Harold F. Hardman

Determination of Experimental myocardial infarct size

Myocardial infarction was produced in anesthetized dogs by a 2-hr occlusion and 30-min reperfusion of the left anterior descending cornary artery. A balloon-reservoir perfusion system was used for reperfusion and delineation of perfusion bed size (area at risk) with Patent blue dye. Infarct mass was determined by a histochemical staining technique with triphenyl tetrazolium chloride. Regional myocardial perfusion in infarcted, ischemic, and normal regions was measured with radioactive microspheres. Infarct size was 8.5 +/- 1.6 g and accounted for irreversible damage in 9.2 +/- 1.9% and 32.5 +/- 4.8% of the left ventricle and area at risk, respectively. Regional myocardial blood flow within infarcted regions was constant over the 2-hr occlusion period (0.10 +/- 0.03 to 0.11 +/- 0.02 ml/min/g). Following reperfusion, these areas demonstrated significantly lower flow than did normal regions, Ischemic but noninfarcted tissue also had no change in flow over the occlusion period, but flow returned to normal following reperfusion. This study describes reliable methodology for production and determination of infarct size with simultaneous measurement of several factors involved in the relative extent of irreversible tissue damage.

Changes in ischemic blood flow distribution and dynamic severity of a coronary stenosis induced by beta blockade in the canine heart.

The effects of equipotent β1‐receptor‐blocking doses of propranolol, metoprolol and sotalol on distal coronary pressure, stenosis resistance and regional myocardial blood flow (endo/epi) were studied in anesthetized dogs with a severe noncircumferential stenosis of the left circumflex coronary artery. No significant differences between the three β blockers were observed for overall hemodynamics and regional myocardial blood flow. After drug treatment, subendocardial blood flow (0.47 ± 0.05 to 0.78 ± 0.05 ml/min/g) and endo/epi (0.67 ± 0.04 to 1.18 ± 0.04) increased significantly (p < 0.05) in the ischemic region. These changes were associated with a marked increase in distal coronary perfusion pressure and a decrease in heart rate. Resistance across the stenosis decreased significantly (p < 0.05) after, β‐receptor blockade (3.2 ± 0.3 to 1.4 ± 0.2 units). Atrial pacing to control heart rate only partially attenuated these changes. These results suggest that a favorable redistribution of ischemic blood flow after β blockade is the result of an increase in distal diastolic pressure‐time index and an autoregulation‐induced increase in distal bed vascular resistance due to a decrease in myocardial oxygen demand associated with β blockade. The latter effect also resulted in a decrease in the dynamic severity of a proximal coronary stenosis.

Comparative effects of cardioselective versus noncardioselective beta blockade on subendocardial blood flow and contractile function in ischemic myocardium

Abstract The comparative effects of three beta adrenergic antagonists, bevantolol (CI-775, a new cardioselective agent), practolol and propranolol, on regional myocardial blood flow and contractile function distal to a severe flow-limiting stenosis of the left circumflex coronary artery were studied in the anesthetized dog. Equivalent beta 1 receptor blocking doses of each agent were administered 30 minutes after production of a stenosis sufficient to reduce resting coronary blood flow and contractile force approximately 40 percent. Regional myocardial blood flow and contractile force were measured with radioactive labeled microspheres and Brodie-Walton strain gauge arches, respectively. After treatment with propranolol (0.3 mg/kg), subepicardial flow in the ischemic area decreased significantly whereas subendocardial flow was maintained, resulting in an increased endocardial/epicardial blood flow ratio (0.59 ± 0.05 to 0.93 ± 0.09) (mean ± standard error of the mean). No significant change was observed in contractile performance of the ischemic area. Practolol (1.0 mg/kg) also produced a significant increase in endocardial/epicardial ratio (0.59 ± 0.05 to 0.69 ± 0.10) in the ischemic myocardium. Contractile performance remained unchanged. In contrast, after treatment with bevantolol (1.0 mg/kg), subendocardial flow (0.64 ± 0.13 to 0.77 ± 0.13 ml/min per g) and contractile function increased significantly (36.0 ± 11.0 percent) in ischemic myocardium. A marked increase in endocardial/ epicardial ratio (0.59 ± 0.05 to 0.93 ± 0.09) was also observed. These results suggest that a redistribution of blood flow within an ischemic region of the myocardium occurs with either beta 1 or a simultaneous beta 1 and beta 2 receptor blockade. Furthermore, these data indicate a possible advantage of a new cardioselective beta adrenergic antagonist, bevantolol, in improving ischemic subendocardial blood flow and contractile function.

