Preservation of high-energy phosphates by verapamil in reperfused myocardium

To determine whether verapamil prevents depletion of adenine nucleotides during and after severe myocardial ischemia, dogs were subjected to 15 min occlusions of the left anterior descending coronary artery followed by 240 min of reperfusion. One hour before occlusion, dogs were randomly assigned to a treatment group (n = 10) to which an infusion of intravenous verapamil was given until the onset of reperfusion or to an untreated saline group (n = 9). Verapamil reduced mean aortic pressure and heart rate. After 15 min of ischemia, endocardial adenosine triphosphate (ATP) level, determined by needle biopsy, decreased in the untreated group from 34.7 +/- 2.0 to 24.4 +/- 2.7 nmol X mg protein-1 (p less than .005 vs preocclusion) and in the verapamil group from 32.8 +/- 1.5 to 30.3 +/- 1.5 nmol X mg protein-1 (NS vs preocclusion). Dogs receiving verapamil had significantly higher ATP levels than untreated animals after 90 and 240 min of reperfusion. In untreated animals the sum of inosine and hypoxanthine levels increased during occlusion from very low levels to 4.6 +/- 1.1 nmol X mg protein-1 in the epicardium and to 6.8 +/- 1.5 nmol X mg protein-1 in the endocardium (p less than .05 compared with preocclusion values). In verapamil-treated dogs inosine and hypoxanthine levels increased to only 1.2 +/- 0.3 (epicardium) and 1.9 +/- 0.6 nmol X mg protein-1 (endocardium) (both NS compared with preocclusion values). After 90 min of reperfusion the sum of ATP, adenosine diphosphate, adenosine monophosphate, inosine, and hypoxanthine levels was decreased in the endocardium by 10.2 nmol X mg protein-1 in the untreated group, but no change was observed in verapamil-treated animals. We conclude that breakdown of ATP to inosine and hypoxanthine during severe ischemia is reduced by verapamil, resulting in higher ATP concentrations during occlusion and reperfusion and decreased washout of the diffusible purines inosine and hypoxanthine during reperfusion.     

Effects of transient increased afterload during experimentally induced acute myocardial infarction in dogs

Alterations in afterload may occur during acute myocardial infarction (AMI), but it is unknown whether such alterations cause long-term changes in the left ventricular topography or alter healing of the AMI. AMI was produced by ligation of the left anterior descending coronary artery in open-chest dogs. Eight dogs were randomized to a methoxamine group with an infusion dose of 30 micrograms/kg/min starting 1 hour after ligation for 4 hours to increase systemic systolic pressure by 40 to 50 mm Hg, and 8 were randomized to a saline control group (n = 8). Seven days later the dogs were killed and the hearts examined. The ratio of infarct wall thickness to noninfarct wall thickness was 1.13 +/- 0.03 (mean +/- standard error of the mean) in control dogs and was 0.98 +/- 0.03 in the dogs treated with methoxamine (p less than 0.005). An expansion index was determined as previously reported and expansion was considered to have occurred if this index exceeded 1.09. The expansion index was 0.98 +/- 0.06 in the control group and 1.18 +/- 0.07 in the methoxamine group (p less than 0.05). Histologic analysis suggested a lag in the healing rate in the methoxamine-treated dogs. Thus, early, brief increases in afterload cause infarct expansion and thinning and appears to slow the early healing phase of AMI in dogs.     

Hypothermic, Closed Circuit Pericardioperfusion: A Potential Cardioprotective Technique in Acute Regional Ischemia

Objectives. This study sought to determine whether infarct size can be reduced by hypothermic pericardioperfusion.

Background. We have shown that myocardial infarct size can be reduced by topical cooling of the heart. The present study tests whether myocardial cooling and protection can be produced by hypothermic pericardioperfusion using a catheter.

Methods. The catheter was sutured into the pericardial space of anesthetized rabbits. Beginning 30 min before coronary artery occlusion, the space was perfused with either chilled (n = 10) or body temperature (n = 10) fluid. The artery was occluded for 30 min and reperfused for 3 h.

