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Objective: This study tested the hypothesis that endogenous adenosine depresses anaerobic glycolysis in preischaemic and moderately ischaemic myocardium., Methods: Isolated, working guinea-pig hearts, perfused with glucose-fortified Krebs-Henseleit buffer, were subjected to 15 min mild hypoperfusion (coronary flow 60% of baseline) followed by 10 min ischaemia (coronary flow 20% of baseline). Adenosine A1 receptors were blocked with 8-p-sulfophenyl theophylline (8-SPT; 20 microM). Glucose oxidation and lactate production from exogenous glucose were assessed from 14CO2 and [14C]lactate formation, respectively, from [U-14C]glucose. Energy metabolites, glycolytic intermediates and glycogen were measured in extracts of stop-frozen preischaemic, mildly hypoperfused and ischaemic myocardium., Results: Adenosine receptor blockade did not affect left ventricular function assessed from heart rate x pressure product and pressure x volume work although coronary flow was slightly reduced. Adenosine receptor blockade increased glucose uptake (P < 0.05) by 100% during preischaemia and by 74% during mild hypoperfusion, and increased lactate production from exogenous glucose (P < 0.05) by 89% during preischaemia and fourfold during mild hypoperfusion, but did not stimulate glucose oxidation under any condition. Glycogen degradation was not increased by adenosine receptor blockade during ischaemia. Crossover plots of glycolytic intermediates revealed that phosphofructokinase was activated by adenosine receptor blockade at all three levels of perfusion., Conclusion: Endogenous adenosine attenuates anaerobic glycolysis in normally perfused, hypoperfused and ischaemic myocardium by blunting phosphofructokinase activity; this effect is mediated by adenosine A1 receptors.

This study was conducted to determine if mechanisms that reduce right coronary (RC) blood flow (RCBF) and right ventricular (RV) oxygen consumption (MVO2) during moderate RC hypotension preserve RV high-energy phosphates. RC arteries of anesthetized dogs were cannulated and perfused with arterial blood supplied by a pressurized extracorporeal circuit. RC perfusion pressure (RCPP) was either kept constant at 100 mmHg or reduced to 60 or 30 mmHg for 20 min followed by a freeze-clamp biopsy of RV. Left ventricular (LV) biopsy was also performed to compare energy metabolism between RV and LV.RCBF and MVO2 significantly decreased when RCPP was reduced to 60 mmHg, but RV segment shortening (%SS) was unchanged; ATP, creating phosphate (CrP) and phosphorylation state of CrP ([CrP]/[Cr][Pi]) did not differ from control values. RV %SS, CrP, and phosphorylation state fell markedly at 30 mmHg RCPP. At 100 mmHg RCPP, CrP phosphorylation state in RV was only 35% of that in LV. These results indicate that RV increases its energetic efficiency without significant changes in high-energy phosphates or CrP phosphorylation state during moderate RC hypotension. Furthermore, the RV myocardium maintains a much lower energy level than LV myocardium, commensurate with its lower energy requirements.

Objective: We have previously demonstrated that myocardium is capable of down-regulating its O2 requirements and thus avoiding ischaemia when O2 supply is limited. The present study tested the hypothesis that endogenous adenosine produced this protective response when O2 supply was decreased by moderate coronary hypoperfusion or moderate coronary hypoxaemia., Methods: In anaesthetised dogs, hearts were exposed by left thoracotomy and instrumented for measuring intraventricular pressure and regional myocardial segment length. The left anterior descending coronary artery was isolated, cannulated, and extracorporeally perfused. Coronary O2 supply was moderately reduced by lowering coronary perfusion pressure from 100 to 60 mmHg or by lowering coronary arterial O2 content by 50%. Hearts were treated with intracoronary infusions of adenosine, adenosine deaminase to degrade endogenous adenosine or with erythro-9-(2-hydroxy-3-nonyl)-adenine x HCl (EHNA) to inhibit adenosine degradation by endogenous adenosine deaminase, during beta-adrenergic stimulation with isoprenaline. Cardiac power in the left anterior descending perfusion territory was indexed by the product of heart rate x left ventricular peak systolic pressure x percent systolic segment shortening. O2 utilisation efficiency was taken as the ratio of power index/myocardial O2 consumption., Results: Prior to a reduction in O2 supply, isoprenaline did not alter O2 utilisation efficiency. Intracoronary adenosine increased O2 utilisation efficiency during isoprenaline stimulation by 23% (P < 0.05). EHNA slightly increased O2 utilisation efficiency during isoprenaline stimulation (10%; P < 0.05); adenosine deaminase was without effect. When coronary perfusion pressure was decreased, adenosine deaminase sharply lowered cardiac power and O2 utilisation efficiency during isoprenaline stimulation, whereas EHNA augmented isoprenaline-enhanced power and increased efficiency. During hypoxaemia, adenosine deaminase lowered regional power but not efficiency during isoprenaline infusion; EHNA did not affect power but lowered O2 consumption and increased efficiency. Myocardial lactate extraction and contractile function during isoprenaline stimulation were not attenuated by reduced O2 supply, indicating that myocardial ischaemia did not occur under these conditions., Conclusion: Endogenous adenosine increases myocardial O2 utilisation efficiency during beta-adrenergic stimulation, and thus helps avert ischaemia when myocardial O2 supply is reduced.

Objective: The aim was to test the role of interstitial adenosine in protective downregulation of myocardial energy demand during myocardial hibernation., Methods: Isolated working guinea pig hearts, perfused with glucose fortified Krebs-Henseleit, were subjected to 60 min global low flow ischaemia followed by 30 min reperfusion. Left ventricular performance was assessed from heart rate-developed pressure product and pressure-volume work. Cytosolic energy level was indexed by creatine phosphate and ATP phosphorylation potentials measured in snap frozen myocardium. Lactate and purine nucleosides (adenosine, inosine) were measured in venous effluent., Results: When coronary flow was lowered by 80% for 60 min, heart rate-pressure product and pressure-volume work fell 87% and 75%, respectively, and stabilised at these low levels, but fully recovered when flow was restored. Myocardial ATP phosphorylation potential fell by 67% during the first 10 min of ischaemia, but subsequently recovered to preischaemic levels despite continuing ischaemia, indicating down-regulation of myocardial energy demand. Lactate release increased about 10-fold during ischaemia and remained increased until reperfusion. Purine nucleoside release varied reciprocally with phosphorylation potential, peaking at 10 min of ischaemia, then gradually returning to the preischaemic level during the subsequent 50 min of ischaemia. The ecto 5'-nucleotidase inhibitor alpha,beta-methylene adenosine 5'-diphosphonate (50 microM) decreased ischaemic purine nucleoside release by 41%, but did not attenuate postischaemic contractile recovery. The unspecific adenosine receptor antagonist 8-p-sulphophenyl theophylline (8-SPT, 20 microM) doubled ischaemic lactate release and lowered coronary venous purine nucleoside release by 21%. 8-SPT increased phosphorylation potential at 10 min ischaemia relative to untreated hearts, but blunted the subsequent rebound of phosphorylation potential. 8-SPT treatment during ischaemia resulted in a significantly higher cytosolic phosphorylation potential at 30 min of reperfusion, but did not affect postischaemic contractile function., Conclusions: We conclude that activation of adenosine receptors results in recovery of cytosolic energy level of moderately ischaemic working myocardium, but this energetic recovery is not solely responsible for postischaemic contractile recovery.

