Cardiac seasonal variation, a qualitative change in pharmacologic response to ethylenediamine.
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Biomedical subjects
H F Hardman
Publications and source records attributed to H F Hardman.
Evaluation of various adrenergic blocking agents in isolated rabbit and turtle hearts.
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Animals↗
An effect of pH upon epinephrine inotropic receptors in the turtle heart.
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Animals↗
Effect of propranolol on enzymatic and histochemical estimates of infarct size in experimental myocardial infarction.
Acute myocardial infarction was produced in anesthetized dogs by ligation of the left anterior descendens coronary artery. Propranolol (2 mg/kg i.v.) administered 4 hours post ligation was examined for its ability to reduce infarct size estimated by histochemical and enzymatic methods. There was a signficant correlation between these two methods in their estimation of infarct size. Treatment with propranolol significantly decreased infarct size estimated with both methods. It is concluded that some portion of the myocardium can be protected against infarction by pharmacologic intervention as late as 4 hours after the onset of coronary artery occlusion.
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Transmural gradient of coronary blood flow following dihydropyridine calcium antagonists and other vasodilator drugs.
The effects of the dihydropyridine calcium antagonists, nifedipine, nitrendipine and FR 7534 on the transmural distribution of coronary blood flow (endo/epi) were compared to the structurally unrelated calcium antagonists, verapamil and diltiazem and to the non-calcium antagonist vasodilator drugs, chromonar and dipyridamole in anesthetized dogs. The increase in transmural blood flow produced by diltiazem, verapamil, chromonar and dipyridamole was equally distributed between subendocardium and subepicardium (no change in endo/epi). On the other hand, the increase in myocardial blood flow produced by the dihydropyridine calcium antagonists nifedipine, nitrendipine and FR 7534 was relatively selective for subepicardial regions resulting in a significant and dose-related decrease in endo/epi. This unusual effect of the dihydropyridine calcium antagonists to produce a redistribution of flow within normal myocardium was not shared by the non-dihydropyridine calcium antagonists or non-calcium antagonist vasodilators studied. The redistribution of flow was not related to changes in heart rate, aortic blood pressure or to the level of total coronary blood flow. Such an effect may be related to the distribution of dihydropyridine receptors across the left ventricular wall, antagonism of the action of adenosine, or changes in regional intramyocardial tissue pressure and extravascular resistance.
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Transmural perfusion gradients distal to various degrees of coronary artery stenosis during resting flow or at maximal vasodilation.
Regional myocardial perfusion (assessed by 15 mu tracer microspheres) was determined at various levels of stenosis of the left circumflex coronary artery in anesthetized dogs. Measurements during control and at three levels of stenosis produced by a micrometer-driven mechanical occluder were made in each heart. No change was found in the transmural distribution of coronary blood flow until 93% stenosis. At levels above 93% stenosis there was a linear decrease in subendocardial perfusion with only minor changes in subepicardial perfusion. During maximal vasodilation produced by reactive hyperemia, the decrease in subendocardial flow was observed at levels greater than 60% stenosis. It is concluded that the subendocardium of the left ventricle has a large vasodilator reserve and severe stenoses are required to disrupt flow when autoregulation is intact. When autoregulation is abolished, reduction in subendocardial flow occurs at lesser degrees of stenosis.
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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 less than 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 less than 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.
Adrenergic beta-Antagonists↗
Comparative effects of a new calcium antagonist, FR 7534, nitroglycerin, and dipyridamole on regional myocardial blood flow and cardiac contractility during partial coronary artery occlusion in the dog.
The present study was designed to determine the effects of three different types of coronary vasodilators--FR 7534 (a new calcium antagonist), nitroglycerin, and dipyridamole--on the transmural blood flow and contractile function in the normal and ischemic myocardium of anesthetized dogs. Radioactive microspheres (15 muc) and Walton-Brodie strain gauge arches were used to measure tissue blood flow and contractile force, respectively. During 5 min intravenous infusions of nitroglycerin (5 microgram/kg/min) or dipyridamole (50 microgram/kg/min), which produced approximately 20% reductions in mean aortic pressure, blood flow and contractile force in ischemic myocardium decreased significantly. Under similar conditions, FR 7534 (10 microgram/kg/min) produced a significant decrease in ischemic contractile force, but tissue blood flow to the ischemic area did not change. In contrast, when mean aortic pressure was controlled by administration of methoxamine, nitroglycerin produced significant increases in ischemic blood flow (42%) and contractile force (47%), whereas dipyridamole produced significant decreases (41 and 32%, respectively). On the other hand, FR 7534 plus methoxamine produced a significant increase in ischemic blood flow (70%); however, ischemic contractile force did not change. These results demonstrate FR 7534 to affect the oxygen supply-demand balance in ischemic myocardium favorably by maintaining blood flow and depressing contractility during hypotension or by increasing flow during controlled systemic pressure.
