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Myocardial infarction appears after 20 min of regional no-flow ischemia in vivo, but only after a much longer duration of global ischemia in isolated hearts. We tested whether repetitive myocardial stretching (RMS), as occurs in segmental ischemia, is involved in the pathogenesis of myocardial cell injury. Furthermore, we evaluated the role of stretch-activated channels by using Gadolinium (Gd3+). Isolated piglet hearts were perfused with red cell enriched Krebs-Henseleit buffer. RMS was induced by inflating a balloon in the left ventricle, using a control system to provide a pressure of 120 mmHg during one-third of the cycle and 0 mmHg during the rest of the cycle, with a frequency 150 per min. Function and metabolism were compared during 2 h of low-flow ischemia (10% of control), with and without RMS, followed by 1 h of reperfusion. Non-RMS hearts were exposed to saline (Isch), or Gd3+ 25 micromol/l (Gd3+-Isch). During ischemia, left ventricular systolic pressure (LVSP) stabilized in non-RMS hearts, but a further decrease, combined with increased anaerobic metabolism occurred in RMS hearts. After 30 min of reperfusion in the non-stretched hearts, LVSP returned to 77+/-4% of control (mean+/-s.e.) in the Isch group, and to 74+/-2% in the Gd3+-isch group (between groups; P=n.s.). In hearts exposed to RMS, LVSP returned to only 46+/-4% of control (RMS) and to 51+/-3% in the Gd3+-RMS group (both P=0.01 v Isch). The same alterations were seen for LV dP/dt. In RMS hearts, tissue concentrations of ATP were reduced and concentrations of lactate increased. We conclude that stretching of ischemic myocardium severely increases anaerobic metabolism and reduces functional and metabolic recovery. Blockade of stretch activated channels by Gd3+ does not prevent this effect. Thus, the reduced recovery induced by RMS is due to factors other than ion fluxes through stretch-activated channels.

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Different conclusions have been reached with regard to the effect of endothelin (ET-1) on cardiac contractility. We examined systolic and diastolic function in response to constant known concentrations of ET-1 with or without ET-1 induced reductions in coronary flow (CF). Rat hearts (n = 21) were buffer-perfused using constant coronary flow (cCF) or constant perfusion pressure (cPP). Left ventricular function was assessed isovolumically. Addition of ET-1 (10(-9) M) in the cCF group caused a gradual increase in PP from 61 +/- 2 to 165 +/- 6 mmHg (mean +/- SE) (P < 0.01). Within 10 min left ventricular systolic pressure (LVSP) increased from 111 +/- 2 to a maximum of 134 +/- 4 mmHg (P < 0.01) and [LVdP/dt] increased from 1640 +/- 81 to a maximum of 2020 +/- 92 mmHg s-1 (P < 0.01). After 15 min left ventricular end diastolic pressure (LVEDP), a measure of diastolic stiffness (DS), also increased. With ET-1 (10(-8) M), similar haemodynamic alterations appeared more rapidly. In the cPP group, ET-1 (10(-9) M) caused a sharp decrease in CF and LVSP fell from 115 +/- 8 to 62 +/- 12 mmHg at 10 min (P < 0.001). Systolic function remained stable at a reduced level for 1 h. DS did not change. Thus, ET-1 possesses positive inotropic effects and increases diastolic stiffness. Both effects may be masked by vasoconstriction-induced ischaemia.

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We examined the effects of endothelium-dependent responses on coronary perfusion pressure (CPP) in isolated, blood-perfused neonatal pig hearts under conditions of controlled coronary flow. Baseline CPP was increased 8%-21% by the cyclooxygenase inhibitor indomethacin (10-100 microM), and 30%-92% by NG-monomethyl-L-arginine (L-NMMA, 10-100 microM), an inhibitor of nitric oxide (NO) synthase, suggesting that both prostaglandin and nitric oxide synthesis contribute to basal coronary tone. Both acetylcholine (ACh) and bradykinin (BK) decreased CPP. These effects were enhanced by preconstriction with endothelin-1. L-NMMA markedly attenuated BK-induced coronary vasodilation and converted the ACh response to constriction, indicating a significant role for NO release in these responses. After 1 h of total, global normothermic ischemia and 45 min of reperfusion, vasoconstrictor responses to endothelin-1 and ACh were enhanced, while BK-induced dilation was significantly reduced. L-Arginine supplementation during reperfusion did not restore vasodilatory responses to ACh or BK. The magnitude of L-NMMA-induced coronary vasoconstriction during reperfusion was similar to that observed without ischemia-reperfusion. Coronary vasodilation in response to sodium nitroprusside, a NO precursor that causes endothelium-independent vasodilation by directly activating smooth muscle guanylate cyclase, was unaffected by ischemia-reperfusion. We conclude that NO production in the neonatal coronary circulation contributes to both basal tone and the response to ACh and BK. After ischemia-reperfusion, basal NO production and smooth muscle relaxation mediated by guanylate cyclase are intact, whereas agonist-stimulated dilation is significantly impaired.