Simultaneous in vivo infusions of two different colored 10 microns microsphere suspensions into the left anterior descending (LAD; red spheres) and left circumflex (LCx; blue spheres) coronary arteries of nine anesthetized dogs identified a specific region of canine myocardium perfused by both arterial branches. Subsequently, the LAD was ligated and a third (green) set of micropheres was infused into the patent LCx artery. Analysis of 40 microns serial sections of tissue revealed interface zones with capillaries perfused by both arteries. The first zone, defined as the Interface Transistion Zone (ITZ) was formed by an intermingling of microvessels supplied by the parent arteries of the adjacent perfusion territories; it separated tissue containing only one or the other colored microspheres. Another zone, defined as the Boundary Watershed Zone was located within the ITZ and had capillaries containing both red and blue microspheres. The width of ITZ was 53377 +/- 817 microns (mean +/- SD), and the width of the BWZ was 3358 +/- 618 microns. Green microspheres, infused into the LCx following coronary occlusion were also found in the ITZ and BWZ. Furthermore, capillaries perfused exclusively by the LAD before occlusion (tissue with red but not blue microspheres) adjacent to the perfusion interface contained green microspheres as well as red/green aggregates, indicating lateral extension of the LCx perfusion territory. This extension of the LCx territory was quantitated by comparing the location at which densities of green microspheres or green/red aggregates decreased abruptly compared to the location of the original ITZ and BWZ boundaries, respectively. Results showed that LAD occlusion caused a 24% expansion of the ITZ and a 48% expansion of the BWZ. In addition, all expansions were significantly greater in subepicardial compared to subendocardial regions (p < 0.001). These results clearly demonstrate the capability of microvascular anastomoses in providing blood flow to the periphery of an ischemic region. Furthermore, the perfusion interface is labile and might be amenable to manipulation.

Objective: The mechanism by which changes in coronary perfusion alter myocardial oxygen consumption (MVO2; Gregg phenomenon) is controversial. This study examined the effect of coronary perfusion on myocardial contractile force and systolic ventricular stiffness in the intact, ejecting heart., Methods: During selective perfusion of the left anterior descending coronary artery, coronary blood flow was changed with or without concurrent changes in coronary perfusion pressure in 19 alpha chloralose anaesthetised dogs. Regional myocardial segment length (end diastolic length; end systolic length) and developed force were measured with piezoelectric crystals and with a miniature force transducer, respectively. MVO2 was calculated from coronary flow and arteriovenous O2 difference. The slope of the force-length curve during ejection period (delta F/delta SL) was used as an index of systolic myocardial stiffness., Results: When coronary perfusion pressure was varied from 60 to 180 mm Hg (protocol 1, n = 11), maximum developed force (Fmax), delta F/delta SL, and MVO2 increased with perfusion pressure while end diastolic length, segmental shortening, and other haemodynamic variables stayed constant. When coronary blood flow was increased at constant perfusion pressure by infusion of either a low dose or a high dose adenosine (protocol 2, n = 8), Fmax, delta F/delta SL, and MVO2 increased while end diastolic length, segmental shortening, and other haemodynamic variables stayed constant. MVO2 and delta F/delta SL increased more steeply with flow in protocol 1., Conclusions: (1) Increased coronary blood flow enhances myocardial contractile force, systolic ventricular stiffness, and MVO2 in the intact, ejecting heart. (2) Coronary blood flow induced changes in myocardial contractile force and systolic ventricular stiffness, but not end diastolic length, are probably responsible for coronary blood flow related changes in MVO2.

Pressure-flow autoregulation minimizes changes in coronary blood flow (CBF) when coronary perfusion pressure (CPP) is altered. This investigation determined if autoregulation also minimizes CPP-induced changes in coronary vascular volume (CVV) and CVV-dependent changes in myocardial oxygen consumption (MVO2). In 11 anesthetized dogs, the left anterior descending coronary artery was cannulated, and responses to 20-mmHg changes in CPP were examined over a range of CPP from 60 to 180 mmHg. Changes in CPP had no significant effect on systemic hemodynamics or on left ventricular end-diastolic segment length, end-systolic segment length, or percent segment shortening. In hearts with effective pressure-flow autoregulation [closed-loop gain (GC) > 0.4], CVV increased 0.06%/mmHg change in CPP. For the same hearts, MVO2 increased 0.04%/mmHg change in CPP. In hearts with ineffective autoregulation (GC < 0.4), CVV increased 0.97%/mmHg (P < 0.001 vs. autoregulating hearts), and MVO2 increased 0.41%/mmHg (P < 0.001 vs. autoregulating hearts). MVO2 and CVV were correlated (r = 0.69, P < 0.0001) independently of autoregulatory capability, but only when autoregulation was poor and capacitance was elevated did CPP significantly affect MVO2. We conclude that pressure-flow autoregulation protects myocardium from CPP-induced changes in CVV, which in turn produces changes in oxygen consumption.

Regional blood flow to the cheek and tongue of anesthetized dogs was measured before and after application of six different doses of snuff (3.12 to 100 mg/kg body weight) to the right cheek. Dose-independent vasodilation was observed at the site of application, whereas dose-dependent vasoconstriction was observed contralaterally. Aortic, central venous, and ventricular pressures were significantly increased (p < 0.05) at the higher doses. Plasma nicotine concentrations increased stepwise with dose.

