Effect of myocardial ischaemia and antilipolytic agents on lipolysis and fatty acid metabolism in the in situ dog heart

Myocardial metabolism was studied in open-chest dogs before and during induction of myocardial ischaemia by coronary artery occlusion. Blood was sampled from a local coronary vein draining ischaemic tissue and from coronary sinus draining predominantly nonischaemic tissue. In the basal state, induction of myocardial ischaemia stimulated myocardial lipolysis as shown by release of glycerol from the ischaemic zone. During isoprenaline infusion, free fatty acids (FFA) extraction across the ischaemic myocardium was substantially increased, but no glycerol release occurred. Pretreatment with nicotinic acid or sodium salicylate markedly depressed FFA extraction across ischaemic myocardium, both during basal and isoprenaline stimulated lipolysis and nicotinic acid most likely inhibited lipolysis in the ischaemic zone. Thus, reduced severity of acute ischaemic injury by antilipolytic treatment might be due to a combination of inhibited myocardial lipolysis and reduced FFA extraction.     

Distribution of coronary blood flow during acute coronary occlusion in dogs. Effect of nicotinic acid and sodium salicylate

The effects of the antilipolytic agents nicotinic acid (NA) and sodium salicylate (SS) on the distribution of coronary blood flow during acute myocardial ischaemia were studied in open chest dogs. Fifteen min following experimental coronary artery occlusion, blood flow in the ischaemic myocardium was on average 28% of flow in the non-ischaemic myocardium. The reduction in blood flow in the ischaemic mycardium was more pronounced in the endocardial than in epicardial halves of the myocardium. No significant change in blood flow was observed after administration of NA or SS in either the ischemic or nonischemic part of the myocardium. Both drugs reduced the extent of myocardial ischaemic injury as shown by reduced epicardial ST-segment elevations. Arterial concentrations of fatty acids were lowered by NA or SS, whereas the mechanical activity of the heart remained unchanged. It is concluded that the reduction of acute myocardial ischaemic injury effected by NA or SS is not due to changes in myocardial blood flow, but more likely to lower myocardial oxygen demand related to reduced fatty acid utilization.     

Distribution of coronary blood flow during acute coronary occlusion in dogs. Effect of nicotinic acid and sodium salicylate

The effects of the antilipolytic agents nicotinic acid (NA) and sodium salicylate (SS) on the distribution of coronary blood flow during acute myocardial ischaemia were studied in open chest dogs. Fifteen min following experimental coronary artery occlusion, blood flow in the ischaemic myocardium was on average 28% of flow in the non-ischaemic myocardium. The reduction in blood flow in the ischaemic mycardium was more pronounced in the endocardial than in epicardial halves of the myocardium. No significant change in blood flow was observed after administration of NA or SS in either the ischemic or nonischemic part of the myocardium. Both drugs reduced the extent of myocardial ischaemic injury as shown by reduced epicardial ST-segment elevations. Arterial concentrations of fatty acids were lowered by NA or SS, whereas the mechanical activity of the heart remained unchanged. It is concluded that the reduction of acute myocardial ischaemic injury effected by NA or SS is not due to changes in myocardial blood flow, but more likely to lower myocardial oxygen demand related to reduced fatty acid utilization.     

Relative rates of oxidation of glucose and free fatty acids by ischaemic and non-ischaemic myocardium after coronary artery ligation in the dog

