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Biomedical subjects

H F Hardman

Publications and source records attributed to H F Hardman.

At least 19 recordsLinked to original sources
PubMed1987

Cardiovascular actions of a new dihydropyridine calcium antagonist, 8363-S: comparison with nifedipine and nicardipine in awake, unsedated dogs.

The systemic and coronary hemodynamic actions of a new dihydropyridine, 8363-S, were compared with nifedipine and nicardipine in conscious, instrumented dogs following intravenous and oral administration. All agents produced similar reductions in arterial and ventricular pressures and increases in heart rate, dP/dt, and coronary blood flow velocity, following intravenous infusion. Following oral administration, all agents had qualitatively similar actions; however, there was a marked difference in potency. 8363-S was found to be most potent in that 0.25 mg/kg produced equivalent or larger changes from control than 0.5 mg/kg nifedipine or 1.0 mg/kg nicardipine. Furthermore, 8363-S had a longer duration of action following oral administration. The results suggest that important differences in bioavailability exist amongst dihydropyridines which may have important therapeutic implications.

Administration, Oral↗
PubMed1987

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

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-micrograms/kg bolus followed by 25 micrograms/kg/min i.v.), nifedipine (10-micrograms/kg bolus followed by 3 micrograms/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 X 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.

Animals↗
PubMed1986

Beneficial actions of superoxide dismutase and catalase in stunned myocardium of dogs.

Recent evidence suggests that oxygen free radicals may partially mediate irreversible ischemia-reperfusion injury in the myocardium. In the present study, the effect of a combination of two oxygen free radical scavengers, superoxide dismutase plus catalase (SOD + CAT), on the recovery of subendocardial segment function following 15 min of coronary artery occlusion followed by 3 h of reperfusion ("stunned" myocardium) was compared with a control group in barbital-anesthetized dogs. Myocardial segment shortening (%SS) in the subendocardium of nonischemic and ischemic areas was measured by sonomicrometry and regional blood flow by radioactive microspheres. SOD and CAT were infused into the left atrium 30 min before and throughout the occlusion period. Compared with the control group, %SS in the subendocardium of the ischemic region was significantly (P less than 0.05) greater in the SOD plus CAT-treated group during occlusion and throughout reperfusion. Since there were no significant differences in hemodynamics or regional myocardial blood flow between the SOD plus CAT and the control groups, these results suggest that toxic oxygen free radicals may be partially involved in the reversible ischemic injury that occurs during short periods of coronary occlusion followed by reperfusion.

Animals↗
PubMed1985

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.

Animals↗
PubMed1984

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)

Animals↗
PubMed1984

Effects of nicorandil, a new antianginal agent, and nifedipine on collateral blood flow in a chronic coronary occlusion model.

The effects of nicorandil and nifedipine on collateral blood flow were compared in anesthetized dogs with a well-developed collateral circulation produced by Ameroid constriction (6-8 weeks) of the left anterior descending (LAD) coronary artery. The radioactive microsphere technique was used to determine myocardial perfusion in the normal left circumflex (LC) region and in the LAD region distal to the Ameroid constrictor. Low and high doses of nicorandil (25 and 50 micrograms/kg/min) or nifedipine (1 and 3 micrograms/kg/min) were infused i.v. to reduce mean arterial and left ventricular systolic pressure approximately 10 and 25 mm Hg, respectively. A low dose of nicorandil had no effect on myocardial perfusion whereas nifedipine increased subepicardial blood flow in both the LC and LAD regions. The high dose of nifedipine further increased both subepicardial and subendocardial perfusion to the LC region and subepicardial blood flow to the LAD region whereas nicorandil had no effect. When aortic blood pressure was returned to control by occluding a snare around the descending thoracic aorta during infusion of the high dose, nicorandil and nifedipine increased subepicardial and subendocardial blood flow to LAD and LC regions. Whereas nicorandil increased flow to both tissue layers equally, nifedipine increased subepicardial perfusion primarily. In summary, nifedipine increased collateral blood flow in a chronic coronary occlusion model despite the presence of systemic hypotension, whereas nicorandil only increased flow when aortic blood pressure was maintained. However, nicorandil increased myocardial blood flow equally across the left ventricular wall, whereas nifedipine primarily increased subepicardial blood flow.