Objective: The aim was to examine whether an absolute reduction in energy supply is required for preconditioning against myocardial infarction, and whether an episode of increased adrenergic activity with or without supply-demand imbalance is capable of triggering cardioprotection., Methods: 41 anaesthetised dogs were subjected to 60 min left circumflex artery occlusion followed by 5 h reperfusion (control group, n = 8). The left stellate cardiac nerve was stimulated for 5 min starting 10 min before coronary occlusion in the stimulation group (STIM group, n = 8). The left circumflex artery flow increase that normally accompanies adrenergic stimulation was prevented by a pneumatic occluder in another group (STIM-R group, n = 8). Infarct size and area at risk were determined by triphenyl tetrazolium chloride staining and Evans blue dye, respectively. Regional myocardial blood flow during ischaemia and during stimulation (STIM-R group) was measured with radioactive microspheres., Results: In the STIM group, adrenergic stimulation increased the coronary blood flow by approximately twofold from baseline. In the STIM-R group, transmural myocardial blood flow in the flow restricted left circumflex artery region was 64% of the flow to the non-flow-restricted left anterior descending coronary artery region. Haemodynamic variables were not different among the experimental groups except during adrenergic stimulation. Collateral blood flow and area at risk were comparable among the three groups. Infarct size as a percentage of area at risk (%IS/AAR) was significantly smaller in the STIM-R group [7.6(3.2)%] than in the control group [27.9(7.3)%], whereas %IS/AAR in the STIM group [21.7(4.1)%] was not. Furthermore, the regression line between collateral blood flow and %IS/AAR was significantly shifted downward in the STIM-R group, but not in the STIM group., Conclusions: (1) Transient energy supply-demand imbalance triggers infarct size limitation; an absolute reduction in energy supply is not required for preconditioning. (2) Increased adrenergic activity without supply-demand imbalance seems unable to trigger appreciable cardioprotection.

Objective: Adenosine is a well known vasodilator believed to contribute to metabolic adjustments of the coronary circulation. The purpose of this study was to assess changes in interstitial fluid adenosine, adenosine metabolites, and lactate during prolonged regional, non-ischaemic myocardial hypoxia., Methods: To induce regional hypoxia, the left anterior descending coronary artery of anaesthetised dogs (n = 9) was perfused at constant pressure (100 mm Hg) with deoxygenated blood (PO2 approximately 2.6 kPa) for 60 min via an extracorporeal shunt. Cardiac interstitial fluid was sampled by cardiac microdialysis, using dialysate metabolite levels as indices of interstitial fluid concentrations., Results: During hypoxia, coronary blood flow increased 3.9-fold, while myocardial oxygen consumption was maintained relatively constant. There were no changes in global cardiac function, systemic arterial pressure, or heart rate during regional hypoxia, indicating that the hypoxic stimulus did not augment sympathetic nervous system activity. Dialysate adenosine was not increased at any point of the hypoxic period, but was decreased by 25 min hypoxia. Dialysate levels of inosine, hypoxanthine, and xanthine were increased transiently during the first 10 min of hypoxia while there was a sustained increase in dialysate lactate. In the presence of erythro-9-(2-hydroxy-3-nonyl) adenine, an adenosine deaminase inhibitor, adenosine was the predominant purine metabolite and increased transiently during hypoxia., Conclusions: Flux through the adenosine production and degradation pathways is transiently increased during hypoxia. However, the lack of an increase in interstitial fluid adenosine does not support a role for adenosine in the sustained hyperaemic response to regional myocardial hypoxia.

Objective: The aim was to evaluate the hypothesis that the oxygen demand of stimulated myocardium is downregulated and ischaemia avoided when oxygen supply is limited., Methods: Isoprenaline stimulation during reduced coronary perfusion pressure or moderate coronary hypoxaemia was studied in relation to myocardial oxygen demand, power, and oxygen utilisation efficiency (O2Effic) in 19 anaesthetised open chest dogs. The left anterior descending coronary artery was perfused with normoxic blood at 100 or 60 mm Hg or with moderately hypoxic blood [CaO2 = 9.8(SEM 0.2) ml.dl-1] at 100 mm Hg. Myocardial oxygen demand was estimated from oxygen consumption (MVO2), and power index was computed from heart rate, left ventricular pressure, and segment shortening. O2Effic was calculated from power index divided by MVO2. Lactate extraction and contractile function were used as indices of myocardial ischaemia., Results: Isoprenaline under control conditions increased coronary blood flow, MVO2, and power index, but did not alter lactate extraction. Reducing coronary perfusion pressure to 60 mm Hg decreased oxygen delivery by 31.6(5.7)% (p < 0.05). MVO2 fell by 26.6(8.6)% (p < 0.05), but power index and lactate extraction were not reduced. At reduced coronary perfusion pressure, isoprenaline-induced elevation of MVO2 decreased from 26.0(1.5) to 15.7(2.6) ml.min-1 x 100 g-1 (p < 0.05), but the isoprenaline-induced rise in power index was not significantly lessened, nor was lactate extraction altered. O2Effic was increased by reduced coronary perfusion pressure and by isoprenaline during reduced coronary perfusion pressure. Hypoxaemia increased coronary blood flow but did not alter oxygen delivery, MVO2 or power index. Isoprenaline-induced elevation of MVO2 decreased from 25.2(1.7) to 19.1(0.5) ml.min-1 x 100 g-1 (p < 0.05), and power index decreased by 33(9.1)% (p < 0.05). O2Effic was not altered by hypoxaemia or by isoprenaline during hypoxaemia., Conclusions: Oxygen demand of isoprenaline stimulated myocardium is downregulated and ischaemia is avoided when oxygen is limited. Downregulation of oxygen demand is achieved by increasing oxygen utilisation efficiency in the presence of reduced coronary perfusion pressure and by decreasing power in the presence of hypoxaemia.

Objective: The aim was to test whether a brief period of non-ischaemic hypoxia can attenuate cardiac contractile dysfunction, ie, "stunning", due to repeated coronary artery occlusions., Methods: 20 anaesthetised dogs underwent six 5 min occlusions of the left anterior descending coronary artery with intervening 10 min reperfusions, prior to 90 min reperfusion. In the treated group (n = 9), hearts were preconditioned by 5 min extracorporeal left anterior perfusion with severely hypoxic blood [O2 content 14(SEM 3) ml.litre-1] followed by 10 min reperfusion, prior to the repeated coronary occlusions. Controls (n = 9) were sham preconditioned by 5 min extracorporeal perfusion with normoxic blood [O2 content 179(7) ml.litre-1]. Regional contractile function was assessed by systolic segmental shortening measured by microsonometry. Regional myocardial oxygen consumption, an index of ATP utilisation, was measured in these protocols to evaluate the hypothesis that reduction of myocardial energy demand could be a mechanism of hypoxic preconditioning., Results: Hypoxic preconditioning slightly decreased systolic segmental shortening [64.1(9.5)% of baseline at 10 min reoxygenation v 85.5(6.5)% for control, p < 0.05]. In contrast, 5 min coronary occlusion in controls produced more marked cardiodepression [segmental shortening 33.5(10.1)% of baseline at 10 min reperfusion; p < 0.05 v 10 min reoxygenation in the hypoxic-preconditioned group]. Systolic shortening was preserved in hypoxic-preconditioned hearts as compared to controls during each 10 min reperfusion period. Furthermore, functional recovery at 90 min reperfusion after the last occlusion in hypoxic preconditioned hearts was more complete than in control hearts, at 40.8(13.1)% v -16.1(14.4)%; p < 0.05. However, myocardial oxygen consumption was not suppressed by hypoxic preconditioning., Conclusions: Five minutes of hypoxic preconditioning attenuated contractile dysfunction due to repeated brief ischaemia/reperfusion stress. This protective effect was not due to the suppression of myocardial energy demand.