Abstract. 1. Small regional ischaemic lesions, involving about 7 % of the volume of the whole heart, were produced in the greyhound dog by ligation of a branch of the anterior descending coronary artery. Arteriovenous differences across ischaemic tissue were studied by cannulation of a local vein visibly draining the ischaemic area, whereas arteriovenous differences across the non-ischaemic tissue were obtained by coronary sinus samples. This system permitted study of those ischaemic cells draining into the local vein and perfused by residual collateral circulation. Flow factors were common to all metabolites measured in local venous blood, thereby allowing detection of changes in substrate metabolism relative to each other. As the contribution of local venous blood to coronary sinus blood was negligible, it was possible to use coronary sinus values as non-ischaemic control data for each local venous sample.—2. The contributions of glucose, free fatty acids (FFA) and other substrates (lactate, pyruvate, ketones, triglycerides) to the residual oxidative metabolism of the ischaemic, infarcting dog myocardium were indirectly assessed by calculations of the oxygen extraction ratio (OER), and directly by the rate of ¹⁴CO₂ formation from ¹⁴C-labelled glucose or palmitic acid.—3. Within two hours of arterial ligation, the arteriovenous difference of glucose across the ischaemic tissue was increased relative to that of IT A. Whether calculated from OER or from ¹⁴CO₂ data, there was an increase in the oxidation rate of glucose relative to that of FFA. In absolute terms the oxygen uptake of ischaemic tissue fell almost as much as the flow rate, and the glucose uptake probably fell too. Nevertheless, glucose competed more favourably than did FFA for the residual oxidative metabolism of the ischaemic tissue.—4. In coronary sinus blood, draining predominantly non-ischaemic tissue, formation of ¹⁴CO₂ accounted for about half the uptake of ¹⁴C-glucose and formation of ¹⁴C-lactate was very low. In local venous blood draining predominantly ischaemic tissue, ¹⁴CO₂ formation accounted for about 30–40% and ¹⁴C-lactate for about 10% of the arteriovenous difference of ¹⁴C-glucose. The chemical oxygen extraction ratio of glucose and FFA could account for 90–100% of the residual oxygen uptake of the ischaemic myocardium 60–100 min. post-ligation, with glucose accounting for nearly twice as much oxygen as FFA. Thus an unexpected finding was that a major part of the glucose extracted by the ischaemic myocardium was oxidized, possibly because local venous blood drained the less severely ischaemic areas.—5. The major fate of labelled FFA extracted by the non-ischaemic myocardium also appeared to be oxidation. After arterial ligation, rates of FFA oxidation fell as assessed by both OER calculation and by rates of ¹⁴CO₂ formation. More ¹⁴C-label was recovered in the “mitochondrial” and less in the “microsomal” lipid fractions of the ischaemic tissue.—6. Lactate uptake by the normal myocardium was changed to lactate discharge by the ischaemic myocardium. Initially, tissue glycogen was the major source of the lactate formed, but 60–120 min. after arterial ligation there was less discharge of lactate and circulating ¹⁴C-gIucose became a major source of venous lactate.—7. It was concluded that not only was anaerobic metabolism of glucose accelerated by coronary artery ligation, but the aerobic metabolism of glucose increased relative to that of FFA.     

Does α1-adrenergic blockade influence regional blood flow regulation in hearts with coronary artery occlusion?

Summary. The effects of selective α₁-adrenergic blockade with doxazosin on regional myocardial tissue blood flow was studied in anaesthetized cats with acute coronary artery occlusion. Reflex tachycardia was prevented by selective β₁-adrenergic blockade with atenolol and coronary perfusion pressure was kept constant by partial stenosis of the descending aorta. Administration of atenolol reduced cardiac mechanical work-load by its negative inotropic and chronotropic effects, and reduced myocardial tissue blood flow in normally perfused myocardium. This reduction was most pronounced in the endocardial half-layer of the myocardium adjacent to the ischaemic region. Administration of doxazosin in this situation clearly reduced peak systolic and coronary perfusion pressure. But when coronary perfusion pressure was raised to pre-administration values, measurements of regional blood flow revealed no changes either in ischaemic or non-ischaemic myocardium. Also, there was no sign of redistribution of blood flow between endocardial and epicardial tissue in any area. This study, therefore, indicates that α₁-adrenoceptors play a minor role in the regulation of coronary blood flow in normal myocardium as well as ischaemic myocardium.     