Effects of three bradycardiac drugs on regional myocardial blood flow and function in areas distal to a total or partial coronary occlusion in dogs.

The effectiveness of three bradycardiac drugs for increasing distal coronary perfusion pressure and decreasing stenosis resistance (SR) in partially occluded vessels, and thereby for increasing collateral blood flow and segmental function (%SS) in an occluded area dependent on the stenotic vessel, was studied in anesthetized dogs. Initially, the distal portion of the left anterior descending (LAD) coronary artery was occluded followed by subsequent stenosis of the left circumflex (LC) coronary artery that supplies collateral flow to the ischemic LAD area. A decrease in LC flow (35 +/- 3 to 24 +/- 3 ml/min) and distal coronary pressure (109 +/- 4 to 47 +/- 4 mm Hg) resulted in an increase in SR (0.03 +/- 0.02 to 2.97 +/- 0.53 U), and decreases in LC %SS (9.3 +/- 1.1% to 1.9 +/- 2.0%), subendocardial blood flow (1.11 +/- 0.06 to 0.43 +/- 0.05 ml/min/g), and LAD collateral flow (0.36 +/- 0.11 to 0.22 +/- 0.05 ml/min/g). Upon intravenous administration on the beta-receptor-blocking drug sotalol (0.3 mg/kg) or metoprolol (0.1 mg/kg) and the non-beta-blocking bradycardiac drug N-dimethyl-propranolol (5.0 mg/kg) in doses that produced similar decreases in heart rate (30 to 40 beats/min), distal coronary pressure, subendocardial blood flow, and %SS in the LC area were markedly improved. SR was significantly reduced (2.97 +/- 0.53 to 1.66 +/- 0.37 U). The improvement in %SS of the LC area was highly correlated (r = .93, p less than .001) with the increase in subendocardial blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of nicorandil, a nicotinamide nitrate derivative, and nifedipine on myocardial reperfusion injury in dogs.

Summary The effects of the nicotinamide nitrate compound nicorandil (SG-75) and the slow channel calcium entry blocker nifedipine on the recovery of subendocardial segment shortening (% SS) were compared with a vehicle-treated group following 30 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion. Sonomicrometry was used to determine % SS in ischemic and nonischemic myocardium, and radioactive microspheres were used to determine regional myocardial blood flow. Nicorandil (100-μg/kg bolus followed by 25 μg/kg/min i.v.). nifedipine (10-μg/kg bolus followed by 3 μg/kg/min i.v.). or vehicle (saline) was administered 15 min prior to and throughout the occlusion period. Both drugs produced equivalent decreases in the heart rate × systolic pressure product before and during LAD occlusion. In addition, total left ventricular weights, the area at risk, the percent of the left ventricle at risk, and collateral blood flow were similar in all three groups. During coronary occlusion. % SS in the ischemic region was equally depressed in each series and passive systolic lengthening resulted. However, following reperfusion, only the nicorandil-treated animals showed an improvement in myocardial segment function through 3 h of reperfusion as compared with the control group. Transmural myocardial blood flow within the ischemic region during reperfusion returned to control values in all three groups: however, the endocardial/epicardial blood flow ratio (endo/epi) was significantly decreased in the control and nicorandil-treated dogs. In contrast, the endo/epi was greater than the preocclusion control in the nifedipine series during reperfusion. Thus, although the mechanism of action of nicorandil in this model is unknown, the improvement in % SS in the nicorandil-treated group was not related to changes in peripheral hemodynamics or improved regional blood flow, since nifedipine produced similar changes in hemodynamics and resulted in a better recovery of perfusion.

The effect of adenosine on myocardial metabolism and oxygen consumption in the isolated dog heart preparation.

Abstract The effects of adenosine on myocardial metabolism and oxygen consumption were examined in the isolated supported dog heart preparation (ISHP) perfused at a constant coronary blood flow. Heart rate was controlled by right atrial pacing. Coronary arterial and venous blood samples were collected and oxygen content, lactate, glucose and free fatty acid levels were determined. From arterialvenous differences and coronary blood flow, oxygen consumption and substrate uptake were determined. A 3 min intracoronary infusion of adenosine (50 and 100 μg/min) produced a significant dose-dependent decrease in MVO 2 while increasing glucose uptake and decreasing the uptake of lactate. The decrease in oxygen consumption, the increase in glucose uptake and the decrease in the uptake of lactate were all found to be dependent on the initial MVO 2 . These findings suggest that, in addition to its putative role as a regulator of coronary vascular resistance, adenosine might also exert important metabolic effects on the heart.