While the presence of microvascular intercommunication within an individual myocardial arterial bed is well documented, there is a paucity of data to support the existence of anastomoses emanating from independent arterial beds. Simultaneous in-vivo infusion of two different colored microsphere suspensions into the left anterior descending (LAD) and left circumflex (LCx) coronary arteries identified a specific interface region of canine myocardium that was perfused by both arterial branches. Subsequent microscopic/morphometric analysis of 40 microns serial sections in eight hearts revealed clustering of microspheres in their respective perfusion territories (red microspheres in the LAD region away from the interface, blue microspheres in the LCx field away from the interface), along with a mutually perfused borderzone. In each tissue section, two regions within this zone were identified and their maximum widths measured. One region was defined as the Interface Transition Zone (ITZ) (mean width = 5251 +/- 770 microns; mean +/- SD). This region was formed by an intermingling of microvessels supplied by the parent arteries of the adjacent perfusion territories; it separated tissue containing only one or the other colored microspheres. The second region was defined as the Boundary Watershed Zone (BWZ) (mean zone width = 3151 +/- 611 microns; mean +/- SD). This region was formed by capillaries containing sphere aggregates of both colors; it was located exclusively within the ITZ. In addition, the ITZ and BWZ were significantly wider in subepicardial than in subendocardial regions (p less than 0.001).

Objective: The aim was to test whether a brief period of non-ischaemic hypoxia can precondition myocardium., Methods: 60 anaesthetised adult mongrel dogs of either sex underwent 60 min occlusion of the left anterior descending coronary artery, followed by 5 h reperfusion. In treated groups, hearts were either preconditioned with 5 min coronary perfusion with hypoxic blood [O2 content 9.2(SEM 0.6) ml.litre-1] or 5 min occlusion followed by a 10 min reperfusion period prior to 60 min occlusion. The effect of these treatments on myocardial infarct size and regional contractile function was assessed., Results: Infarct size, determined by tetrazolium staining, as a percentage of anatomical area at risk was markedly decreased in hypoxia preconditioned hearts, at 7.2(1.8)% v 22.4(4.6)% in controls (p < 0.01), but did not differ from ischaemia preconditioned hearts [4.6(1.7)%; p < 0.01 v control]. Anatomical area at risk, expressed as a percentage of left ventricular mass, and collateral blood flow to the inner two thirds of the ischaemic wall did not differ among the groups. Regional contractile function was depressed following ischaemic preconditioning but not following hypoxic preconditioning. During reperfusion following 60 min occlusion, marked paradoxical systolic lengthening was evident in ischaemia preconditioned and control hearts but not in hypoxia preconditioned myocardium., Conclusions: Five minutes of hypoxic and ischaemic preconditioning were equipotent in preventing infarction, whereas ischaemic preconditioning caused a greater decrement in postischaemic contractile function.

The purpose of this study was twofold: 1) to verify a report that a suspension of 8-phenyltheophylline (8-PT) completely abolished hypoxia-induced coronary vasodilation [H. M. Wei, Y. H. Kang, and G. F. Merrill. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H1043-H1048, 1989] and 2) to determine the effect of dissolved 8-PT on hypoxic hyperemia. The left anterior descending coronary artery of anesthetized dogs was cannulated and perfused at either constant flow or constant pressure. An 8-PT suspension (40 micrograms.kg-1.min-1) produced a twofold elevation of coronary perfusion pressure at constant flow, a 97% decrease in coronary flow at constant pressure, and regional akinesia in both conditions. The coronary vasculature was unresponsive to 60-s coronary occlusion, exogenous adenosine, and hypoxia after infusion of the 8-PT suspension. These findings are consistent with obstruction of the coronary microvasculature by the 8-PT suspension. An 8-PT solution (40 micrograms.kg-1.min-1) produced 95 +/- 3% (P less than 0.001, n = 6) attenuation of exogenous adenosine-induced vasodilation at constant pressure, a 28 +/- 5% (P less than 0.01, n = 6) attenuation of reactive hyperemia, and a 24 +/- 6% (P less than 0.05, n = 6) decrease in hypoxia-induced vasodilation. An 8-PT solution had no effect on systolic segment length shortening and myocardial oxygen consumption. We conclude that 8-PT, when in solution, attenuates but does not abolish the coronary vasodilatory response to hypoxia. Hence, adenosine appears to contribute to hypoxia-induced vasodilation but is not uniquely responsible for the hyperemic response.

To investigate the myocardial protective effect of adenosine (ADO), the left anterior descending artery of 10 dogs was cannulated and perfused at a pressure of 100 mmHg. Hypoxic coronary perfusion was conducted for 60 min followed by 60 min of normoxic reperfusion (group 1, control, n = 5). In group 2 (n = 5), ADO was continuously infused at a rate of 40 micrograms/kg/min for 30 min before and during 60 min of hypoxic blood perfusion and for 60 min following normoxic reperfusion. In group 1, R wave amplitude and TQ segment of the epicardial surface electrocardiogram (EPIECG) were reduced, the ST segment was elevated, and a new Q wave developed during hypoxic blood perfusion. However, at 60 min of normoxic reperfusion, the R wave amplitude recovered to approximately 60% of its control value. Also, ST segment elevation was restored to normal and the new Q wave disappeared. The TQ segment returned to normal after approximately 20 min of hypoxic perfusion. Histological analysis showed myocardial infarction in the subendocardium, but not in the subepicardium. In group 2, EPIECG findings during hypoxic blood perfusion were similar to those observed in group 1. However, the recovery of ST segment elevation during normoxic reperfusion was slower than that observed in group 1. R wave restoration did not occur in group 2. Furthermore, the new Q wave remained present throughout the normoxic reperfusion period. Transmural infarction and severe congestion were observed histologically in this group. Obvious contraction bands were not demonstrated histologically in either group. These findings suggest that ADO did not protect myocardial viability during 60 min of hypoxic blood perfusion, but instead, ADO exacerbated ischemic injury during regional hypoxic perfusion.