Moderate normovolaemic haemodilution increases regional myocardial blood flow but has no effect on experimental infarct size

Regional myocardial blood flow was measured with radioactive microspheres before and 1, 3, 6, and 12 h after occlusion of the left anterior descending coronary artery (LAD) in anaesthetized cats. In one group of cats, 1 h after LAD occlusion, moderate normovolaemic haemodilution was started with a dextran 40 solution, which reduced the haematocrit by 20-25% throughout the rest of the experiment. In the other group, the haematocrit was kept at the original level. Infarct size was measured planimetrically 12 h after the coronary ligation, using the tetrazolium staining technique for disclosing the ischaemic myocardium. Haemodilution increased blood flow in the non-ischaemic myocardium and in the so-called 'border zone' comprising both normal, and ischaemic tissue. However, in the severely ischaemic myocardium dependent on collateral blood flow, where there was no admixture of non-ischaemic myocardium, the blood perfusion was not significantly affected by the haemodilution. After 12 h of ischaemia the infarct size in the control group was fully comparable with that in the haemodiluted group: 28 +/- 3 and 27 +/- 4 (percentage of the left ventricle, mean +/- SEM), respectively.     

Myocardial blood flow conditions at re-perfusion following acute ischaemia

The purpose of this study was to investigate the effect of re-perfusion upon distribution of radioactive microspheres in ischaemic myocardium. Ten anaesthetized cats were given 15-micron microspheres prior to left anterior coronary artery occlusion, at 1 h of occlusion, and after 1 h of subsequent re-perfusion. Pre-occlusion blood flow estimates were lower in tissue which had been ischaemic compared with nonischaemic regions in the same heart (1.44 versus 1.87 ml X min-1 X g-1, p less than 0.001), corresponding to 23% apparent loss. Loss also occurred in ischaemic right ventricular tissue (32%). In left ventricular ischaemic endocardium, apparent loss was due to development of oedema. Oedema was also significant in epicardial ischaemic tissue. Correction for oedema eliminated two-fifths of the loss, while three-fifths was due to physical loss. Oedema increased linearly with the level of re-perfusion. During re-perfusion, myocardial blood flow in previously ischaemic tissue was inhomogeneously distributed and, on average, 28% lower than in non-ischaemic myocardium. The 15-micron spheres appeared to pass through capillaries in the ischaemic subepicardium, but this process was not enhanced by reperfusion.     

Effects of prostaglandin-E1 on ST segment elevation and regional myocardial blood flow during experimental myocardial ischaemia in dogs

Abstract. The effects of prostaglandin E₁ (PGE₁) on myocardial ischaemia (as measured by epicardial ST segment changes), myocardial flow and substrate exchange has been studied in dogs. Myocardial ischaemia was induced by intermittent external clipping of a branch of the left anterior descending coronary artery.
During occlusion with a continuous intravenous infusion of isoprenaline, elevated epicardial ST segments (∑ST), were raised to 46 ± 6 mV (mean ± SEM). Pretreatment with PGE₁ reduced ∑ST to 34 ± 6 mV ( P <0.001), but had no effect on mean aortic blood pressure (AP¯) or on regional myocardial blood flow. Isoprenaline infusion increased plasma free fatty acids (FFA) to 1925 ± 150 μmol/l and this was reduced to 1320 ± 220 μmol/l by PGE₁ ( P <0.005).
During occlusion without isoprenaline, PGE₁ did not effect ∑ST or plasma FFA when infused intravenously or into the left atrium. Mean aortic blood pressure decreased from 131 ± 7 to 108 ± 10 (PGE₁ i.v.) or 109 ± 8 mmHg (PGE₁ i.a.) ( P <0.001). This was associated with a decrease in regional myocardial blood flow, both in the ischaemic and non-ischaemic myocardium. However, when blood pressure was maintained constant, intravenous PGE₁ tended to decrease occlusion-induced ST segment elevation.
These results suggest that PGE₁ can reduce isoprenaline-stimulated myocardial ischaemia through its antilipolytic action but in the absence of catecholamine stimulation the main effect is to reduce blood pressure thereby counterbalancing any potentially beneficial effects on the ischaemic myocardium.     

