adhesion rose to 45 +/- 3%; TF increased to 212 +/- 30 microliters/min. In contrast, ramiprilat caused post-ischemic adhesion and TF to decline to basal values. In the presence of uric acid (UA) PMN adhesion declined to 26 +/- 2%, however, the subsequent increase in TF after withdrawal of UA was not markedly attenuated. On the other hand, infusion of UA after application of PMN caused a significant decrease of TF. The extracellular antioxidants SOD/catalase were without effect. As shown using luminol enhanced chemiluminescence. No was able to scavenge oxygen free radicals released by activated PMN. These findings indicate that enhanced PMN adhesion in reperfusion leads to an increase in coronary permeability. Scavenging of oxygen free radicals with NO or UA appears to mitigate both, postischemic PMN adhesion and PMN-induced vascular injury, even after adhesion.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Catalase; Cell Adhesion; Cell Membrane Permeability; Coronary Vessels; Free Radicals; Guinea Pigs; In Vitro Techniques; Luminescent Measurements; Male; Myocardial Ischemia; Myocardial Reperfusion; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Nitric Acid; Nitric Oxide Synthase; Nitroarginine; Ramipril; Superoxide Dismutase; Uric Acid

The angiotensin-converting enzyme inhibitor ramiprilat has been previously demonstrated to protect myocardium from ischemia/reperfusion injury. The objective of these investigations was to examine the roles of bradykinin, angiotensin II, and nitric oxide in the cardioprotective effects of ramiprilat.. Anesthetized, open-chest rabbits were instrumented for production of myocardial ischemia (30 minutes) and subsequent reperfusion (120 minutes), after which myocardial infarct size was measured. Animals were treated intravenously with either saline solution, ramiprilat (50 micrograms/kg), the bradykinin2 receptor antagonist HOE 140 (1 microgram/kg), ramiprilat + HOE 140, angiotensin II (2.5 ng.kg-1.min-1), the angiotensin II receptor antagonist losartan (20 mg/kg), ramiprilat + angiotensin II, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (100 micrograms.kg-1.min-1), or ramiprilat + NG-nitro-L-arginine methyl ester.. Among all treatment groups myocardial infarct size was reduced significantly below saline control only by ramiprilat (-54%) and ramiprilat + angiotensin II (-37%). Pretreatment with HOE 140 or NG-nitro-L-arginine methyl ester abolished the cardioprotective effect of ramiprilat. Neither stimulation nor antagonism of angiotensin II receptors altered infarct size from the saline control level. Also, when isolated neonatal rat cardiomyocytes were exposed to hypoxia/reoxygenation, ramiprilat (100 mumol/L) and bradykinin (10 nmol/L) improved cell viability (approximately 60%), and the protective effect of both agents was reversed by administration of HOE 140 (10 mumol/L).. These results indicate that the in vivo cardioprotective effect of ramiprilat can be abolished by antagonizing bradykinin receptors or inhibiting nitric oxide synthase, and that the effect is not related to angiotensin II receptor activity. The potential bradykinin-sparing property of ramiprilat may promote increased bradykinin-stimulated nitric oxide production leading to cardioprotection. Part of the cardioprotective effects of ramiprilat/bradykinin/nitric oxide may occur locally as demonstrated by the in vitro results using isolated cardiomyocytes.

Topics: Adrenergic beta-Antagonists; Amino Acid Oxidoreductases; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Heart; Imidazoles; Losartan; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rabbits; Ramipril; Receptors, Angiotensin; Receptors, Bradykinin; Tetrazoles