The role of cardiac neural stimulation in the absence of direct effects of nicotine and other circulating factors was evaluated by perfusing a region of left ventricular myocardium with blood from a reservoir during systemic nicotine infusion. In normally perfused myocardium, contractile function increased, but in reservoir-perfused myocardium, function deteriorated. To evaluate direct effects of nicotine on myocardial contractile function, nicotine was infused directly into a perfused coronary artery. An intracoronary concentration of nicotine equivalent to that caused by intravenous administration (0.69 +/- 0.08 micrograms per ml plasma) had no effect on myocardial contractile function. An intracoronary nicotine concentration of 5 micrograms/ml was required to directly increase contractile function to approximately the same extent observed during intravenous nicotine. To evaluate the role of circulating catecholamines in the myocardial contractile response to intravenous nicotine, observations were made before and after bilateral adrenalectomy. Adrenalectomy markedly attenuated the pressor response to intravenous nicotine and abolished the positive cardiac inotropic response. We conclude that the adrenal release of catecholamines is primarily responsible for increased myocardial contractile function during intravenous nicotine.

Coronary shunting of 9 +/-1 micrometer and 25 +/- 5 micrometer radiolabeled microspheres was examined in anesthetized, open-chest dogs, whose left common coronary arteries were perfused at controlled pressures. Shunting was estimated from the difference in radioactivity between perfusion line and coronary sinus blood samples during selective elevations of coronary perfusion pressure (CPP), left ventricular afterload, and inspired oxygen. A linear relationship was found between coronary shunting of 9-micrometer microspheres and CPP over the range 100-200 mmHg. According to regression analysis, percent shunt flow was 4.0% at control CPP (100 mmHg) and 10.0% at CPP of 200 mmHg. No shunting of 25-micrometer microspheres occurred at any CPP. Raising afterload did not affect shunting at control CPP but attenuated the increase in shunting at elevated CPP. Changing inspired gas from room air to 100% oxygen did not influence shunting at control or elevated CPP. Raising CPP to 150 and 200 mmHg also released 2.5% and 5.9% of pretrapped 9-micrometer microspheres, respectively. This study demonstrates that vessels permitting passage of microspheres across coronary circulation are sensitive to elevated perfusion pressure.

The effect of increased pericardial pressure on blood flow to acutely ischaemic and normal myocardium was investigated and the mechanisms responsible for this effect evaluated in eight open chest anaesthetised dogs. After coronary artery occlusion regional myocardial blood flows were estimated from the tissue content of radioactive microspheres administered systemically during control conditions, mild tamponade (pericardial pressure 8.4(1.0) mmHg), severe tamponade (pericardial pressure 13.3(1.4) mmHg), and severe tamponade (pericardial pressure 13.5(1.6) mmHg) with aortic blood pressure held constant by blood volume expansion. Mild tamponade decreased aortic blood flow by 20% and aortic pressure by 90%. Right and left atrial blood pressures were moderately increased. Blood flow to ischaemic and normal myocardium was not significantly altered. Severe tamponade decreased aortic blood flow by 50% and aortic pressure by 35%. Heart rate increased by 18%, and right and left atrial pressures were appreciably increased. Blood flow to ischaemic and normal myocardium decreased in proportion to the decrease in aortic pressure, but the transmural distribution of flow in ischaemic myocardium was not altered. During severe tamponade with constant aortic pressure, right and left atrial blood pressures were further increased, but blood flow to ischaemic and normal myocardium was similar to that observed under pre-tamponade control conditions. These results show that blood flow to acutely ischaemic myocardium during tamponade is determined primarily by aortic pressure.

To determine whether right coronary (RC) flow reserve persists at perfusion pressures below the apparent autoregulatory range, the RC artery of 18 anesthetized dogs was cannulated and perfused at controlled pressures. RC blood flow (RCBF) fell from 65.3 +/- 6.1 to 33.7 +/- 2.3 ml.min-1.100 g-1 as RC perfusion pressure (RCPP) was reduced from 80 to 40 mmHg. At 40 mmHg, intracoronary adenosine increased RCBF by 97.9 +/- 10.6 ml.min-1.100 g-1 (P less than 0.001). RCBF fell to 9.5 +/- 1.7 ml.min-1.100 g-1 at 20 mmHg, and RCBF did not significantly increase during adenosine, although RC vasodilation was observed in four dogs. Regional right ventricular (RV) blood flows at RCPP of 80 and 40 mmHg were measured by radioactive microsphere technique. Before adenosine infusion, RCBF was distributed uniformly across the RV free wall at normal and low perfusion pressures. During adenosine infusion, blood flow in both regions increased significantly, but the flow reserve was greater in the subendocardial region at both normal and reduced pressures. RV myocardial O2 consumption (MVo2) was decreased significantly at 40 mmHg, however, there was no evidence of ischemia at this pressure, since the RV lactate extraction ratio was normal (n = 8). Thus RV O2 demand fell when RC O2 supply was reduced, although a flow reserve was available. RV MVo2 was restored to normal when right coronary flow reserve was mobilized by adenosine infusion. For RCBF from 65 to 365 ml.min-1.100 g-1, RC venous O2 content rose and RV MVo2 was essentially constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial cells isolated from adult rat heart bind (3H)dihydroalprenolol. Sixty-one percent of this binding appeared to be at the beta adrenoceptors since it was inhibited by saturating quantities of the beta antagonist propranolol or by the beta agonist isoprenaline. The binding is stereoselective as the l-isomer of isoprenaline caused greater inhibition than the d-isomer. The binding of (3H)dihydroalprenolol to beta adrenoceptors was saturable; half maximum binding occurred at about 8 nM and full saturation at 30--40nM.

The effect of combined alpha- and beta-adrenergic blockade with phenoxybenzamine and propranolol, respectively, on changes in left ventricular myocardial oxygen consumption and blood flow during nicotine administrations (36 micrograms/kg/min, i.v.) was evaluated in anesthetized, open-chest dogs. Myocardial blood flow was estimated by injection of 8 to 10 micrometers diameter radioactive microspheres into the left atrium, and myocardial oxygen consumption was computed from the Fick principle. Before adrenergic blockade, nicotine caused a market (+151%) elevation in myocardial oxygen consumption and a parallel increase in myocardial blood flow. The increase in myocardial blood flow was uniform transmurally. These cardiac changes were accompanied by elevations in systemic arterial and left atrial pressures, peripheral vascular resistance, and heart rate, but by no change in aortic flow or in myocardial contractility. After adrenergic blockade, nicotine caused somewhat lesser, though still marked, elevations in myocardial oxygen consumption (+60%) and blood flow (+43%). Again, myocardial blood flow increases were uniform transmurally. Also, nicotine-induced increases in systemic arterial and left atrial pressure and in peripheral vascular resistance persisted after adrenergic blockade, whereas heart rate remained constant and aortic flow and myocardial contractility declined. The results indicate that nonadrenergic mechanisms contribute significantly to the increase in myocardial oxygen demand during nicotine infusion.