Prostacyclin and regional coronary blood flow in experimental myocardial infarction

Infusion of prostacyclin (PGI₂) has been reported to affect infarct size and myocardial blood flow favourably in various animal models of myocardial ischaemia. Recent data suggest that a similar effect of PGI₂ may occur also in humans with acute myocardial infarction. We addressed the hypothesis that PGI₂ redistributes myocardial blood flow following coronary ligation, and that this effect favours perfusion of myocardium at risk and thereby limits infarct size. Following ligation of a distal branch of the left coronary artery in anaesthetized dogs, PGI₂ (2–4 ng/kg/min) was infused for 72 h. Regional myocardial blood flow was assessed immediately after the coronary ligation and at the end of the drug infusion, by injection of ⁵⁷Co- and ¹¹³Sn-labelled microspheres, respectively. Coronary ligation reduced regional coronary blood flow by 40–70%. During the subsequent 72 h the blood flow increased, being at the end of the period 50–70% of the flow in the non-ischaemic myocardium. PGI₂ did not affect the spontaneous improvement of regional myocardial blood flow, as assessed at the end of the infusion. PGI₂ also failed to affect infarct size, either when expressed in relation to total left ventricular mass, or in relation to area at risk. We conclude that PGI₂, when infused immediately after coronary ligation in dogs in a clinically relevant dose, neither affects regional myocardial blood flow in the ischaemic regions, nor the size of the myocardial infarction.     

Regional perfusion in hearts with acute coronary artery occlusion and subsequent β2- and α1-adrenergic blockade

Summary. Blockade of cardiac adrenoceptor subtypes, coronary or myocardial, might elicit compensatory interaction from remaining unblocked subtypes. An attempt to explore this interplay was made by studying regional myocardial blood flow alterations associated with β₂-adrenergic blockade followed by β₁-adrenergic blockade in anaesthetized cats with acute coronary occlusion. In order to maintain constant needs for perfusion, atrial pacing was established and the aortic blood pressure was kept constant. In myocardium remote from the ischaemic region, β₂-adrenergic blockade produced higher endocardial blood flow whereas no flow changes were observed close to the ischaemic region. With subsequent β₁-adrenergic blockade, blood flow increased endocardially in non-ischaemic regions, but remained unchanged in epicardial tissue. Control experiments without coronary ligation revealed no increase in left ventricular oxygen consumption during the experiments and support the theory that the observed blood flow increase in the coronary ligation group, following drug interventions, was not caused by increased cardiac work. This study indicates that combined β₂- and α₁-adrenergic blockade alters the balance between receptor subtypes. Unopposed β₁-mediated vasodilation is the most likely candidate to explain why endocardial flow was increased.     

Does infarct size influence loss of embolised 15-micrometer microspheres from ischaemic myocardium?

The relationship between myocardial infarct size and loss of 15-micron microspheres from ischaemic tissue was investigated in anaesthetized cats. Radioactive microspheres were injected in the left atrium before and 5 h after left anterior descending coronary artery occlusion. Left ventricular hypoperfused zone (HZ) averaged 36.6% and infarct size (IS) 31.6%. Thus, 86% of HZ evolved into necrosis. Preocclusion blood flow was lower in ischaemic (1.62 ml/min per g) compared with non-ischaemic myocardium (2.09, p = 0.002), indicating 22% microsphere loss. In ischaemic subendocardium, oedema (3.7%) could account for the apparent loss. In ischaemic subepicardium, oedema was less pronounced and 18% physical sphere loss occurred. Subepicardial loss increased in proportion to IS and IS/HZ ratio (r2 = 0.71; p less than 0.005). Non-entrapment of 15-micron spheres in coronary circulation averaged 0.6%, and preocclusion spheres appeared in coronary sinus blood throughout the ischaemic period. In systemic circulation, non-entrapment during injection of preocclusion spheres was 7.8%, but only 1.8% 5 h later. Release of postocclusion spheres took place during KCl injection. Thus, myocardial ischaemia is associated with alterations in microvascular function allowing release of entrapped 15-micron spheres. Also, the magnitude of microsphere loss per gram tissue is related to infarct size.     

