Norine L. Capurro

Lack of effect of aspirin on myocardial infarct size in the dog

Pretreatment with platelet-inhibitory doses of aspirin (3 mg/kg body weight) has been shown to augment epicardial collateral flow by more than 50 percent (p less than 0.05) 4 hours after ligation of the left anterior descending coronary artery in dogs. To determine whether this favorable influence of aspirin is sufficient to decrease the amount of infarcted tissue, either intravenous aspirin, 3 mg/kg (n = 17), or saline solution (n = 17) was administered to dogs 10 minutes before occlusion of the left anterior descending coronary artery. Administration of saline solution or aspirin was repeated every 24 hours. By 72 hours, 5 dogs in each treatment group had died. Survivors were killed at 72 hours. The portion of the left ventricle at risk of infarction was delineated by perfusion of the aortic root with Evans blue and simultaneous perfusion of the distal left anterior descending coronary artery with saline solution under equal physiologic pressures. Slices of the stained heart were incubated with triphenyltetrazolium to identify gross infarct (with histologic confirmation). Total mass of left ventricle, myocardium at risk, and infarct size were measured in each dog. A direct relation was found between the mass at risk and the mass infarcted (r = 0.84, p less than 0.001). Aspirin-treated dogs did not differ from control dogs in percent ventricle at risk (mean +/- standard error 37 +/- 2 versus 40 +/- 2), percent infarct weight/left ventricle (29 +/- 3 versus 31 +/- 2) or percent infarct weight/weight of ventricle at risk (78 +/- 4 versus 77 +/- 3). Thus, despite aspirins ability to inhibit platelet aggregation and to increase epicardial collateral flow by more than 50 percent, aspirin treatment failed to reduce infarct size in this dog model.

Comparison of Nitroglycerin-, Nitroprusside-, and Phentolamine-Induced Changes in Coronary Collateral Function in Dogs

The recent use of vasodilators to improve ventricular function in acute myocardial infarction led us to investigate the effects of nitroglycerin, nitroprusside, and phentolamine on coronary collateral flow. Dogs were studied 2-4 wk after an ameroid constrictor was placed around the left anterior descending (LAD) coronary artery. Retrograde flow and peripheral coronary pressure were measured from a cannula inserted in the LAD distal to the ameroid. Systemic arterial pressure was held constant by an aortic cuff. When administered intracoronary (i.c.), nitroglycerin, 0.3-100 mug/min, or nitroprusside, 3-100 mug/min, produced quantitatively similar, dose-dependent increases in retrograde flow. Neither drug, i.c., changed peripheral coronary pressure. Nitroglycerin, 3-300 mug/min, intravenous (i.v.), produced dose-dependent increases in retrograde flow; nitroprusside, i.v., increased retrograde flow only in high doses (100-300 mug/min). Nitroglycerin and nitroprusside, i.v., produced similar increases in peripheral coronary pressure. Phentolamine, 1-300 mug/min, i.v., decreased retrograde flow, and did not change peripheral coronary pressure. Nitroprusside was considerably more potent than nitroglycerin in decreasing systemic arterial pressure and in reducing total coronary resistance. Thus, (a) although i.c. nitroglycerin and nitroprusside produce similar effects on collateral function, i.v. nitroglycerin is more effective than i.v. nitroprusside in augmenting collateral flow; (b) phentolamine has deleterious effects on collateral function; and (c) the relative vasodilator potencies of nitroglycerin and nitroprusside vary in different vascular beds; thus, for a given reduction in systemic arterial pressure, nitroprusside is less effective in increasing retrograde flow.

Beneficial effect of physical training on blood flow to myocardium perfused by chronic collaterals in the exercising dog.

SUMMARYTo determine the effect of physical training on collateral blood flow, we measured regional myocardial blood flow (MBF) by injecting 15 A radioactive microspheres at rest and during exercise in 14 dogs with chronic coronary occlusive lesions. Seven dogs subsequently trained for 6 weeks while the other seven remained in kennels. Training effect was documented by decrease in heart rate during exercise that averaged 35 beats/min. MBF studies were repeated after 6 weeks. Myocardial samples were obtained from normally perfused zones (NZ) and from regions supplied via collaterals (collateral dependent zones or CZ). Initially, endocardial blood flow in CZ averaged 1.10 ml/min/g (83% of NZ, P < 0.05) at rest and 1.36 ml/min/g (69% of NZ, P < 0.05) during exercise, indicating relative underperfusion. Epicardial blood flow was equal in NZ and CZ. After 6 weeks MBF was not significantly changed in control animals. After training, however, MBF to underperfused endocardium of CZ during exercise was 39% greater than it had been prior to training. The epicardial portion of CZ (not exhibiting underperfusion) showed no change in MBF during exercise after training.Our data suggest that beneficial effects of training in coronary disease may include improvement in MBF to underperfused collateraldependent portions of myocardium.