This study was conducted in 12 dogs to evaluate regional hemodynamic responses during intravenous infusion of nicotine (36 micrograms/kg/min) in the conscious state and compare them with those in the same dogs following either pentobarbital (n = 6) or chloralose anesthesia (n = 6). Values for regional blood flow were obtained with 15-microns radioactive microspheres and used to calculate regional vascular conductance. In the conscious state, nicotine increased aortic pressure (+70%) and caused hyperventilation that reduced arterial PCO2 (-44%). These systemic effects were associated with decreases in vascular conductance in the renal cortex (-48%), pancreas (-81%), duodenum (-58%), and cerebral cortex (-55%), whereas no significant change in vascular conductance was evident in spleen, liver, or myocardium. Pentobarbital anesthesia blunted the increases in aortic pressure and respiratory activity and the reductions in vascular conductance in the renal cortex, pancreas, duodenum, and cerebral cortex during nicotine infusion. In contrast, chloralose anesthesia accentuated the increase in aortic pressure and the decrease in vascular conductance in the renal cortex during nicotine infusion, while it converted no change in vascular conductance in the spleen into a decrease and no change in vascular conductance in the myocardium into an increase. Chloralose anesthesia blunted nicotine-induced hyperventilation. These findings demonstrate that general anesthetic agents may have markedly different effects on cardiovascular reflex pathways. They emphasize the importance of considering the particular characteristics of the anesthetic agent used in interpreting results from studies of cardiovascular pharmacology and physiology in anesthetized animals.

Renal (cortex and medulla) and splanchnic (duodenum, liver, pancreas and spleen) blood flows were measured with 25-mu radioactive microspheres in anesthetized, open-chest dogs. The effects of nicotine (36 micrograms/kg/min i.v.) before and after selective alpha adrenergic blockade (phenoxybenzamine, 1 mg/kg i.v.) and before and after combined alpha and beta adrenergic blockade (phenoxybenzamine, 1 mg/kg i.v. and propranolol, 1 mg/kg i.v.) were evaluated. Before adrenergic blockade, nicotine increased arterial pressure (+82%) but had heterogeneous directional effects on regional blood flows: pancreas (-64%), duodenum (-33%), kidney cortex (-31%), kidney medulla (-17%), liver (+5%) and spleen (+71%). Vascular conductance was reduced in kidney cortex (-61%), kidney medulla (-57%), duodenum (-59%), liver (-46%) and pancreas (-79%) and was not altered in spleen. Selective alpha adrenergic blockade prevented the hypertensive response to nicotine, but heterogeneous changes in regional flows persisted: pancreas (-40%), spleen (-40%), kidney medulla (-35%), kidney cortex (-31%), liver (+50%) and duodenum (+74%). After combined alpha and beta adrenergic blockade, nicotine increased systemic arterial pressure (+75%) and decreased vascular conductance in all tissues. Results indicate: 1) a heterogeneous influence of nicotine in renal and splanchnic circulations associated with regional differences in activities of alpha and beta adrenergic receptors and 2) a potent nonadrenergic vasoconstrictor response in these circulations to nicotine after blockade of alpha and beta adrenergic receptors.

Active and reactive hyperemias have been observed in the skeletal muscle circulation tachyphylactic to exogenous adenosine following 3-h supramaximal doses of the vasodilator. These findings failed to support a need for adenosine in metabolic control of skeletal muscle blood flow. The present study was conducted to determine if the coronary circulation also develops tachyphylaxis to adenosine while remaining sensitive to other metabolically linked vasodilator mechanisms. Experiments were conducted in eight pentobarbital-anesthetized, open-chest dogs whose blood flow in the left anterior descending coronary artery (LAD) was measured electromagnetically during 3-h infusion of adenosine into the LAD. Measurements of regional myocardial blood flow (radioactive microspheres), myocardial O2 consumption (Fick principle), and percent segment shortening (ultrasonic crystals) were also obtained. Adenosine was infused into the LAD at a rate of 27.0-72.0 mumol/min, depending on blood flow rate. Calculated concentration of adenosine in LAD blood averaged 0.484 +/- 0.111 mumol/ml, which was well in excess of that required for maximal coronary vasodilation. LAD blood flow averaged 21.5 +/- 2.2 ml/min during the preadenosine control condition. LAD blood flow after 3 h adenosine (123.3 +/- 23.0 ml/min) was not significantly different from that after 1-3 min adenosine (105.8 +/- 17.9 ml/min). There was no significant transmural variation in LAD blood flow during adenosine infusion. Adenosine had no significant effect on myocardial O2 consumption or percent segment shortening. Our results demonstrate persistent transmural vasodilation in the canine coronary circulation during long-term, supramaximal doses of adenosine and are consistent with a role for endogenous adenosine in maintenance of coronary vasodilation during sustained elevations in myocardial energy demands.

Radioactive microspheres (15 mu) were used to measure regional cerebral blood flow during intravenous infusion of nicotine (36 micrograms/kg/min) in anesthetized, open chest dogs. Experiments were conducted with uncontrolled mean aortic pressure and intact autonomic receptors (Series I; n = 9), and in four groups of dogs with mean aortic pressure held constant (Series II); 1) with intact autonomic receptors (n = 6), 2) after beta adrenergic blockade (n = 8), 3) after alpha and beta adrenergic blockade (n = 6), 4) after alpha and beta adrenergic and cholinergic blockade (n = 4). In Series I, nicotine raised mean aortic pressure (+ 72%) and increased flow in cerebral cortex (+ 67%), cerebellum (+ 38%), pons (+ 46%), medulla (+ 39%), and spinal cord (+ 48%). In all regions, but cortex, increases in vascular resistance limited nicotine-induced increases in flow. In Series II, nicotine changed flow only in cortex. Without blockade, nicotine increased cortical flow (+ 38%); but beta blockade abolished this increase in flow. After alpha and beta blockade nicotine again raised cortical flow (+ 29%), and additional cholinergic blockade had no effect on this response. It is concluded that nicotine causes predominant beta receptor mediated vasodilation in cerebral cortex, although it also activates alpha (vasoconstrictor) receptors and a non-adrenergic, non-cholinergic vasodilator mechanism in this region of brain.

