Emma Riva

Improvement of cardiac function by allopurinol in patients undergoing cardiac surgery

Allopurinol reduces formation of cytotoxic free radicals during myocardial ischemia/reperfusion in animals. To evaluate the effect of allopurinol on cardiac performance and metabolism after coronary bypass in humans, we divided 33 patients into two groups: 15 patients (controls) received no allopurinol and 18 patients received 200 mg allopurinol intravenously (i.v.) 1 h preop-eratively. Hemodynamic measurements were made with a triple-lumen thermodilution pulmonary artery catheter before cardiopulmonary bypass (CPB), 30 min after completion of CPB and 6 h later in the intensive care unit (ICU). A catheter placed into the coronary sinus was used for blood sampling for measurement of lactate and creatine phosphokinase MB. Peripheral blood was obtained for measurement of xanthine oxidase activity (XO), uric acid, and thiol groups. A myocardial biopsy was taken for measurement of thiol group content and XO before CPB and after heparin neutralization with prota-min (a few minutes after CPB). Treated patients had better recovery of cardiac output (CO) and left ventricular stroke work (LVSW) 30 min and 6 h after completion of CPB than did controls. Allopurinol significantly reduced plasma XO. Plasma concentrations of uric acid increased significantly in both groups 30 min after completion of CPB, but the increase in controls was greater (p < 0.02) than with allopurinol. Thiol group levels increased (p < 0.05) only in controls. Our results demonstrate improvement of cardiac function in coronary artery bypass surgery with allopurinol that is related to its metabolic effects consistent with protection against XO catalyzed free radical-mediated injury.

Superoxide dismutase and the reduction of reperfusion-induced arrhythmias: In vivo dose-response studies in the rat

SummaryUsing anesthetized rats we have investigated the dose-response characteristics for the ability of superoxide dismutase (SOD) to reduce the vulnerability of the rat heart to reperfusion-induced arrhythmias in vivo. Hearts (n=15 in each group) were subjected to 7 min of regional ischemia followed by 10 min of reperfusion. In the control group (saline), 73% (11/15) of the hearts fibrillated during reperfusion, 20% (3/15) had atrioventricular block and 47% (7/15) died as a result of ventricular arrhythmias. Superoxide dismutase, administered as an intravenous bolus2 min prior to reperfusion exerted a marked protective effect. At its most effective dose (10 mg/kg body wt i.e. 27,000 IU/kg body wt) reperfusion-induced ventricular fibrillation was reduced to 33% (5/15). Reperfusion-induced atrioventricular block was eliminated (0/15) and mortality was reduced to 7% (1/15, p<0.05). The protective effects were however very dose-dependent and at higher doses SOD exhibited no antiarrhythmic actions during reperfusion. These results, together with our previous findings in vitro, lend further support to our proposition that oxygen-derived free radicals may play a role in the induction of potentially lethal cardiac arrhythmias and that antifree radical interventions, even when givenafter the onset of ischemia, can be highly protective.

Effects of a New Angiotensin-Converting Enzyme Inhibitor (Idrapril) in Rats with Left Ventricular Dysfunction after Myocardial Infarction

We evaluated the effects of a new angiotensin-converting enzyme (ACE) inhibitor (idrapril) in terms of hemodynamics and ventricular remodeling after myocardial infarction in rats. The animals were randomly assigned to four experimental groups. Myocardial infarction was induced by left coronary artery ligation in the first two groups treated with either idrapril (300 mg kg-1 day-1) or vehicle for 4 weeks after myocardial infarction. Two groups of sham-operated rats were treated accordingly. Hemodynamics were measured, and the diastole-arrested hearts were analyzed morphometrically to quantify left ventricular (LV) remodeling and infarct size. In infarcted rats, idrapril reduced the arterial systolic blood pressure (SBP) from 128 +/- 10 to 97 +/- 6 mm Hg (p < 0.05) and LV end-diastolic pressure (LVEDP) from 19 +/- 3 to 13 +/- 3 mm Hg (p < 0.01). The decrease in diastolic wall stress conferred by idrapril to infarcted rats (from 499 +/- 99 to 269 +/- 68 dynes mm-2, p < 0.05) was mainly due to a reduction in LVEDP and, to a lesser extent, in LV volume. Idrapril also reduced body and heart weights as compared with those of vehicle-treated animals. Four-week treatment with idrapril initiated immediately after myocardial infarction reduced LVEDP and limited LV wall stress, a major prognostic factor for the progression toward chronic ventricular failure.

Isolated, perfused neontal rat heart preparation for studies of calcium and functional stability

We describe an isolated, perfused preparation for neonatal rat hearts to assess the relationship between extracellular calcium and (1) cardiac function and (2) contractile stability over 2 hours of perfusion. Neonatal (3 to 5 days old) rat hearts (n = 6 per group) were perfused for 30 minutes (Langendorff) with oxygenated buffer (37 degrees C) containing 1.4 mmol/L calcium (control period) and 90 minutes with buffer containing 0.5, 0.8, 1.0, 1.2, 1.4, 1.8, or 2.5 mmol/L calcium. Upon changing from 1.4 mumol/L to either a higher or low calcium concentration there were no significant changes in left ventricular developed pressure, heart rate, or coronary flow. However, left ventricular developed pressure progressively deteriorated in a time-dependent and calcium-dependent manner. Thus, after 90 minutes, developed pressure fell to 18% +/- 2%, 27% +/- 3%, 41% +/- 5%, 47% +/- 8%, 55% +/- 10%, 64% +/- 5% and 76% +/- 4% of its initial value with 0.5, 0.8, 1.0, 1.2, 1.4, 1.8, and 2.5 mmol/L calcium. In conclusion, in studies with the neonatal rat heart, extracellular calcium concentrations in the range of 1.8 to 2.5 mmol/L are recommended.

Effect of lisinopril and isosorbide-5-mononitrate on hemodynamics and mortality in rats with permanent coronary artery occlusion

Summary: We studied the hemodynamic effects of lisinopril and isosorbide-5-mononitrate in rats with permanent coronary occlusion. Rats (n = 35) underwent left coronary occlusion, and ECGs were recorded before and after occlusion. Ventricular arrhythmias were observed in 57% (20 of 35) of animals. Treatment was given immediately after coronary occlusion and for 2 subsequent days. The control group received 100 mg/kg lactose (i.e., 80% vehicle for isosorbide-5-mononitrate). Lisinopril (100 mg/kg body weight) and isosorbide-5-mononitrate (400 mg/kg body weight) reduced systolic blood pressure (SBP) from 134 ± 9 to 115 ± 9 mm Hg (p < 0.05) and from 137 ± 9 to 126 ± 9 mm Hg, respectively; the hypotensive effect lasted 2–3 days. No effect on BP was noted in the control group. Overall mortality was 23%; 8 of 35 animals died within 10–15 min of coronary occlusion. Survival after 4 weeks was similar in each group (∼80%). Left ventricular pressure (LVP) was measured 4 weeks after coronary artery occlusion and was similar in each group. However, dP/dt was lower in hearts with infarction than in hearts with none (12,608 ± 906 vs. 8,992 ± 1,242 mm Hg/s). The extent of the infarction was the same in groups with coronary artery occlusion. Lisinopril is more effective than isosorbide-5-mononitrate in reducing BP after acute myo-cardial infarction (AMI). Medium-term survival (4 weeks) is not jeopardized by effective treatment with angiotensin-converting enzyme (ACE) inhibitors or long-acting nitrates.