The objective of this investigation was to determine the role of nitric oxide synthase in the action of the angiotensin-converting enzyme inhibitor, ramiprilat, to reduce myocardial ischemia/reperfusion injury. Ramiprilat, the nitric oxide synthase inhibitor NG-nitro-L-NAME (L-NAME), ramiprilat plus L-NAME, or saline (n = 8 each group), were administered i.v. in intact animal preparations of experimentally induced acute myocardial ischemia. Anesthetized, open-chest rabbits were instrumented for measurement of systemic hemodynamics and left ventricular pressure from which left ventricular +dP/dtmax was derived. Animals were subjected to 30 min of left main coronary artery occlusion (marginal branch) followed by 2 hr of reperfusion. Ramiprilat (50 micrograms/kg) or saline was administered 5 min before reperfusion, and those rabbits receiving L-NAME (100 micrograms/kg/min) were pretreated starting 30 min before occlusion throughout the remainder of the experiment. After reperfusion, myocardial infarct size (IS) was determined via tetrazolium staining and expressed as a percentage of area at risk (AR). IS/AR% was significantly reduced in rabbits administered ramiprilat (19 +/- 3%) compared to those receiving saline (39 +/- 2%), ramiprilat plus L-NAME (43 +/- 4%) or L-NAME alone (43 +/- 2%; mean +/- S.E.M.; P < .05). AR as a percent of total left ventricular mass was not different between any of the four treatment groups. Systemic hemodynamic effects were not significantly different between groups. The results indicate that the effect of ramiprilat to reduce infarct size is abolished by pretreatment with L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Oxidoreductases; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Blood Pressure; Female; Heart; Male; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rabbits; Ramipril

The anti-ischemic properties of the ACE inhibitor ramiprilat (ram) were investigated in electrically driven Langendorff hearts from rabbits whose endogenous angiotensin-I content has been previously shown to be very low (constant pressure: 70 cm H2O, Tyrode solution, Ca2+ 1.8 mmol/l). Cumulative concentration-response curves showed that the reduction in global coronary flow (CF) by exogenous angiotensin-I was concentration dependently inhibited by ram (P < 0.05). Myocardial ischemia (MI) was induced by occlusion of a left coronary artery branch and MI was quantified by NADH surface fluorescence photography. MI was significantly enlarged (+23%) (P < 0.05) by exogenous angiotensin-I (6 x 10(-9) mol/l). Addition of ram (10(-8) mol/l) to the perfusion buffer simultaneously with angiotensin-I, completely prevented the reduction of CF by angiotensin-I (P > 0.05) and significantly diminished MI even below control values (-25%) (P < 0.05). In the absence of exogenous angiotensin-I, ram alone (10(-8) mol/l) did not significantly enhance CF (P > 0.05), supporting findings demonstrating a very low endogenous angiotensin-I content in isolated rabbit hearts. However, ram alone (10(-8) mol/l) significantly diminished MI (-24%) (P < 0.05). We conclude that ram does possess direct cardioprotective properties that are independent of the inhibition of angiotensin-II generation but that may be related to potentiation of the effects of bradykinin.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Coronary Circulation; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Myocardial Ischemia; NAD; Rabbits; Ramipril

To establish that bradykinin is formed in the heart we measured bradykinin in the venous effluent from rat isolated hearts perfused with Krebs-Henseleit buffer. In addition, we examined the effect on bradykinin outflow of the angiotensin converting enzyme (ACE) inhibitor, ramiprilat. From rat isolated normoxic hearts a bradykinin outflow of 0.85 +/- 0.1 ng ml-1 perfusate g-1 wet weight was measured. Perfusion with ramiprilat increased the bradykinin concentration to 2.8 +/- 0.3 ng ml-1 perfusate g-1 wet weight. During ischaemia bradykinin outflow maximally increased 8.2 fold to 7.0 +/- 0.5 ng ml-1 perfusate g-1, and in ramiprilat-perfused hearts 5.8 fold to 16.0 +/- 1.8 ng ml-1 perfusate g-1. In the reperfusion period bradykinin outflow normalized to values measured in the respective pre-ischaemic period. The presents data show that bradykinin is continuously formed in the rat isolated heart. Ischaemia increases bradykinin outflow from the heart. Presumably by inhibiting degradation of kinins, ACE inhibition significantly increased the bradykinin concentration during normoxia, ischaemia and reperfusion.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cardioplegic Solutions; Glucose; In Vitro Techniques; Male; Myocardial Ischemia; Organ Preservation; Ramipril; Rats; Rats, Wistar; Tromethamine