After restoration of antegrade blood flow by coronary artery bypass grafting to a region of myocardium supplied by well-developed collateral vessels, there is regression of collateral supply to that region. There is controversy as to how rapidly this regression occurs, how soon collateral flow might return after an acute occlusion of the bypass graft, and how effective pharmacologic agents such as nitroglycerin might be in accelerating this return. To investigate this problem, 14 canine hearts were collateralized by Ameroid occlusion of the left anterior descending coronary artery. Regression and recovery of well-developed collateral function were studied after opening and closing an aorta-coronary bypass. Before bypass, peripheral coronary pressure was 82 +/- 2 mm Hg, retrograde flow 63 +/- 7 ml/min, collateral flow 21 +/- 2 ml/min, and collateral resistance 0.96 +/- 0.13 mm Hg/ml/min. One hundred minutes of bypass perfusion significantly decreased peripheral coronary pressure by 27%, retrograde flow by 52%, and collateral flow by 42%, and significantly increased collateral resistance by 319%. When the bypass was acutely occluded for 30 minutes, collateral resistance decreased spontaneously by 37%. When intracoronary nitroglycerin was administered for 5 minutes immediately after bypass occlusion, collateral resistance rapidly decreased by 72%, but subsequent collateral regression was not alleviated. Increased flow through regressed collateral vessels during retrograde flow diversion was associated with a decrease in collateral resistance. Results demonstrate rapid but not instantaneous regression and recovery of mature collateral function in response to requirements of collateral-dependent myocardium. Regressed collateral vessels can be dilated by nitroglycerin. Flow-dependent changes in collateral vascular tone appear to be responsible for early regression and recovery of collateral function.

The hypothesis that adenosine mediates the coronary vasodilatory response to hypoxia was tested by determining if intracoronary infusion of the adenosine degrading enzyme, adenosine deaminase (ADA), would attenuate this response. Efficacy of ADA was also evaluated by examining its effect on the coronary responses to exogenous adenosine and to 20-s myocardial ischemia. Experiments were conducted in 14 anesthetized, open-chest dogs ventilated 3-5 min with 3% O2-5% CO2-92% N2 to induce systemic hypoxia. Under control, pre-ADA conditions, hypoxia (arterial PO2 19 +/- 2 mmHg) caused left anterior descending (LAD) coronary blood flow to increase from 100 +/- 12 to 382 +/- 47 ml X min-1 X 100 g-1 (+282%). After infusion of ADA (5 U X kg-1 X min-1 for 8-10 min) into the LAD, equally severe hypoxia (arterial PO2 18 +/- 3 mmHg) caused a significantly smaller increase in LAD flow, 79 +/- 9 to 234 +/- 41 ml X min-1 X 100 g-1 (+195%). Oxygen consumption in the LAD perfusion field was unchanged by hypoxia before ADA but fell significantly during hypoxia after ADA. ADA also attenuated significantly the coronary vasodilatory response to exogenous adenosine and to 20-s ischemia. The results of this investigation demonstrate a significant role of adenosine in the coronary vasodilatory response to systemic hypoxia.

Dynamic variation in the transmural distribution of myocardial blood flow was studied in 36 anaesthetised open-chest dogs during the course of the reactive hyperaemia following a 90 s occlusion of the left anterior descending coronary artery. Myocardial blood flow was estimated from tissue uptake of radioactive microspheres, 9 to 10 micrometers in diameter. Endo/epi flow ratios indicated asynchronous reactive hyperaemic responses across the free wall of the left ventricle; flow was preferentially to subepicardium during the initial (pre-peak) phase, whereas flow was preferentially to subendocardium during the prolonged recovery phase. The mean of endo/epi flow ratios obtained during the peak plateau of coronary artery reactive hyperaemia indicated essentially uniform transmural distribution. However, further analysis indicated that this was result of ratios less than 1 early in the peak plateau and ratios greater than 1 late in the peak plateau. Reversal of the endo/epi flow ratios due to regionally asynchronous maximum flows is responsible for the prolonged plateau at peak flow observed in measurements of coronary artery reactive hyperaemia. Transmural asynchrony of peak reactive hyperaemic flow may also account for underestimates in vasodilator capability of ischaemia based on measurements of either coronary artery or myocardial blood flow.

Myocardium (EM) and average total body (ETB) extractions of 86-Rb were determined in 24 anesthetized, open-chest dogs. Blood from the coronary sinus and from the pulmonary artery reflected the uptake of 86-Rb by myocardium and the total body, respectively, and extractions were computed from the relative arteriovenous differences (A-V/A). While the arterial concentration of 86-Rb was constant, EM varied from 0.66 plus or minus .02 (SE) at 2-2.5 min to 0.65 plus or minus 0.02 at 5-5.5 min, and ETB varied from 0.63 plus or minus 0.01 to 0.58 plus or minus 0.01 over the same interval. Mean extractions were similar statistically at 2-2.5 min, but individual differences as great as 30% were encountered at the 95% confidence level. After 3 min of 86-Rb administration, EM significantly exceeded ETB (P is less than 0.05) due to the more rapid decline with time of ETB. The similarity of the early extractions of 86-Rb by myocardium and by the total body supports, in general, the use of the radiorubidium uptake method for measuring coronary blood flow. However, the administration of the indicator should be brief, and rather large errors in individual estimates must be anticipated.

1. The effects of coronary artery occlusion and reperfusion on pressure-induced changes in coronary blood flow and blood volume were investigated. 2. The left anterior descending coronary artery (LAD) of canine hearts was cannulated and perfused independently with arterial blood by a controlled pressure system. LAD flow was measured continuously with an electromagnetic flowmeter and LAD volume was measured in the steady-state by indicator dilution. Measurements were made with perfusion pressure at 100 mmHg (control), 50 mmHg, and 150 mmHg before and after 2 h of LAD occlusion followed by 2 h of reperfusion. 3. With perfusion pressure at control, occlusion-reperfusion reduced LAD flow 19%, but had no significant effect on LAD volume. 4. Steady-state LAD flow and volume always varied directly with changes in perfusion pressure; after occlusion-reperfusion these variations were accentuated. 5. Analysis of transient and steady-state flow responses indicated diminished capability of arteriolar resistance vessels for active, autoregulatory adjustments in lumenal calibre following changes in perfusion pressure. 6. The results of this study demonstrate that occlusion-reperfusion causes derangement to pressure-volume and pressure-flow control mechanisms in the coronary circulation.

To test the hypothesis that adenosine contributes to the coronary hyperaemia produced by regional non-ischaemic myocardial hypoxia coronary blood flow and myocardial oxygen extraction and consumption were continuously monitored in 21 anaesthetised open chest dogs under the following conditions: control 1--postinstrumentation, steady state control; hypoxia 1--3-5 min of regional (LAD) hypoxaemia (partial pressure of oxygen, PO2, 21.4(2.0) mmHg (3.1(0.2) kPa), coronary arterial oxygen content, CaO2, 3.9(0.4) ml.100 ml-1 (39(4) ml.litre-1): control 2--repeat steady state control; and hypoxia 2--3-5 min repeat regional hypoxaemia (PO2 18.9(2.4) mmHg (2.5(0.3) kPa); CaO2 3.6(0.6) ml.100 ml-1 (36(6) ml.litre-1) blood). Left anterior descending artery perfusion pressure was held constant for all conditions. Control 2 and hypoxia 2 were performed in the presence of locally infused adenosine deaminase (n = 16) or saline vehicle (n = 5). The 16 dogs given adenosine deaminase were further subdivided into those perfused with blood deoxygenated by a donor canine lung (group 1, n = 11) and those perfused with blood from a paediatric oxygenator (group 2, n = 5). Systemic haemodynamics, heart rate, and coronary arterial PO2 and O2 contents were similar during the two control periods and during the two exposures to hypoxia in all three groups. Left anterior descending artery blood flow increased by approximately 400% (p less than 0.05) in all three groups during the first exposure to hypoxia. Myocardial oxygen consumption was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