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OBJECTIVE: ATP gated potassium (KATP) channels and adenosine are of crucial importance in coronary blood flow regulation and activation of KATP channels and adenosine receptor stimulation protect against infarction and development of stunning. The aim of this study was to test the hypothesis that opening of KATP channels and adenosine receptor stimulation are involved in perfusion-contraction matching, in acute hibernation, and in recovery after reperfusion. METHODS: 30 isolated piglet hearts (2-10 d old) and 20 isolated rabbit hearts were studied. The isolated piglet hearts were perfused with modified Krebs Henseleit (KH) solution enriched by washed human red blood cells; the isolated rabbit hearts were perfused with modified KH buffer. The effects of the KATP channel opener aprikalim (1 microM), the KATP channel antagonist glibenclamide (30 microM), and the adenosine receptor antagonist 8-(p-sulphophenyl)theophylline (SPT, 300 microM) on 2 h of low flow (10%) ischaemia and 1 h reperfusion were compared with saline in the piglet hearts. The effects of aprikalim (1 microM), glibenclamide (30 microM), and saline during 90 min of low flow (10%) ischaemia followed by 1 h reperfusion were also examined in the isolated rabbit hearts. RESULTS: At constant coronary flow aprikalim reduced perfusion pressure from 53(SEM 5) to 25(1) mm Hg (p < 0.001) in piglet hearts and from 55(5) to 39(5) mm Hg (p < 0.05) in rabbit hearts. Glibenclamide increased perfusion pressure from 47(5) to 61(6) mm Hg (p < 0.01) in piglet hearts and from 45(4) to 81(5) mm Hg (p < 0.001) in rabbit hearts. SPT increased perfusion pressure from 55(6) to 67(6) mm Hg (p < 0.05) in piglet hearts. Left ventricular systolic pressure remained unchanged in both models. During stepwise reductions in coronary flow a parallel stepwise reduction in left ventricular systolic pressure was observed in all groups. At 2 h of low flow ischaemia systolic pressure was 39(4)%, 37(5)%, 41(4)%, and 37(3)% of control for hearts treated with saline aprikalim, glibenclamide, and SPT, respectively. During the low flow period systolic pressure and MVO2 stabilised. An almost identical pattern occurred in rabbit hearts. After 30 min of recovery of piglet hearts left ventricular systolic pressure increased to 78(5)% (saline), 74(5)% (aprikalim), 84(5)% (glibenclamide), and 77(4)% (SPT) of control. The recovery as percentage of control in rabbit hearts was 63(11) (saline), 69(8) (aprikalim) and 56(13) (glibenclamide). CONCLUSION: Coronary vascular tone is highly responsive to KATP channel modulation and adenosine receptor blockade. KATP channels do not modulate either perfusion-contraction matching or acute hibernation and functional recovery during reperfusion in the red blood cell perfused piglet heart or the crystalloid perfused rabbit hearts. Moreover, adenosine receptor antagonism does not affect these phenomena in piglet hearts.

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Cell viability is maintained during prolonged ischemia (ISCH) in isolated heart systems because mechanical function is nil (acute hibernation). By contrast, a noncontracting ischemic segment in an in vivo heart exhibits irreversible damage after < or = 30 min. To explore this difference, isolated rabbit hearts were buffer perfused and exposed to elevations of ventricular balloon pressure (BP) during ISCH to mimic systolic stresses of a dyskinetic (DYSK) segment. Relationships of magnitude and duration of stress to recovery of systolic function and metabolism were assessed. After 30 min of reperfusion (R30) in hearts subjected to 90 min of ISCH [10% coronary flow (CF)] and BP = 0, peak systolic pressure (PSP) returned to 69% of control. With BP set at 120 mmHg, recovery was to only 24%. With BP = 80, PSP at R30 was 46%. Extent of recovery was inversely affected by the duration of elevated pressure. Tissue ATP was reduced from 18.5 to 3.7 and glycogen from 164 to 28 mumol/g in the BP = 120 group. CF and myocardial O2 consumption were reduced to 50% at R30; there was a threefold increase in wall stiffness. These data suggest that mechanical stress of DYSK contributes significantly to metabolic and functional deterioration of ischemic myocardium.