Acute Coronary Occlusion: Prolonged Increase in Collateral Flow Following Brief Administration of Nitroglycerin and Methoxamine

Regional coronary blood flow was determined with the radioactive microsphere technique 10 an 70 minutes and 2 1/2 and 5 hours after abrupt occlusion of the left anterior descending coronary artery in 12 closed chest sedated dogs. In six dogs, nitroglycerin, 200 to 400 microng/min, was infused intravenously 10 to 70 minutes after occlusion. Methoxamine was administered to return blood pressure and heart rate to prenitroglycerin levels. Ten minutes after occlusion (before treatment) collateral flow values and ischemic zone endocardial/epicardial flow ratios were equivalent in untreated (0.11+/-0.03 ml/min per g; 0.31+/-0.05) and treated dogs (0.14+/-0.02 ml/min per g; 0.29+/-0.03). In untreated dogs, collateral flow did not change over 5 hours; the endocardial/epicardial flow ratio was decreased at 5 hours (0.21+/-0.05, P less than 0.05). In contrast, in treated dogs, collateral flow and the endocardial/epicardial flow ratio were increased at 70 minutes (0.27+/-0.04 ml/min per g, P less than 0.05; 0.53+/-0.10, P less than 0.05). Most importantly, collateral flow remained elevated 5 hours after occlusion (0.26+/-0.03 ml/min per g, P less than 0.05) although treatment was discontinued 70 minutes after occlusion. Hence, collateral flow was unchanged over 5 hours of occlusion in untreated dogs, but short-term treatment with nitroglycerin and methoxamine resulted in a sustained increase in collateral flow. These findings may be a result of stimulation by nitroglycerin and methoxamine of the spontaneous rate at which intrinsic collateral function increases after ischemia. Alternatively, nitroglycerin and methoxamine may maintain cell viability until collateral vessels develop spontaneously.

Shortened platelet survival time and enhanced heart rate responses after abrupt withdrawal of propranolol from normal subjects.

Although clinical observations suggest that abrupt discontinuation of propranolol therapy may precipitate myocardial ischemia and infarction in patients with coronary occlusive disease, the physiologic consequences of propranolol withdrawal are not fully understood. Platelet survival times and heart rate responses to exercise, upright tilt and isoproterenol were therefore examined in 14 normal subjects before and after abrupt withdrawal of propranolol. Propranolol, 80 to 240 mg/day, was given for 24 to 79 days; its effect was confirmed by a lower heart rate during exercise and during infusion of isoproterenol. In 10 subjects, the mean survival time of chromium-51-tagged blood platelets decreased from 10.0 days before propranolol to 7.8 days after its withdrawal (p <0.05). One day after withdrawal, the rise in heart rate with exercise or tilt was slightly increased from values before propranolol therapy. Two days after withdrawal of propranolol the mean peak heart rate during exercise (165 beats/min) was 12 beats/min higher (p <0.01) than the value before propranolol. On this same day heart rate increased more after tilt without medication (+6 beats/min, p <0.05) and more after tilt following vagal blockade (+8 beats/min, p <0.02) than before treatment with propranolol. Seven days after propranolol withdrawal, heart rate responses to exercise or tilt remained increased. Isoproterenol-induced heart rate responses (5 to 40 ng/kg per min, n = 14), white blood cell beta receptor function (cyclic adenosine monophosphate production after isoproterenol and 3H-I-dihydroalprenolol binding, n = 9) and plasma norepinephrine values at rest and during exercise (n = 7) were each unaltered after propranolol. The results suggest that abrupt withdrawal of propranolol is accompanied by a shortening of platelet survival and enhancement of sympathetically mediated reflex increases in heart rate. These changes may each play a role in the increased incidence of ischemic episodes observed after withdrawal of propranolol from patients with coronary occlusive disease. However, the number of beta receptors and their sensitivity to adrenergic agonists do not seem to be changed uniformly after abrupt withdrawal of propranolol.