Results. After 30 min of pericardioperfusion, myocardial temperature was reduced to 34.1 ± 0.9°C in chilled hearts compared with 38.9 ± 0.4°C in control hearts, p < 0.001, a reduction in myocardial temperature of 5°C. Risk areas were similar in both groups (32 ± 4% left ventricle in cooled and 31 ± 3% in control hearts, p = NS). However, infarct size in cooled hearts was significantly reduced by 49% (18 ± 3% of risk area vs. 35 ± 6%, p = 0.025). Tamponade did not develop, and there were no significant differences in heart rate, arterial pressure or body temperature between groups.

Conclusions. A significant reduction in myocardial temperature, without the development of cardiac tamponade, can be attained using a pericardial catheter to cool the pericardial space. This reduction in temperature causes a significant reduction in necrotic damage. This technique might be used to cool and protect the heart as an adjunct to thrombolysis or during minimally invasive cardiac surgery.     

Effects of nisoldipine, a new calcium antagonist, on myocardial infarct size and cardiac dynamics following acute myocardial infarction

While some calcium antagonists are effective in reducing myocardial infarct size, this beneficial effect may be accompanied by negative inotropic effects. In the following study, a new dihydropyridine calcium antagonist, nisoldipine, was assessed for its effect on infarct size, hemodynamics, and regional function as assessed by percent systolic wall thickening of the left ventricle (SWT) by 2D echocardiography. Open-chest, anesthetized dogs were subjected to 6 h of coronary artery occlusion. After 10 min of coronary artery occlusion, the ischemic area at risk of infarction (AR; % of left ventricle) was determined by left atrial injection of 99mTc-labeled albumin microspheres with subsequent postmortem autoradiography. After 6 h, the hearts were excised, and the area of necrosis (AN) determined by incubation of left ventricular slices in triphenyltetrazolium chloride stain. Treated dogs received 0.005 mg/kg nisoldipine by intravenous infusion at 1.91 ml/min (lasting approximately 8.7 min) during three dosing periods: 15 min, 2 h, and 4 h postocclusion. The AR of eight controls (25.7 +/- 1.8%) was not significantly different from that of 11 treated dogs (25.1 +/- 1.9%). However, the AN/AR X 100 of treated dogs was significantly less than that of controls (62.8 +/- 9.3 vs. 91.6 +/- 7.0%; p less than 0.05). Mean arterial pressure fell in treated dogs by 15.7% (p less than 0.01) at 15 min and by 5.7% (p less than 0.05) at 4 h but not at 2 h postocclusion. Heart rate was not affected by nisoldipine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acodazole hydrochloride: phase I trial, pharmacokinetics, and evaluation of cardiotoxicity in dogs

Acodazole (NSC 305884) was examined in a Phase I trial evaluating a 1-h infusion repeated every 21 days in 37 patients with advanced carcinomas. Cardiac toxicity was dose-limiting at 1370 mg/m2, manifested as multiple premature ventricular contractions, QTc interval prolongation, and decreasing heart rate. Other toxicities included mild to moderate nausea and vomiting and local reaction near the i.v. injection site requiring the use of central venous catheters. Antineoplastic activity was not observed. Acodazole levels assayed by high-performance liquid chromatography disclosed a peak plasma level of 19 +/- 4 (SEM) micrograms/ml for 1370 mg/m2. Acodazole plasma levels decreased in a triphasic manner over a 100-fold range. The volume of distribution at steady state was 238 +/- 18 liter/m2 suggesting extensive tissue binding. The total body clearance was 13.6 +/- 0.9 liter/h/m2; the percentage of urinary excretion was 29 +/- 2% for 48 h. To evaluate cardiac toxicity, acodazole was administered to five dogs at 2262 mg/m2 (1-h infusion) which provided plasma concentrations similar to those achieved at 1370 mg/m2 in humans. Consistent findings in dogs were drug-related prolongation of QTc intervals, and reduction in heart rate, left ventricular dP/dt, and mean blood pressures. Clinical development of acodazole requires studies to further elucidate and alleviate this cardiac toxicity.