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Oxidative metabolism in reperfused neonatal myocardium has not been characterized. A blood-perfused isovolumic heart preparation was used to quantify metabolic and mechanical responses of the neonatal left ventricle to global normothermic ischemia and reperfusion. Hearts from piglets aged 2-7 days were subjected to either 2 hrs of total ischemia at 37 degrees C followed by 1 hr of reperfusion or 3 hrs of perfusion alone; glucose and palmitate oxidation were measured in separate experiments by incorporation of the appropriate [14C]-labeled substrate into the perfusate. In the pre-ischemic period, glucose, palmitate, and lactate contributed 10%, 41%, and 36%, respectively, to oxidative metabolism. After 2 hrs of total normothermic ischemia, oxidation of exogenous glucose was 165% and 229% of control values at 30 and 60 minutes of reperfusion, respectively; palmitate oxidation was 110% and 143% of control values at these times. Despite increased glucose oxidation, palmitate oxidation accounted for 69% of myocardial oxygen consumption after 1 hr of reperfusion, with glucose responsible for 25%. Lactate use was minimal during reperfusion. Reperfusion was accompanied by rapid and parallel recovery of oxygen utilization, mechanical function, and high-energy phosphates. The neonatal piglet heart demonstrates significant metabolic and mechanical tolerance to prolonged ischemia. Although glucose utilization increased markedly, palmitate was the primary substrate for energy production in the post-ischemic neonatal heart.

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We have recently shown that low-flow (10%) ischemia in the isolated piglet heart causes an abrupt fall in mechanical function and metabolic activity (acute hibernation), with nearly complete preservation of high-energy phosphates and glycogen after 2 hours of ischemia. We attempted to determine if norepinephrine, as occurs in vivo, would modify the hibernation process. Piglet hearts were perfused at 37 degrees C with red blood cell-enhanced Krebs-Henseleit solution. Performance of the left ventricle was assessed isovolumetrically. With control coronary flow, norepinephrine (40 ng/ml) caused a approximately 50% increase in pressure-rate product and the rate of change of pressure. When coronary flow was reduced to 10%, these measures fell to levels identical to those of ischemic hearts not exposed to norepinephrine. Changes in myocardial O2 metabolism paralleled mechanical function. Lactate release was quantitatively similar in both groups. However, myocardial adenosine triphosphate was reduced from 29 +/- 1 to 13 +/- 2 mumol/gm and glycogen from 300 +/- 46 to 77 +/- 15 mumol/gm by the presence of norepinephrine. Left ventricular compliance was reduced to 51 +/- 5%, compared with 87 +/- 8% in the group without norepinephrine (p less than 0.001). In the norepinephrine group, correlation between left ventricular stiffness and adenosine triphosphate was poor (r = -0.32). Thus hibernating myocardium does not manifest progressive deterioration in the presence of high concentrations of norepinephrine. Diastolic function is less well preserved, however.

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BACKGROUND: Recovery from prolonged low-flow ischemia was studied in isolated, isovolumically beating neonatal piglet hearts (n = 11) and compared with controls (n = 5). METHODS AND RESULTS: Hearts were perfused with red blood cell-enhanced Krebs-Henseleit buffer with physiological oxygen-carrying capacity. Left ventricular mechanical function was assessed with a fluid-filled balloon. Measurements of peak systolic pressure, pressure-rate product (PRP), and +dP/dtmax were obtained at various filling pressures. Myocardial oxygen delivery and metabolism (MVO2) and lactate uptake were measured at 30-minute intervals. Control data were obtained with coronary flow (CF) set at 2 ml.min-1.g-1. CF was then reduced to 0.2 ml.min-1.g-1 for 2 hours. Thereafter, reperfusion was instituted at control levels. Hearts not subjected to ischemia were studied at identical time intervals. In these, function remained at greater than 80% after more than 3.5 hours of study. Reduction of CF to 10% was accompanied by an abrupt diminution in function (pressure-rate product) and MVO2 to 20% of control and by lactate release. These measures remained constant for the full 2 hours of ischemia. Incremental return of CF caused a lockstep increase in mechanical function and metabolism. At 30 minutes of reperfusion, PRP was 78% of time-matched controls (p = 0.05), and dP/dtmax did not differ. Increasing calcium to 5 mmol/l returned PRP (and dP/dtmax) to preischemia levels. Myocardial ATP and creatine phosphate concentrations were identical in both groups, although glycogen was lower in the ischemic hearts. CONCLUSIONS: Acute hibernation is associated with protection of the in vitro heart from prolonged normothermic ischemia. Systolic function was only modestly lower, and velocity (dP/dtmax) did not differ from control hearts. The minimal "stunning" was fully reversible with calcium.