Effect of experimental non-insulin requiring diabetes on myocardial microcirculation during ischaemia in dogs

Abstract To examine whether chronic high blood glucose may influence myocardial microcirculation during acute myocardial ischaemia in the dog, a non-insulin-requiring diabetes was induced by the streptozotocin-alloxan method. Seventy-five days later, myocardial ischaemia was provoked by occluding the left anterior descending coronary artery for 2h and micro-circulation regulation was assessed in the ischaemic and non-ischaemic myocardium by the radioactive microsphere method. Diabetic dogs were compared with normal dogs. Diabetic dogs had higher blood glycated haemoglobin (2·66±0·4%) and fructosamine (397±62 μ mol l^-1) than control dogs (0·66±0·2, P <0·004 and 229 ± 13, P <0·03, respectively). Haemodynamic data in the two groups were not different at any time. The size of the ischaemic zone was similar in both groups. During the 2h ischaemia in the ischaemic zone subendocardial ( P = 0·22) and subepicardial ( P <0·05) blood flow slightly increased in control dogs whereas there was a 63% ( P <0·02) and 35% ( P = 0·06) reduction respectively in diabetic dogs. In the non-ischaemic zone, blood flow of controls tended to increase ( P <0·006 in the subepicardium and P <0·06 in the subendocardium) whereas in diabetic dogs blood flow tended to decrease ( P = 0·03 in the subendocardium and in the subepicardium). This first investigation on myocardial microcirculation in diabetic dogs during ischaemia suggests that one of the possible causes of increased mortality rate from ischaemic cardiac disease in diabetics might be related to a paradoxical and unfavourable pattern of myocardial blood flow during ischaemia.     

Effects of verapamil on intracellular lipid accumulation in cat hearts with 3 h of regional-ischaemia

In the regionally ischaemic heart lipid droplet accumulation is found in the ischaemic area and is most pronounced in the periphery. The purpose of the present study is to explore the potential effects of the calcium-channel-blocker verapamil on this accumulation. The drug is known to reduce the intensity of myocardial ischaemic injury. The myocardial ultrastructure was studied in anaesthetized open chest cats with 3 h of coronary artery occlusion. Biopsies were taken from the ischaemic, border and normally perfused myocardium defined in vivo injections of fluorescein and verified by blood flow measurements using radiolabelled microspheres. Arterial concentration of non esterified fatty acids (NEFA) was measured during the ischaemic period. A higher accumulation of lipid droplets was found in the central ischaemic myocardium of verapamil-treated cats than in control animals (p less than 0.05). The normally perfused and borderline areas were unaffected by verapamil as far as lipid accumulation was concerned and showed the same pattern as in the untreated group. The increased accumulation of lipid droplets in the ischaemic myocardium, after treatment with verapamil, may reflect a preserved metabolic activity in the ischaemic tissue or result from a higher supply of fatty acids due to increased perfusion of the central ischaemic tissue.     

Regional myocardial tissue blood flow during β-adrenergic blockade in cat hearts with acute ischaemia

Summary. Selective β₁ or β₂-adrenergic blockade was achieved by practolol or IPS 339, respectively, in cats with acute ligation of a coronary artery. During blockade, heart rate was kept constant by atrial pacing and blood pressure reduction was prevented by aortic clamping. Regional myocardial blood flow was measured by the distribution of 15 μm labelled microspheres. Practolol slightly reduced epicardial blood flow in ischaemic myocardium, while blood flow in border and normally perfused myocardium remained unchanged. Following IPS 339, myocardial tissue flow increased in normally perfused myocardium, on average by 37% in the endocardium and 30% in the epicardium. No changes occurred in the other regions. The flow changes brought about by IPS 339 were unrelated to haemodynamic changes, and the coronary vascular resistance was reduced. These results are indicative of coronary vasodilation related to β₂-adrenergic receptor blockade and was confined to well-oxygenated areas surrounding the acutely ischaemic zone.     