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Separation of overlap and collateral perfusion of ischemic canine myocardium: important considerations in the analysis of vasodilator-induced coronary steal.
Coronary steal was studied in dogs with a left anterior descending (LAD) coronary artery occlusion by use of a special technique to exclude contamination from overlapping circulations with true collateral blood flow. Different degrees of vasodilation in nonischemic myocardium were produced by the selective coronary dilator, chromonar, at a constant heart rate and aortic blood pressure. A map of the ischemic area was made, and criteria used to identify ischemic tissue samples included: (1) all samples within the LAD perfusion area, as defined by a dye technique; (2) tissue samples with blood flows less than 25% normal area flow; (3) samples from within the central ischemic zone; and (4) tissue samples with overlap blood flow less than 2% normal area flow. When criteria 1 and 2 were used to identify ischemic myocardium, chromonar (5 and 7.5 mg/kg, i.v.) produced no change in ischemic blood flow. On the other hand, when tissue samples from the central ischemic zone or those which had less than 2% overlap flow (criteria 3 and 4) were used to identify ischemic myocardium, chromonar produced a dose-related decrease (p less than 0.01) in transmural collateral perfusion (25 +/- 4 and 33 +/- +/- 5;33 +/- 3 and 41 +/- 6%, respectively). Other indices of collateral function, peripheral coronary pressure (23 +/- 4 and 25 +/- 3%), retrograde flow (20 +/- 3 and 26 +/- 4%), and retrograde conductance (21 +/- 4 and 30 +/- 4%), also decreased significantly. These results indicate that moderate to maximal coronary vasodilation produces a true coronary steal in the absence of changes in aortic pressure and heart rate. In addition, these data demonstrate that significant amounts of overlap flow are contained in superior, inferior, and lateral borders of the ischemic zone, and that strict criteria to identify ischemic myocardium are needed when studying the effect of drugs on true coronary collateral blood flow.
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Enhanced subendocardial perfusion distal to a flow-limiting coronary artery stenosis in dogs: comparative effects of nicorandil, a potential new antianginal agent, and nitroglycerin.
The purpose of this study was to compare the effects of nicorandil [SG-75; 2-nicotinamidoethyl nitrate (ester)] and nitroglycerin on the distribution of blood flow between subendocardium and subepicardium [endocardial/epicardial blood flow ration (endo/epi)] distal to a proximal flow-limiting coronary artery stenosis in anesthetized dogs. Myocardial blood flow distribution was determined by use of 15-micron radioactive microspheres. Various indices of reactive hyperemia (peak flow, duration, volume) and poststenotic coronary pressures were used to assess the severity of ischemia in the area distal to the stenosis. Partial ischemia was produced by a 10-s total left circumflex coronary occlusion followed by 110 s of reflow to 50-60% of the control flow. Microspheres were injected during steady-state conditions during the partial reflow period. In the absence of drug, coronary artery stenosis produced marked underperfusion of the subendocardium (endo/epi, 0.55 +/- 0.05). Following administration of nicorandil (60 micrograms/kg i.v.) or nitroglycerin (15 micrograms/kg i.v.), the endo-epi during a subsequent partial reflow (stenosis present) period was significantly increased (0.67 +/- 0.06). The duration of reactive hyperemia and reactive hyperemic flow were also decreased by both compounds following release of the stenosis. These results suggest that nicorandil and nitroglycerin reduce subendocardial ischemia distal to a flow-limiting coronary artery stenosis. This beneficial effect may partially explain the efficacy of these two compounds in the therapy of angina pectoris.
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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, midmyocardium, 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.
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