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It has been suggested that cardiac injury by catecholamines may be the result of coronary constriction leading to ischemic damage. Allopurinol (ALLO) has been shown to reduce the extent of myocardial necrosis in various systems. Hence the possibility that ALLO might limit norepinephrine (NE) injury was tested. Rabbit hearts were infused with NE (3 micrograms/min/kg) for 90 minutes, with or without ALLO (50 micrograms/min/kg). Control specimens infused with saline solution plus ALLO were also prepared. Hearts were excised 48 hours later and studied as isovolumic isolated heart preparations. Peak systolic pressure, coronary flow, and myocardial oxygen consumption were significantly reduced in the hearts infused with NE but not in the NE + ALLO hearts. Myocardial adenosine triphosphate and glycogen concentrations were 29% and 26% lower in the NE hearts compared with control hearts. These reductions were absent in the NE + ALLO group. Moreover, rates of creatine phosphokinase and lactic dehydrogenase release were sharply elevated in the NE hearts but not in those also given ALLO. These findings are consistent with the changes observed histologically. The amount of myocardial damage was less in the ALLO + NE group compared with the NE group (p less than 0.02). This appears to be the first report to demonstrate that ALLO reduces myocyte damage by NE. Possible mechanisms include decreased free radical production, scavenging of free radicals, and preservation of the adenine nucleotide pool. Because xanthine oxidase activity is absent in the rabbit, the latter two mechanisms are more likely explanations for the findings.

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The effects of reduced dietary fat intake on plasma lipid levels were examined in diabetic rats. One week after induction of diabetes (D) with streptozotocin (65 mg/kg, iv), the animals were fed food pellets consisting of 1.5% (D1.5), 2.5% (D2.5) or 5% (D5) fat for two weeks. Irrespective of the diets, both food and water consumed by untreated diabetic rats were 2- to 5-fold greater respectively compared to normal. Plasma glucose concentrations were also similarly increased. Plasma and skeletal muscle lipid levels were significantly greater than controls in D2.5 and D5, but not in the D1.5 group. Plasma and muscle lipid concentrations correlated directly with fat consumption. In D5 rats receiving insulin treatment, plasma glucose and lipid concentrations were comparable to control values. These findings indicate that the degree of hyperlipidemia in chronically diabetic rats is directly related to dietary fat intake. They also demonstrate that dietary interventions can modulate some of the metabolic abnormalities in diabetes.

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Catecholamines given in high concentrations produce myocardial damage in several mammalian species. The histological changes are similar to those found in patients given large amounts of pressor agents and in those who develop pheochromocytomas. They include myofiber necrosis, myofibrillar degeneration, and mononuclear leukocytic infiltration. Cardiac function is significantly impaired. Endogenous release of catecholamines can also induce myocardial injury in rabbits infused with tyramine. Anatomic and functional abnormalities described in various models of catecholamine cardiomyopathy are summarized. The several major theories regarding pathogenesis are reviewed. Recent data suggesting that O2-derived free radical generation is involved are discussed.

