ramipril and Arrhythmias--Cardiac

ACE inhibitor therapy reduces the risk of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, and need for revascularization in high-risk patients with clinical heart failure, overt left ventricular systolic dysfunction, or vascular disease. In patients with clinical heart failure or overt left ventricular systolic dysfunction, ACE inhibitor therapy also reduces the risk of sudden or arrhythmia-related cardiac death. The objective of this study was to assess the effect of the ACE inhibitor ramipril on sudden unexpected death or resuscitated cardiac arrest among the 9297 individuals without clinical heart failure or overt left ventricular dysfunction enrolled in the Heart Outcomes Prevention Evaluation (HOPE) trial.. During the median follow-up of 4.5 years, the composite outcome of unexpected death, documented arrhythmic death, or resuscitated cardiac arrest was reduced by 21% in patients randomized to ramipril therapy compared with those randomized to placebo. There were 155 (3.3%) composite outcome events in patients randomized to ramipril therapy compared with 195 (4.2%) such events in patients randomized to placebo (RR 0.79, 95% CI 0.64 to 0.98, P=0.028). There were trends toward reductions in fatal primary outcome events (unexpected death or documented arrhythmic death; RR 0.81, 95% CI 0.64 to 1.02, P=0.072) and in nonfatal primary outcome events (resuscitated cardiac arrest; RR 0.65, 95% CI 0.38 to 1.13, P=0.127) in the ramipril treatment group.. Ramipril reduces the risk of fatal and nonfatal serious arrhythmic events in high-risk patients without clinical heart failure or overt left ventricular systolic dysfunction.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Double-Blind Method; Female; Follow-Up Studies; Heart Arrest; Humans; Life Tables; Male; Middle Aged; Neurotransmitter Agents; Ramipril; Risk; Survival Analysis; Treatment Outcome; Vitamin E

HYPOTHESIS/INTRODUCTION: Our aim was to investigate whether a non-hypotensive dose of ramiprilat and losartan has myocardial protective effects during myocardial ischemia/reperfusion in vivo.. Three groups of rats were given 10 mg/kg per day of losartan for one (L-1W), four (L-4W) or 10 (L-10W) weeks. Another three groups were given 50 µg/kg per day of ramiprilat for one (R-1W), four (R-4W) or 10 (R-10W) weeks. The animals underwent 30 min of left anterior descending artery occlusion and subsequent reperfusion for 120 min.. Myocardial infarct size (IS) was reduced in R-1W (28.4 ± 6.3%, p < 0.001), R-4W (27.8 ± 7.4, p < 0.001), L-4W (31.8 ± 6%, p < 0.05) and L-10W (25.3 ± 5.7, p < 0.001) groups compared with a saline group (48.3 ± 7.8%). A significant reduction in the number of ventricular ectopic beats (VEBs) was noted in groups R-1W (209 ± 41, p < 0.01), R-4W (176 ± 39, p < 0.01), L-4W (215 ± 52, p < 0.05) and L-10W (191 ± 61, p < 0.01 vs. saline 329 ± 48). The incidence of irreversible ventricular fibrillation (VF) and mortality were decreased significantly only in L-10W group. There were no significant decreases in episodes of VT, the incidence of irreversible VF and mortality in all of the groups treated with ramiprilat.. These data indicate that losartan and ramiprilat protect the heart against ischemia/reperfusion injury independently of their hemodynamic effects but in a time-dependent manner.

Topics: Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Drug Therapy, Combination; Heart; Heart Rate; Kaplan-Meier Estimate; Losartan; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Ramipril; Rats; Rats, Wistar

To study the protective effects of ramipril in combination with BQ-123 on myocardial ischemia/reperfusion (I/R) injury in vivo in anesthetized rats.. Healthy male Wistar rats were divided into 5 groups randomly and subjected to 30 min of myocardial ischemia followed by 120 min reperfusion. Ramipril, BQ-123 and their combination were given to rats respectively. To observe the protection of their combination against myocardial I/R injury. HR, MAP and the change of ST-segment were observed. Ventricular arrthymias were monitored. The activity of creatine kinase (CK) and lactate dehydrogenase (LDH) in plasma, the infarct size and morphologic change were examined.. Compared with I/R group, the elevation of ST-segment was decreased. Onsets of VPC and VT were delayed, durations of VPC and VT were shortened, especially their combination. Incidences of VPC, VT and VF were decreased. Activity of plasma CK and LDH was decreased, especially their combination. IS, IS/AAR and the morphology of myocardium were improved, especially their combination.. Ramipril, BQ-123 and combined using these two agents protected myocardium from I/R injury in vivo. The protective effects on delaying onset of VA, shortening duration of VA, decreasing the activities of CK and LDH, decreasing infrarct size and improving morphology of myocardium were better than using ramipril and BQ-123 alone.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Creatine Kinase; Drug Synergism; L-Lactate Dehydrogenase; Male; Myocardial Reperfusion Injury; Peptides, Cyclic; Ramipril; Rats; Rats, Wistar

