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)

Heparin inhibits bovine testicular hyaluronidase activity in myocardium of dogs with coronary artery occlusion.

Bovine testicular hyaluronidase (BTH) reduces experimental myocardial infarct size and ameliorates electrocardiographic signs of ischemia. This study was done to determine if heparin, an in vitro inhibitor of hyaluronidase activity, blocks the action of BTH in the myocardium of dogs after coronary artery occlusion. BTH was administered intravenously as 5,000 NF units/kg at 0.5 and 2.5 hours after coronary occlusion. Heparin was administered intravenously as a 150-unit/kg loading dose, followed by 10 units/kg per hour i.v., beginning 15 minutes before coronary occlusion. The area of myocardial ischemia at risk was assessed by a radiolabeled microsphere technique; the area that developed necrosis was assessed by a histochemical technique. In vivo activity of BTH was assessed by a colorimetric analysis of the BTH substrate, i.e., hyaluronic acid (HA), extracted from myocardial tissue. For biochemical analysis of HA, the heart was divided into anterior myocardium, which included ischemic tissue and posterior nonischemic myocardium. The myocardial HA content of dogs treated with BTH plus heparin (anterior, 3.44 +/- 0.40 micrograms HA/mg protein; posterior, 3.69 +/- 0.33 micrograms HA/mg protein) was not significantly different from control (anterior, 3.61 +/- 0.29 micrograms HA/mg protein; posterior, 3.55 +/- 0.23 micrograms HA/mg protein). In contrast, BTH lowered myocardial HA content (anterior, 2.16 +/- 0.21 micrograms HA/mg protein; posterior, 2.08 +/- 0.14 micrograms HA/mg protein) compared with either BTH plus heparin or control groups in both anterior myocardium (p = 0.006) and posterior myocardium (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous change of human plasma angiotensin I converting enzyme isoelectric point.

The isoelectric point of angiotensin I converting enzyme (ACE) spontaneously changes from 4.3 to 4.6 during purification from human plasma. The spontaneous change in pI corresponds to that occurring with neuraminidase-treated but not with EDTA-treated samples. There is no detectable difference in the molecular weight of, or lectin binding by, the two forms of ACE with different pI's. These data indicate that ACE in the circulation contains a greater amount of sialic acid than purified ACE. The implication is that purified ACE isoenzymes which differ in sialic acid content may not reflect tissue-specific isoenzymes but rather artifacts of purification.

Effects of ortho-iodo sodium benzoate on acute myocardial ischemia, hemodynamic function, and infarct size after coronary artery occlusion in dogs.

Ortho-iodo sodium benzoate (OISB) decreases the affinity of blood for oxygen, thus enhancing potential tissue oxygen delivery. To test the hypothesis that a change in oxygen affinity would ameliorate regional myocardial ischemic injury resulting from occlusion of the left anterior descending (LAD) coronary artery, experiments were carried out in 55 anesthetized dogs which received an intravenous infusion of OISB. In Protocol I studies (n = 9), preocclusion intravenous infusion of OISB (500 mg/kg) reduced epicardial S-T segment elevation 15 minutes after coronary occlusion, while a similar volume of normal saline solution did not affect this index of ischemic damage. In Protocol II experiments, 34 dogs were randomized to either an OISB or saline group, after which the LAD was ligated, the chest closed, and the animal allowed to recover from anesthesia. Myocardial infarction (MI) size was assessed after the animal died or was killed 8 to 24 hours later, and was found to be 29% smaller in dogs receiving OISB. In 6 dogs, blood P50 (the partial oxygen pressure at which hemoglobin is 50% saturated with oxygen) was increased by OISB infusion, confirming that its administration effected a rightward shift in the oxyhemoglobin dissociation curve. Protocol III studies assessed the effects of OISB on cardiac hemodynamic function and acute myocardial ischemic damage when infusion was begun 15 minutes after LAD occlusion: average epicardial S-T segment elevation was not altered by saline solution, but decreased when OISB was infused during the last 15 minutes of myocardial ischemia. Reductions in heart rate, left ventricular dP/dt, and cardiac output were observed in 7 dogs during OISB infusion, but there were no changes in these measurements during coronary occlusion in 5 dogs receiving a constant infusion of saline solution. There were no changes in regional myocardial blood flow (microsphere technique) to either ischemic or nonischemic zones in either the saline control or OISB treatment groups. Thus, both acute myocardial ischemic injury (assessed by epicardial electrocardiographic mapping) and ultimate MI size are reduced when OISB is infused before experimental coronary artery occlusion. OISB also reduces myocardial ischemic injury when its administration is begun 15 minutes after coronary occlusion, while effecting decreases in heart rate, left ventricular contractility, and cardiac output.

Prolonged abnormalities of myocardium salvaged by reperfusion.

The purpose of this study was to determine if biochemical, functional, and ultrastructural abnormalities persist in nonnecrotic postischemic myocardium salvaged by coronary reperfusion. Anesthetized dogs were subjected to 15 min of occlusion of the left anterior descending (LAD) coronary artery followed by 3 days of reperfusion. Biopsies were obtained for measurement of adenosine 5'-triphosphate (ATP) and creatine phosphate (CP) nmol/mg protein), and regional function was evaluated using sonomicrometry. Myocardial ATP concentration after 15 min of occlusion was 37 +/- 1 nmol/mg cardiac protein in nonischemic subendocardium and 19 +/- 2 nmol/mg in ischemic subendocardium. After the hearts underwent 90 min and 72 h of reperfusion, ATP remained significantly depressed in reperfused subendocardium with values of 25 +/- 5 and 29 +/- 2 nmol/mg, respectively (P less than 0.05 and P less than 0.01 compared with the nonischemic zone in which ATP remained normal). CP levels fell during ischemia but returned to normal by 90 min of reperfusion. Percent systolic shortening of myocardial segments fell from +18 +/- 1% (active shortening) to -13 +/- 2% (passive lengthening) during ischemia and was still significantly depressed at +11 +/- 1% (P less than 0.05 vs. preocclusion) at 72 h of reperfusion. Histological examination showed no necrosis, but ultrastructural abnormalities were present. Therefore brief periods of myocardial ischemia are not associated with necrosis but result in functional, biochemical, and ultrastructural abnormalities, which are present for at lest 3 days after coronary reperfusion.