Local myocardial function following coronary occlusion in cats,Effect on non-ischaemic regions

Summary. The mechanical function and perfusion in ischaemic and non-ischaemic myocardium after coronary occlusion was studied in 10 cats using pressure-length loop analysis and radiolabeled microspheres. Measurements in three regions—ischaemic, adjacent normal and remote normal myocardium—all showed different responses to coronary occlusion. In the ischaemic region loop area, segment shortening and tissue flow were markedly reduced. In the adjacent normal region, both loop area and segment shortening as well as flow increased. In the remote normal region, neither loop area, segment shortening nor flow showed consistent changes. End-diastolic segment length increased in all regions, most in the ischaemic region and least in the remote region. The increased end-diastolic segment length in all regions after coronary occlusion indicates activation of the Frank-Starling mechanism as an attempt to maintain stroke volume. However, the end-diasolic segment length did not increase uniformly for all normal myocardium: it depended on the proximity to the ischaemic region. Increased contractile function in the adjacent normal myocardium due to non-uniform distribution of the Frank-Starling effect is the most likely mechanism behind the left ventricle's ability to partially compensate for loss of contractile mass during acute regional ischaemia in anaesthetized cats.     

Effects of isoproterenol on adenine nucleotide catabolism in cat hearts with acute regional ischaemia

Previous studies have demonstrated that beta-adrenergic agonists cause extension of ischaemic lesions in the myocardium. In the present study the effects of isoproterenol on adenine nucleotide metabolism were investigated in cat hearts with regional ischaemia following permanent coronary occlusion for 45 min. Adenine nucleotides and their metabolites were measured by high performance liquid chromatography and regional myocardial blood flow was measured by 15-microns radiolabelled microspheres in a total of 255 paired tissue samples. Compared with untreated control cats, ATP and the energy charge were more reduced in ischaemic myocardium of isoproterenol-treated cats. Increased amounts of the degradation products inosine and hypoxanthine/xanthine were also found in these regions. These results could be ascribed to increased cardiac performance caused by isoproterenol, which augments the imbalance between energy production and oxygen supply in ischaemic myocardium.     

The influence of hypertonic mannitol on regional myocardial blood flow during acute and chronic myocardial ischemia in anesthetized and awake intact dogs.

The influence of hypertonic mannitol on regional myocardial blood flow and ventricular performance was studied during acute myocardial ischemia in awake, unsedated and in anesthesized dogs and after myocardial infarction in awake unsedated dogs. Regional myocardial blood flow was measured with radioactive microspheres. Generalized increases in regional myocardial blood flow occurred after mannitol in all of the different animal models studied. The increases in coronary blood flow after mannitol were just as impressive in the nonischemic regions as in the ischemic portion of the left ventricle in all of the different models that were examined in this study. Improvement in regional myocardial blood flow to the ischemic area of the left ventricle after mannitol was associated with a reduction in ST segment elevation during acute myocardial ischemia in anesthetized dogs. The increases in regional myocardial flow after mannitol were also associated with increases in contractility, but the increases in flow appeared to be more impressive than the changes in contractility. The data obtained demonstrate that mannitol increases regional coronary blood flow to both ischemic and nonischemic myocardium in both anesthetized and awake, unsedated, intact dogs with acute and chronic myocardial ischemia and that mannitol reduces ST segment elevation during acute myocardial ischemia in anesthetized dogs. Thus the results suggest that under these circumstances the increases in regional myocardial blood flow after mannitol are of physiological importance in reducing the extent of myocardial injury. Since coronary blood flow increased to nonischemic regions the increases in regional myocardial flow demonstrated in this study after mannitol cannot be entirely explained by the mechanism of reduction in ischemic cell swelling.     