The angiotensin-converting enzyme inhibitor ramiprilat, the angiotensin II receptor antagonist losartan, angiotensin II, ramiprilat plus angiotensin II, or saline (N = 6 each group), were administered i.v. in anesthetized, open-chest rabbit preparations of acute myocardial ischemia. Animals were instrumented for measurement of systemic hemodynamics and left ventricular +dP/dtmax, then subjected to 30 min of left anterior descending coronary artery occlusion (marginal branch) followed by 2 h of reperfusion. Ramiprilat (50 micrograms/kg), losartan (10 mg/kg), or saline were administered prior to reperfusion, and angiotensin II (2.5 ng/kg per min) was infused 15 min prior to occlusion and throughout the remainder of the experiment. Losartan was supplemented (10 mg/kg) after 1 h of reperfusion. These non-hypotensive doses of ramiprilat and losartan were demonstrated to significantly antagonize the systemic pressor effects of i.v. challenge with angiotensin I (15% of control, maximum) and II (5% of control, maximum), respectively, for the duration of the experiment. Systemic hemodynamic and +dP/dtmax changes due to occlusion/reperfusion or drug administration were similar between treatment groups. Infarct size was measured post-experimentally using tetrazolium staining and is reported as a percent of area at risk. Infarct size/area at risk (%) was significantly lower in rabbits administered ramiprilat only (20 +/- 6%*) or ramiprilat plus angiotensin II (26 +/- 5%*), compared to those receiving saline (41 +/- 6%), angiotensin II (51 +/- 4%), or losartan (52 +/- 4%, mean +/- S.E.M., * P < 0.05). These data indicate that direct angiotensin II receptor stimulation or receptor antagonism does not alter the degree of myocardial necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Electrophysiology; Female; Hemodynamics; Imidazoles; Losartan; Male; Myocardial Infarction; Myocardial Ischemia; Rabbits; Ramipril; Tetrazoles

The role of NO-formation induced by accumulated endogenous bradykinin (BK) via local ACE-inhibition with ramiprilat (RT) or by adding BK exogenously was evaluated in cultured bovine aortic endothelial cells (BAEC) and in isolated rat hearts with post-ischaemic reperfusion injuries. Furthermore we used the n-octyl-ester of ramipril (RA-octil) which was shown to have no ACE-inhibitory action. In BAEC, ACE-inhibition by RT (1 x 10(-8)-1 x 10(-6) mol/l) or addition of BK (1 x 10(-8)-1 x 10(-6) mol/l) stimulated the formation of NO and prostacyclin (PGI2) as assessed by endothelial cyclic GMP- and 6-keto-PGF1a formation. Cyclic GMP and PGI2 synthesis was completely suppressed by the NO synthase inhibitor NG-nitro-L-arginine (L-NNA, 1 x 10(-5) mol/l) and by the B2 kinin receptor antagonist HOE 140 (1 x 10(-7) mol/l). RA-octil (1 x 10(-8)-1 x 10(-4) mol/l) did not affect endothelial cyclic GMP production in BAEC. In isolated working rat hearts subjected to local ischemia with reperfusion both RT (1 x 10(-8) mol/l) and BK (1 x 10(-9) mol/l) reduced the incidence and duration of ventricular fibrillation. In parallel myocardial function (left ventricular pressure, coronary flow) and metabolism (high energy rich phosphates) were improved showing a comparable fingerprint for RT and BK. Addition of L-NNA (1 x 10(-6) mol/l) or HOE 140 (1 x 10(-9) mol/l) abolished these protective effects of RT and BK. As in the BAEC studies RA-octil was without beneficial effects on the isolated ischaemic rat heart. The findings on BAEC show that inhibition of ACE localized on the luminal side of the vascular endothelium results in increased synthesis of NO and prostacyclin by local accumulation of endothelium-derived BK. Similar mechanisms may occur in the ischaemic rat heart leading to cardioprotection.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Bradykinin; Cattle; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Epoprostenol; Female; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitric Oxide; Ramipril; Rats; Rats, Wistar

The ACE-inhibitor ramiprilat (40 ng/kg/min) was infused for 6 h into the left coronary artery of anesthetized dogs with ligation of the descending branch of this artery. This route of administration and the low dose were chosen to achieve local cardiac effects without affecting systemic hemodynamics. Ramiprilat significantly reduced infarct-size expressed as percentage of the area at risk. The cardioprotective effect of ramiprilat was mimicked by bradykinin and abolished by coadministration of a bradykinin antagonist. These results strongly suggest that bradykinin plays a role in the cardioprotective effect of the ACE-inhibitor ramiprilat.

Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Coronary Vessels; Dogs; Infusions, Intra-Arterial; Molecular Sequence Data; Myocardial Infarction; Myocardial Ischemia; Ramipril