Sulfinpyrazone and aspirin increase epicardial coronary collateral flow in dogs

Clinical studies suggest that sulfinpyrazone and aspirin may be useful in the treatment of coronary artery disease. It was previously shown that pretreatment with a completely platelet-inhibitory dose of aspirin is associated with increased epicardlal collateral flow 4 hours after coronary occlusion in dogs. In this study evaluation was made of platelet inhibitory doses of sulfinpyrazone (30 mg/kg) and aspirin (3 mg/kg) and an aspirin dose (30 mg/kg) 10-fold greater than the minimal dose necessary for complete platelet inhibition. Collateral flow (ml/min per g) was measured 5 minutes after temporary (pretreatment) occlusion of the left anterior descending coronary artery. After release of the occlusion and recovery, a drug dose or saline solution was given, permanent (post-treatment) occlusion instituted, and flow measurement repeated 5 minutes and 4 hours later. Administration of sulfinpyrazone (11 dogs) caused an increase in flow to the ischemic epicardium from 5 minutes after the pretreatment occlusion to 5 minutes after the post-treatment occlusion (mean ± standard error of the mean): Δ = 0.09 ± 0.02, p < 0.01. However, a significant increase was not found in the control group (11 dogs) or in either aspirin-treated group (8 dogs each). All the drug doses caused a significant increase in epicardial collateral flow from 5 minutes after the post-treatment occlusion to 4 hours after the same occlusion: sulfinpyrazone, Δ = 0.08 ± 0.03, p < 0.025; aspirin, 3 mg/kg, Δ = 0.16 ± 0.06, p < 0.05; and aspirin, 30 mg/kg, Δ = 0.14 ± 0.05, p < 0.05. No significant increase was observed during the same interval in control dogs. Endocardial collateral flow 4 hours after post-treatment occlusion was slightly increased in relation to pretreatment values in the sulfinpyrazone group but not in any of the remaining groups. Enhanced collateral flow after coronary occlusion may contribute to some of the beneficial effects ascribed to sulfinpyrazone and aspirin in coronary artery disease.

Relative effects of sulfinpyrazone and ibuprofen on canine platelet function and prostaglandin-mediated coronary vasodilation.

Recent evidence suggests that the platelet-inhibitory drugs sulfin-pyrazone and ibuprofen may have value in treatment of coronary artery disease. However, these drugs do not only block platelet aggregation, but also block synthesis by blood vessels of prostaglandins that promote vasodilation. Platelets may differ from blood vessels in their sensitivity to sulfinpyrazone or ibuprofen. In theory, optimal doses for coronary disease would inhibit potentially deleterious platelet aggregation but not interfere with synthesis of possibly beneficial vasodilator prostaglandins. To determine whether it was possible to identify such optimal doses we measured the effects of intravenous sulfinpyrazone, 0.3–100 mg/kg (n = 9), or sodium ibuprofen, 0.1–3 mg/kg (n = 7), on vasodilation induced by the protaglandin precursor arachidonic acid. We also assessed drug effects on in vitro platelet aggregation in the same animals. Both sulfinpyrazone and ibuprofen caused a dose-related reduction in flow increment after arachidonic acid. Sulfinpyrazone, ≥10 mg/kg, and ibuprofen, ≥1 mg/kg, produced a mean reduction of least 60% (p < 0.02 for each) in the vasodilator response to 1 mg arachidonic acid. Sulfinpyrazone, 0.3 mg/kg, and ibuprofen, 0.1 mg/kg, had no consistent effects on flow. Flow rise after intracoronary prostaglandin E2 was undiminished by sulfinpyrazone or ibuprofen. Sulfinpyrazone, ≥10 mg/kg, and ibuprofen, ≥1 mg/kg, markedly inhibited platelet aggregation induced by adenosine diphosphate, 2.3 x 10-5 M (p < 0.01 for each). Sulfinpyrazone, 0.3 mg/kg, and ibuprofen, 0.1 mg/kg, failed to alter platelet aggregation. Hence, sulfinpyrazone and ibuprofen doses inhibiting platelet function also produced comparable inhibition of arachidonic acid-induced coronary vasodilation, presumably by interfering with arachidonic acid conversion to vasodilator prostaglandins. Neither sulfinpyrazone nor ibuprofen, administered acutely, appears to have an “optimal” dose that in