Animals↗
PubMed1983

Comparative effects of FR 34235, a new slow channel calcium blocker, and nifedipine on hemodynamics and myocardial oxygen consumption in the anesthetized dog.

Five doses of two dihydropyridine calcium antagonists, FR 34235 and nifedipine, were given intravenously to anesthetized dogs to determine effects on hemodynamics and myocardial oxygen balance. Both agents produced dose-related decreases in mean arterial blood pressure and tension time index with little effect on heart rate, dP/dt or myocardial contractile force except at high doses where small decreases were observed. Coronary blood flow increased markedly in the presence of both agents with a maximum increase observed at doses of 10 and 30 micrograms/kg for FR 34235 and nifedipine, respectively. Both compounds decreased myocardial oxygen extraction at all doses and reduced myocardial oxygen consumption at higher doses. These results indicate that FR 34235, a new slow channel calcium blocker, is a potent coronary vasodilator. In addition, this compound possesses oxygen-sparing activity at higher doses.

Anesthesia↗
PubMed1983

Effects of histamine receptor stimulation on regional myocardial blood flow.

The effect of histamine (H) and specific H1 and H2 agonists and antagonists on regional myocardial blood flow was studied in anesthetized dogs by use of tracer microspheres. Intracoronary infusion of histamine (15 and 34 micrograms/min) produced a dose-related increase in transmural myocardial blood flow (from 0.82 to 1.36 and 2.25 ml X min-1 X g-1) without alteration of heart rate or blood pressure. Infusion of the H1 agonist 2-(2-thiazolyl)ethylamine (135 and 442 micrograms/min) produced an increase in transmural perfusion (from 0.69 to 1.22 and 1.65 ml X min-1 X g-1) and a significant (P less than 0.05) increase in the ratio of flow between subendocardium and subepicardium (endo/epi from 0.97 to 1.31 and 1.54). Infusion of the H2 agonist dimaprit (195 and 390 micrograms/min) produced an increase in transmural myocardial blood flow (from 0.97 to 1.49 and 2.00 ml X min-1 X g-1) without a change in endo/epi. The H1-mediated increase in regional myocardial perfusion and endo/epi was blocked by the H1 antagonist diphenhydramine but not by the H2 antagonist cimetidine. These results suggest that stimulation of H1 coronary receptors preferentially distributes flow to the subendocardium, whereas H2 receptors mediate vasodilation in subepicardium as well as subendocardium.

Animals↗
PubMed1982

Role of autoregulation in the beneficial action of propranolol on ischemic blood flow distribution and stenosis severity in the canine myocardium.

The effect of propranolol (0.1 mg/kg i.v.) on distal coronary pressure (DCP), distal bed (DR) and stenosis resistances (SR) and regional myocardial blood flow [endocardial-epicardial (endo/epi)] was studied in two groups of anesthetized dogs with a severe stenosis of the left circumflex coronary artery. In group 1, the ability of the DR to autoregulate was left intact, whereas in group 2, the DR was maximally dilated by pretreatment with the coronary vasodilator, chromonar. Despite similar global hemodynamic effects in both groups after propranolol treatment significant differences were observed in the ischemic area. In group 1, propranolol produced a significant increase in subendo blood flow, endo/epi and DCP in the ischemic region. In addition, DR (1.7 +/- 0.4 to 3.3 +/- 0.6 U) increased and SR decreased (3.4 +/- 0.5 to 1.7 +/- 0.3 U) significantly. In group 2, the changes in endo/epi, DCP, DR and SR were prevented by maximal vasodilation. These results suggest that the favorable changes produced by propranolol on ischemic myocardium are the result of a restoration of the ability of the resistance vessels to autoregulate. This allows for a passive decrease in coronary arteriolar dilation which results in an increase in DR and DCP and a decrease in SR. The increase in DCP may also contribute to the increase in ischemic subendo blood flow after propranolol.