Aminopeptidase P and angiotensin-converting enzyme (ACE) are responsible for the metabolism of exogenously administered bradykinin in the coronary circulation of the rat. It has been shown that ACE inhibitors decrease cytosolic enzyme release from the ischemic rat heart and reduce reperfusion-induced ventricular arrhythmias by increasing endogenous levels of bradykinin. It was hypothesized that the aminopeptidase P inhibitor apstatin could do the same. In an isolated perfused rat heart preparation subjected to global ischemia and reperfusion, both apstatin and ramiprilat (an ACE inhibitor) significantly decreased creatine kinase (CK) and lactate dehydrogenase (LDH) release. The difference between the postischemia and preischemia levels of released CK was reduced 68% by apstatin and 68% by ramiprilat compared with control. The corresponding reductions in LDH release were 74% for apstatin and 81% for ramiprilat. A combination of the inhibitors was not significantly better than either one alone. Apstatin and ramiprilat also significantly reduced the duration of reperfusion-induced ventricular fibrillation by 69 and 61%, respectively. The antiarrhythmic effect of apstatin was reversed by HOE140, a bradykinin B2-receptor antagonist, suggesting that apstatin is acting by potentiating endogenously formed bradykinin. The results demonstrate that the aminopeptidase P inhibitor apstatin is cardioprotective in this model of cardiac ischemia/ reperfusion injury.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Bradykinin; Cardiovascular Agents; Creatine Kinase; Drug Interactions; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Peptides; Perfusion; Protease Inhibitors; Ramipril; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Ventricular Fibrillation

Hypertensive patients with left ventricular hypertrophy (LVH) have been found to have greater peri-infarction and postinfarction mortality. In this study, we evaluated the postinfarction survival, susceptibility to ventricular arrhythmias, and degree of LVH and cardiac fibrosis in the spontaneously hypertensive rat (SHR) and the effects of the ACE inhibitor ramipril and the direct vasodilator hydralazine on these characteristics.. An acute myocardial infarction (MI) was produced by ligation of the left anterior descending coronary artery. Rats were randomized to either control (n=50), hydralazine (n=41), or ramipril (n=45). Treatments were started 4 hours after infarction and continued for 8 weeks. Ramipril and hydralazine reduced arterial pressure similarly. Medications were stopped 72 hours before euthanasia, at which time hemodynamic, programmed electrophysiological stimulation (PES), and morphological studies were performed. Mortality was decreased in ramipril (56%) compared with hydralazine (78%) and control (82%) SHRs (P=0.008). This was accompanied by a decrease in myocardial hypertrophy and fibrosis and a decrease in inducibility of ventricular arrhythmias by PES in the ramipril group regardless of MI size. Treatment with hydralazine had little or no effect on LVH and cardiac fibrosis and did not modify inducibility of ventricular arrhythmias by PES. Ramipril but not hydralazine prevented the increase in LV end-diastolic pressure in rats with large MIs.. In the SHR, the ACE inhibitor ramipril reduces LVH, cardiac fibrosis, and susceptibility to ventricular arrhythmias by PES and improves survival and LV function. Despite a similar decrease in arterial pressure, hydralazine does not have these beneficial effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Fibrosis; Heart Rate; Hemodynamics; Hydralazine; Hypertrophy, Left Ventricular; Male; Myocardial Infarction; Myocardium; Ramipril; Rats; Rats, Inbred SHR; Survival Analysis; Vasodilator Agents

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

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Drug Evaluation; Heart Failure; Heart Function Tests; Hemodynamics; Humans; Middle Aged; Quality of Life; Ramipril; Rheumatic Heart Disease

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

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

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