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We explored the effects of sustained low-flow ischemia on function and metabolism in isolated neonatal hearts. The hearts were extracted from 21 piglets (1-12 days old) and set up as modified Langendorff preparations beating isometrically. They were perfused with red blood cell-enhanced buffer at controlled rates of coronary flow. Mechanical measurements, O2 usage, and substrate oxidation were determined simultaneously at 30-minute intervals for 2 hours. In control hearts, coronary flow was maintained at 1.8 ml/min/g. There was no significant change in mechanical function, diastolic compliance, or O2 or substrate metabolism after 2 hours. In the ischemia group, coronary flow was reduced to 0.2 ml/min/g and sustained for 2 hours. With the onset of ischemia, mechanical function promptly fell to 20% of control. Although O2 delivery was reduced to 11%, O2 extraction doubled so that myocardial O2 consumption was 22% of control, matching mechanical function. Glucose oxidation fell from 37 to 12 nmol/min/g, and lactate release appeared. These measures and ventricular compliance remained constant for the full 2 hours. Concentrations of glycogen and creatine phosphate did not differ from the control group; ATP was 76% of controls. These studies indicate that when myocardial O2 supply is limited, mechanical function rapidly diminishes, largely preserving critical energy stores and preventing irreversible myocellular injury. Although the signal remains to be determined, the strategy is similar to that employed by hibernating species to survive extended periods of O2 deprivation.

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High concentrations of adrenergic agonists are known to cause significant structural damage to the heart, accompanied by depressed cardiac performance. These studies were undertaken to further elucidate mechanisms that contribute to this process. Rabbits were infused with either norepinephrine (NE, 3 micrograms.min-1.kg-1 iv) for 90 min or with an equivalent volume of normal saline (controls). The heart was immediately extracted and studied as an isolated working heart preparation perfused with erythrocyte-enhanced buffer. Stroke work, coronary flow, and O2 metabolism were determined, and substrate oxidation was measured by [14C]glucose or palmitate. Stroke work performed by hearts exposed to NE was only 31% of controls (2.6 +/- 0.4 vs. 8.4 +/- 0.9 g.cm-1.g-1). This was matched by reductions in coronary flow and O2 metabolism. Glucose oxidation was reduced from 54.6 +/- 3.9 to 16.0 +/- 5.3 nmol.min-1.g-1, and palmitate oxidation from 49.8 +/- 5.3 to 21.0 +/- 4.1 nmol.min-1.g-1 in the NE group. However, ATP, creatine phosphate, glycogen, and triacylglycerol concentrations were identical with the control group. O2 delivery per unit substrate oxidation was not lower in the NE group, and O2 extraction did not differ significantly. These findings indicate that the markedly lower contractile performance of the hearts exposed to NE cannot be attributed to a deficiency of metabolic capacity or limitation of O2 or substrate availability because of vasospasm. In view of the brief time (90 min), it is unlikely that leukocyte accumulation was a major factor. The observations are consistent with NE-derived oxidant injury, possibly causing disordered excitation-contraction coupling.

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Studies in which subcellular systems were used suggest that neonatal myocardium has a sharply limited capacity to metabolize fatty acids. The relationship of these findings to the intact heart was tested on piglets, 8 h to 12 days of age. Left ventricular (LV) performance, O2 consumption (MVO2), and fatty acid (FA) uptake and oxidation were measured. Hearts were perfused at 70 cmH2O pressure with buffer containing 2% bovine serum albumin, insulin (100 microU/ml), 5 mM glucose, and 1.5 mM lactate. 14C-labeled palmitate was added (net FA, 0.5 mM). Washed erythrocytes were used to assure adequate O2 delivery. LV end-diastolic pressure (EDP) was controlled with a fluid-filled balloon. FA oxidation was estimated by measuring 14CO2 production. Hearts less than 24 h (group I, n = 6), those approximately 3 days (group II, n = 5), and those 6-12 days of age (group III, n = 10) were compared. Measurements at a low EDP (2-4 cmH2O) and at a higher EDP (7-9 cmH2O) were compared. At the low EDP, rates of FA oxidation for groups I-III averaged 30.0 +/- 3.0, 31.4 +/- 2.9, and 50.2 +/- 2.6 nmol.min-1.g-1, respectively. These values increased to 43.8 +/- 3.7, 42.6 +/- 2.5, and 63.8 +/- 4.0 nmol.min-1.g-1, respectively, at the higher EDP level (P less than 0.01 for each group). Thus within a few hours of birth, pig hearts are able to oxidize long-chain FA, and the rate of oxidation is linked to mechanical function. However, both the oxidation rate and the percentage of MVO2 accounted for by FA oxidation are greater in older hearts.