Animals↗
PubMed1981

Redistribution of myocardial blood flow distal to a dynamic coronary arterial stenosis by sympathomimetic amines: comparison of dopamine, dobutamine and isoproterenol.

The effects of dopamine, dobutamine and isoproterenol on coronary hemodynamics, severity of stenosis, distal bed resistance and transmural myocardial perfusion gradients with radioactive microspheres were studied in dogs with a mild obstruction of the left circumflex coronary artery anesthetized with morphine-chloralose. Changes in transmural blood flow were related to the ratio of the diastolic aortic pressure-time index to tension-time index (DPTI/TTI) and the ratio of the distal diastolic coronary pressure-time index to tension-time index (DDPTI/TTI). At doses of 5 microgram/kg per min, dopamine had no significant effect on DPTI/TTI, DDPTI/TTI or endocardial/epicardial flow ratio; however, dobutamine produced a slight decrease in this flow ratio and in DDPTI/TTI. At doses of 10 microgram/kg per min, both drugs produced a significant (p less than 0.05) reduction in diastolic coronary pressure distal to the stenosis. DDPTI/TTI and endocardial/epicardial flow ratio without change in DPTI/TTI. In comparison, isoproterenol (0.01 and 0.05 microgram/kg per min) produced dose-related decreases in endocardial/epicardial flow ratio, DDPTI/TTI and DPTI/TTI. During infusion of each sympathomimetic agent, there was a corresponding reduction in distal bed vascular resistance but a concomitant increase in stenosis resistance. The results also show that dopamine and dobutamine, as well as isoproterenol, area capable of producing a maldistribution of coronary blood flow distal to a mild coronary arterial stenosis and that such a redistribution of glow is dependent on dose, reduction of the distal diastolic coronary pressure-time index and decrease in DDPTI/TTI. It is further concluded that hemodynamic changes distal to a coronary arterial stenosis seriously jeopardize the usefulness of DPTI/TTI; however, DDPTI/TTI can be used to predict drug effects on the endocardial/epicardial flow ratio in an ischemic area. This study demonstrates that "fixed" stenoses can undergo dynamic processes and sympathomimetic amines increase the resistance to flow through a stenotic coronary artery in the nonfailing heart.

Animals↗
PubMed1981

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.

Animals↗
PubMed1981

Evidence for a caudal brainstem site of action for cannabinoid induced hypothermia.

delta 9-Tetrahydrocannabinol (THC), 11-hydroxy delta 9-tetrahydrocannabinol (11-OH-THC) and the synthetic dimethylheptyl analogue of THC (DMHP) were injected intracerebrally into proven chemosensitive sites in the hypothalamus of unanesthetized cats with implanted microinjection guide tubes. 100 micrograms of each compound was administered in a volume of 8 microliters. Chemosensitivity of all injection sites was established by microinjection of carbamylcholine to induce hyperthermia and tetrodotoxin to induce hypothermia. THC or its analogues produced no significant change in body temperature when injected intracerebrally. However, in the same animals, parenteral administration of THC, 11-OH-THC or DMHP (0.5 to 2.0 mg/kg) induced hypothermic responses ranging from -2.0 to -7.0 degrees C. Intravenous administration of THC was effective in blocking shivering induced by cooling the preoptic region in unanesthetized cats with implanted thermodes. In cats with mid-pontine transections, cooling of the spinal cord by perfusion with an epidural double wall cannula at temperatures of 30, 20, 10 and 0 degrees C produced graded shivering which was recorded electromyographically. Intravenous THC, (0.25-2.0 mg/kg) produced a dose-dependent attenuation of spinal cord induced shivering. These data plus results of prior studies suggest that the tetrahydrocannabinols produce their hypothermic effect at sites in the caudal brainstem. Suppression of shivering at the ponto medullary or spinal cord level may represent an important mechanism which contributes to the lowering of body temperature.