Relationship between myocardial adenine nucleotide catabolism and tissue blood flow rate in experimental ischaemia

A method was developed for tissue preservation and evaluation of the adenine nucleotide metabolism in small samples of myocardium after 45 min of ischaemia. Ischaemia was produced by coronary artery occlusion in anaesthetized cats. Adenine nucleotides and their metabolites were measured by isocratic liquid chromatographic systems which allow quantitative analysis of the nucleotides and their metabolites inosine, hypoxanthine and xanthine in biopsies of 5-20 mg tissue. Regional myocardial blood flow was measured in the tissue surrounding the biopsies by the distribution of 15 micron radiolabelled microspheres. In central ischaemic regions the ATP level was approximately 1 mumol/g wet weight, whereas in normally perfused myocardium the ATP level was approximately 5 mumol/g tissue. In tissue with intermediate flow values, intermediate ATP levels were found. Energy charge, which summarizes all adenine nucleotide concentrations, was reduced from 0.88 to 0.50, and the molar concentrations of inosine, hypoxanthine and xanthine increased in ischaemic tissue. We conclude that this method provides reliable characterization of the local cellular energy status in cat hearts with ischaemic regions.     

Platelet deposition in remote cardiac regions after coronary occlusion

BACKGROUND: Activated platelets might contribute to endothelial dysfunction in non-ischaemic territories during acute myocardial infarction. We assessed platelet deposition, coronary flow reserve and contractile function in remote cardiac regions after transient coronary occlusion and their association with systemic platelet activation. MATERIALS AND METHODS: In 10 pigs (series A) subjected to 48-min occlusion of the left anterior descending coronary artery (LAD), 99mTc-platelet content in the right coronary artery (RCA) and its dependent myocardium was counted after reflow. In 10 pigs (series B) receiving the same occlusion of the RCA, the hyperaemic response at the LAD and systolic shortening in LAD-dependent myocardium were monitored after reperfusion. P-selectin expression on circulating platelets was assessed in both series by flow cytometry. RESULTS: In series A, platelet counts in the RCA and non-ischaemic myocardium were correlated with platelet content, polymorphonuclear leukocyte infiltration and infarct size in the reperfused zone, as well as with the percentage of P-selectin-positive platelets after reflow. In series B, a transient reduction in peak hyperaemic response in the LAD and sustained contractile dysfunction in non-ischemic myocardium were observed after releasing the RCA occlusion, these changes being also correlated with platelet activation status. CONCLUSIONS: Ischaemic injury triggers macro- and microvascular platelet deposition and causes an impairment in coronary flow reserve and contractile function in distant regions of the heart, which are related to activation of circulating platelets.     

Effects of dimethyl quaternary propranolol (UM-272) on oxygen consumption and ischemic ST segment changes in the canine heart.

The effect of dimethyl quarternary propranolol, UM-272, on myocardial oxygen consumption was determined experimentally in anesthetized, open-chest dogs in which the left anterior descending and circumflex coronary arteries were cannulated and perfused at a constant pressure. Coronary arterial and venous blood samples were collected and their oxygen content were measured. Myocardial oxygen consumption was calculated and expressed as milliliters per minute per 100 grams of left ventricle. Mean control myocardial oxygen consumption in five animals was 11.7 +/- 1.9. This was significantly reduced to 7.6 +/- 1.1 after UM-272, 10 mg/kg (P less than 0.5). In separate experiments, hearts were excised from anesthetized dogs and were perfused with oxygenated whole blood via the aorta. Coronary blood flow was held constant and oxygen consumption was calculated and expressed as milliliters per minute per 100 g of myocardium. Mean control oxygen consumption in five hearts was significantly reduced from 3.1 +/- 0.2 to 2.1 +/- 0.1 (P less than 0.01). In addition, the effect of UM-272 on myocardial ischemic injury produced in response to acute coronary artery ligation was assessed. The sum ST segment elevations from six epicardial recording sites was reduced from 34.8 +/- 4.9 to 11.3 +/- 2.1 mV (P less than .05). These data suggest that UM-272 would aid in ischemic heart disease by reducing both oxygen utilization and ischemic damage. These data, although suggestive, do not exclude other mechanisms as being related to the reduction in ST segment elevation, mechanisms which may not involve a reduction in myocardial oxygen consumption.