Comparative effects of two slow channel calcium entry blockers, FR 34235 and nifedipine, on true coronary collateral blood flow.

The effect of a new dihydropyridine calcium entry blocker, FR 34235, on coronary collateral blood flow was compared with that of nifedipine in anesthetized dogs following acute ligation of the left anterior descending coronary artery. A special technique was used to separate true coronary collateral blood flow from overlap flow due to interdigitation of normally perfused tissue contained within the ischemic region. During infusion of doses of both agents, which produced nearly equivalent decreases (15–20 mm Hg) in mean arterial pressure, flow was significantly increased in normal myocardium; however, no change in collateral perfusion to ischemic myocardium was observed. When blood pressure was returned to control by an aortic cuff, blood flow to the normal region further increased. Transmural flow to the ischemic region was also significantly increased by both compounds. Nifedipine increased collateral flow primarily to the subepicardium, whereas FR 34235 increased collateral perfusion to the subepicardium, midmyocar-dium, and subendocardium. These results suggest that dihydropyridine calcium entry blockers may increase collateral blood flow to ischemic myocardium if drug-induced hypotension is minimized. In addition, FR 34235 has a more favorable effect on the transmural distribution of blood flow than nifedipine.

Beneficial actions of bevantolol on subendocardial blood flow and contractile function in ischemic myocardium.

The effect of a new cardioselective beta adrenergic antagonist, bevantolol (CI-775), on regional myocardial blood flow and contractile function distal to a severe flow-limiting stenosis of the left circumflex coronary artery was studied in open-chest dogs. Bevantolol (1 mg/kg, i.v.) or saline was administered 30 min after production of left circumflex stenosis sufficient to reduce resting coronary blood flow and contractile force approximately 40%. Regional myocardial blood flow and contractile force were measured with radiolabeled microspheres and Brodie—Walton strain gauge arches, respectively. No significant changes were observed in the saline-treated group. Following bevantolol treatment subendocardial blood flow (1.30 ± 0.29 to 0.93 ± 0.19 ml/min/g) and contractile force decreased (11.4 ± 4.4%) significantly (p < 0.05) in nonischemic myocardium. Subendocardial blood flow (0.59 ± 0.14 to 0.81 ± 0.14 ml/min/g) and contractile force increased (29.3 ± 3.6%) significantly (p < 0.05) in ischemic myocardium. These results suggest that bevantolol produces a favorable redistribution of flow to ischemic subendocardium. The increase in flow results in an improvement of contractile function in the ischemic region.

The effect of ouabain on nutritional circulation and regional myocardial blood flow

The effect of ouabain on myocardial nutritional circulation (rubidium-86 extraction) and regional myocardial blood flow (radioactive microspheres) was studied in the isolated supported canine heart preparation perfused at a constant coronary blood flow. Ouanbain (25 mug per kilogram, intravenously) produced a significant increase in mycocardial contractile force, peak left ventricular systolic pressure, and myocardial oxygen consumption. Ouabain also decreased rubidium-86 extraction (E86RB), rubidium-86 clearance (C86Rb), and the capillary transport coefficient (PS). Intracoronary infusion of ouabain (10 mug per minute) produced significant increases in contractile force (25,50, and 100 per cent above control), left ventricular systolic pressure, myocardial oxgen consumption, and the epicardial-endocardial blood flow ratio (epi/endo) of the left ventricle. When left ventricular systolic pressure was held constant (100 mm. Hg), ouabain infusion (10 mug per minute, intracoronary) increased myocardial contractile force (25,50, and 100 per cent above control) and myocardial oxygen consumption but did not change the epi/endo of the left ventricle. These results suggest that ouabain reduces E86Rb, C86Rb, and PS by producing a shunting of blood flow from endocardium to epicardium in the left ventricle. The increase in left ventricular systolic pressure appears to be responsible for these changes.

Cardiotonic effects of anthopleurin-A (AP-A), A polypeptide from a sea anemone, in dogs with a coronary artery stenosis

The positive inotropic effect of AP-A was studied in anesthetized dogs with a severe stenosis of the left anterior descending coronary artery. Peak positive dP/dt (mm Hg/s) and % segment shortening (%SS) were used as indices of contractile function. AP-A (1.5-5.0 micrograms/kg, i.v.) produced positive inotropic effects globally (dP/dt, 1700 +/- 100 to 2650 +/- 250 mm Hg/s) and locally in the ischemic zone (%SS, 6.7 +/- 1.7 to 13.7 +/- 1.5%) without changing heart rate, mean arterial pressure or myocardial blood flow. These data suggest that AP-A may be potentially useful in the management of heart failure.