Animals↗
PubMed1981

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 beta 1-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 beta 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 less than 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 less than 0.05) after beta-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 beta 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 beta blockade. The latter effect also resulted in a decrease in the dynamic severity of a proximal coronary stenosis.

Adrenergic beta-Antagonists↗
PubMed1981

Comparison of two dihydropyridine calcium antagonists on coronary collateral blood flow in acute myocardial ischemia.

Effects of two dihydropyridine calcium antagonists on regional myocardial blood flow produced by acute ligation of the left anterior descending coronary artery were examined in the pentobarbital-anesthetized open-chest dog. Equivalent hypotensive doses of nifedipine (1.25 and 2.5 microgram/kg/min) and FR 7534 (5 and 10 micrograms/kg/min) produced similar decreases in mean arterial pressure and myocardial oxygen consumption and increases in coronary blood flow, dp/dt and contractile force in the intact nonischemic dog heart. Heart rate was unaffected. Nifedipine was 4 times as potent as FR 7534. Effects on ischemic myocardial blood flow measured with radioactive microspheres were examined with the same doses and also at controlled mean arterial pressure by use of methoxamine. Despite significant hypotension, nifedipine maintained and FR 7534 increased ischemic blood flow. When perfusion pressure was controlled, both compounds produced significant increases in transmural blood flow to the ischemic region. The increase produced by FR 7534 was significantly greater. Both nifedipine and, to a lesser extent, FR 7534 decreased the subendocardial to subepicardial blood flow ratio in the nonischemic myocardium without altering that of the ischemic myocardium. Drug-induced increases in ischemic blood flow were positively correlated with initial flow rate. The results indicate that both dihydropyridine calcium antagonists are capable of improving the oxygen supply-demand relationship during ischemia by reducing overall myocardial oxygen demand by increasing collateral blood flow.

Animals↗
PubMed1981

Effects of sotalol and vagal stimulation on ischemic myocardial blood flow distribution in the canine heart.

The purpose of the present study was to compare the effect of equivalent decreases in heart rate produced by sotalol and bilateral vagal stimulation on regional myocardial blood flow and coronary perfusion pressure distal to a severe stenosis of the left circumflex coronary artery in anesthetized dogs. Tissue blood flow was measured with radioactive microspheres (15 mu). Vagal stimulation or beta adrenergic blockade produced by sotalol (1.0 mg/kg i.v.) reduced heart rate approximately 35 beats/min. This decrease in rate was accompanied by nearly equivalent increases (P less than 0.05) in diastolic perfusion time and subendocardial blood flow and in the ischemic region. Both interventions also significantly increased the oxygen supply-demand balance (distal diastolic pressure time index divided by the tension time index) in the ischemic region. These values returned to control after cessation of vagal stimulation or during atrial pacing to predrug heart rate. Coronary perfusion pressure distal to the stenosis increased significantly only in the sotalol-treated group. These results suggest that a decrease in heart rate and increase in diastolic perfusion time are important factors in the favorable redistribution of ischemic myocardial blood flow and increase in the oxygen supply-demand balance observed after beta adrenergic blockade with sotalol or after vagal stimulation. Whether these beneficial actions are solely due to the prolonged diastolic perfusion period or to reduced oxygen demand and a return to autoregulation in the ischemic area cannot be determined with certainty.

Animals↗
PubMed1980

Subepicardial steal and reduction of myocardial oxygen consumption by adenosine.

The direct effects of adenosine on cardiac oxygen balance, hemodynamics and regional myocardial perfusion were studied in isolated canine hearts. Intracoronary infusion of adenosine produced a dose-dependent shift in the transmural distribution of coronary blood flow away from left ventricular subendocardium and a reduction in myocardial oxygen consumption (MVO2). The data suggest that adenosine may partially decrease MVO2 by a redistribution of flow from a high to low oxygen-extracting region of the myocardium.

Adenosine↗