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Cardiac mechanical function and coronary flow (CF) were measured in isovolumically beating hearts from neonatal piglets 0.5 to 12 days of age. The hearts were perfused retrogradely at 70 cm H2O with a recirculating modified Krebs-Henseleit solution containing washed adult pig red cells (hematocrit, 25%). They were electrically paced (180 beats/min), and left ventricular developed pressure (delta P), maximum rate of rise of pressure (dP/dt), CF, and myocardial oxygen consumption were measured. These parameters were found to remain stable for at least 60 minutes. In one group, a single dose of amrinone was added to the perfusate to yield a concentration of 50 micrograms/ml. Within 5 minutes delta P decreased from 104.0 +/- 7.1 to 65.3 +/- 8.6 mm Hg (p less than 0.001), and dP/dt fell from 1,160 +/- 96 to 658 +/- 78 mm Hg/sec (p less than 0.001). In a second group, successive doses of amrinone were added to yield concentrations ranging from 5 to 50 micrograms/ml. There was a progressive decrease in delta P and dP/dt to 66.5 +/- 4.2% and 57.6 +/- 4.8% of initial values, respectively. CF increased progressively from 3.2 +/- 0.2 to 6.8 +/- 0.5 ml/min/g. In 3 experiments, amrinone was washed out after achieving the maximum concentration. Depressed mechanical function reversed and delta P and dP/dt returned to control values in each heart. Additionally, CF decreased from 7.6 +/- 0.3 to 5.0 +/- 0.2 ml/min/g. It is concluded that amrinone has concentration-dependent negative inotropic actions in the neonatal piglet heart. Hence, the drug may not be useful in treating heart failure in the human neonate.

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The performance of isolated working rabbit hearts perfused with Krebs-Henseleit (KH) buffer was compared with those in which the buffer was supplemented with washed human red blood cells (KH + RBC) at a hematocrit of 15 percent. When perfused with KH alone at 70 cm H2O afterload and paced at 240 beats/minute, coronary flow was more than double, whereas aortic flow was 40-60 percent of that in hearts perfused with KH + RBC, regardless of left atrial filling pressures (LAFP). Peak systolic pressure reached a plateau at 120 mm Hg in KH + RBC, but at 95 mm Hg in the KH group. Stroke work, however, was similar in the two groups. Despite the high coronary flow, oxygen uptake by hearts perfused with KH was substantially less and did not respond to increases in LAFP as in those perfused with KH + RBC. There was a 20 percent drop in ATP and glycogen content after 90 minutes' perfusion. In contrast, isolated hearts perfused with RBC-enriched buffer remained stable for at least 150 minutes. Irrespective of the perfusate, triacylglycerol content of the muscle remained at similar levels throughout the course of study. Increasing RBC in the perfusate from 15 percent to 25 percent had no additional effect on cardiac performance or oxygen consumption. Our findings demonstrate that in the isolated working rabbit heart inclusion of RBC in the perfusate improves mechanical and metabolic stability by providing an adequate oxygen supply.

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We have previously found that the coronary dilator response to infused adenosine is attenuated in diabetic (alloxan) lambs. Adenosine responsiveness is restored by administration of insulin. The present studies tested the hypothesis that coronary flow changes with hypoxia, if mediated by adenosine, would also be modified. Studies were carried out in eight control and six diabetic lambs. The animals were anesthetized and prepared to maintain constant arterial pressure (reservoir), cardiac output (pump), and heart rate (paced). Atropine and practolol were given. Forced inspired oxygen was reduced in steps. Arterial and coronary sinus blood samples were analyzed for Po2, oxygen content, pH, hematocrit, and glucose. Myocardial oxygen delivery and uptake (MVO2) were calculated. Coronary flow increased identically in both control and diabetic animals as PaO2 was reduced below 60 Torr. Oxygen delivery and MVO2 fell equally in both groups. Acidosis potentiated hypoxic coronary flow changes. Alpha blockade (phentolamine) was without effect in control lambs but caused coronary flow to increase in diabetic lambs. Changes in coronary flow with hypoxia were unaffected, however. Insulin caused no change in the coronary dilator response to hypoxia in either control or diabetic lambs. It is concluded that coronary alpha tone is increased in diabetes but does not modify changes in coronary flow during hypoxia. As coronary flow responses to hypoxia were unaltered in diabetic lambs, and unaffected by insulin, adenosine may not be the primary mediator of coronary vascular dilatation. Potentiation of adenosine by tissue acidosis is apparently insufficient to explain these findings. The mechanism for coronary dilatation during hypoxia is unclear but may involve direct effects of reduced oxygenation of coronary vascular smooth muscle.

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