We compared vasoactive effects of intravenous nicotine (36 micrograms/kg/min) in regional cerebral circulations under pentobarbital and chloralose anesthesia. Experiments were conducted in three groups of dogs: Group I, pentobarbital anesthesia with fixed ventilation; Group II, chloralose anesthesia with fixed ventilation; Group III, chloralose anesthesia with free breathing. Values for regional cerebral blood flow measured with 15 mu radioactive microspheres were used to compute regional cerebral vascular resistance (rCBR). In Group I, nicotine had no effect on rCVR in cerebral cortex, and it increased significantly rCVR in cerebellum (+17%), pons (+13%), medulla (+23%), and spinal cord (+19%). Using chloralose instead of pentobarbital in dogs with fixed ventilation (Group II), caused a significant reduction in rCVR in the cerebral cortex during nicotine, although it did not alter significantly nicotine-induced changes in rCVR in other regions of the brain. Hypocapnic alkalosis during nicotine-induced hyperventilation (Group III) resulted in significant increases in rCVR in all regions of the brain; however, the increases in rCVR in non-cortical regions more than doubled those in the cerebral cortex. The present results indicate: Nicotine-induced vasodilation in cerebral cortex was blunted by pentobarbital anesthesia. Nicotine-induced vasodilation in cerebral cortex under chloralose anesthesia was sufficient to nullify in part the potent vasoconstrictor effect of hypocapnic alkalosis.

Liminal contribution to perfusion of collateral-dependent left ventricular (LV) myocardium was evaluated in six dogs. A portion of LV free wall was rendered collateral-dependent by gradual occlusion of left circumflex artery with Ameroid constrictor. Eight to 10 weeks after implantation of constrictor, measurements of LV myocardial flow were made by left atrial injections of 9-10 micro radioactive microspheres. To measure total collateral flow, microspheres were injected under control conditions, and to measure luminal contribution to collateral flow, microspheres were injected after ligation of right coronary artery during extracorporeal perfusion of left common coronary artery (LCCA) with microsphere-free arterial blood, and during stoppage of flow through LCCA. Under control conditions, myocardial blood flow in collateral-dependent region, 1.01 +/- 0.31 ml/min/gm, was not significantly different from that in normal region, 1.06 +/- 0.32 ml/min/gm. Flow from luminal collateral vessels was negligible (less than 0.005 ml/min/gm) in both collateral-dependent and normal myocardium, and was not affected by stoppage of flow through LCCA. These results indicate that luminal collateral vessels, as well as collateral vessels originating from other noncoronary sources, do not contribute significantly to perfusion of normal or collateral-dependent LV myocardium.

Reperfusion of a coronary artery is followed by a decline of the myocardial blood flow to both the ischemic (reperfused) and border regions, and the appearance of a transmural flow gradient favoring the epicardium. These findings were ascribed to vascular changes in the reperfused coronary bed. The behavior of the myocardial blood flow was investigated (1) after 4 hours of reperfusion following the intracoronary infusion of vasodilators (papaverine and adenosine) and (2) following the intravenous administration of papaverine during the total period of reperfusion. Intracoronary infusion of vasodilators increased flow (147 per cent) to all the layers of the reperfused myocardium but failed to alter the transmural distribution of flow. The flow response to these vasodilators in the normal vascular bed consisted of a marked increase in flow (385 per cent) and a normal, uniform distribution, suggesting that the development of anatomical vascular changes reduced the capacity of the reperfused vasculature to increase flow, and that these changes were more marked in the endocardial layer. The intravenous papaverine infusion during reperfusion normalized the total flow and its distribution in the zone bordering the reperfused myocardium but not to the ischemic, suggesting perhaps that papaverine may be useful in protecting potentially salvageable myocardium.

The effects of increased pericardial pressure on blood flow to collateral dependent and normal myocardium were investigated and the mechanisms responsible for these effects evaluated in 10 anaesthetised dogs after collateral inducement by gradual occlusion of a coronary artery. Regional myocardial blood flows were measured with radioactive microspheres during control conditions, mild tamponade, severe tamponade, and severe tamponade with aortic blood pressure held at the control value by blood volume expansion. Mild tamponade increased heart rate by 10% and decreased aortic blood pressure by 15%. Left atrial and central venous blood pressures were moderately increased, and indices of cardiac function were reduced. Blood flow to collateral dependent and normally perfused myocardium was not significantly altered, but the endocardial to epicardial flow ratio was significantly decreased in collateral dependent myocardium. Severe tamponade decreased aortic blood pressure by 45% and cardiac index by 62%. Left atrial and central venous blood pressures were appreciably increased and cardiac function indices considerably depressed. Blood flow to collateral dependent and normally perfused myocardium was decreased similarly (by 54-57%), but the endocardial to epicardial flow ratio was decreased by a greater degree in collateral dependent myocardium. During severe tamponade at control aortic blood pressure, left atrial and central venous blood pressures were further increased, but blood flow to collateral dependent and normally perfused myocardium returned to within 84% of control and endocardial to epicardial flow ratios were normal. Total peripheral vascular resistance increased during severe tamponade, but coronary vascular resistance remained constant. Thus blood flow to collateral dependent and normally perfused myocardium varied according to net coronary perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Right coronary autoregulation was assessed in 14 open-chest, anesthetized dogs. In Group 1 (n = 5), the left common and right coronary arteries were cannulated and perfused independently. As coronary perfusion pressures varied simultaneously between 70 and 120 mm Hg, right coronary blood flow changed by 48%, whereas left coronary flow changed by 13%. In this pressure range, the autoregulatory closed-loop gain of the right coronary circulation averaged 0.37 +/- 0.01, reflecting a modest autoregulatory capability but significantly less than that of the left coronary circulation, 0.78 +/- 0.08. In Group 2 (n = 9), only the right coronary artery was perfused, and right coronary venous blood was collected for determining arteriovenous oxygen extraction. Autoregulatory gain was similar to that of Group 1, indicating that collateral flow associated with intercoronary pressure gradients does not mask right coronary autoregulation. Right ventricular myocardial oxygen consumption varied directly with perfusion pressure, ranging from 7.1 +/- 1.0 to 2.9 +/- 0.8 ml O2/min/100 g as pressure was reduced from 160 to 40 mm Hg. Thus, right coronary autoregulation is masked by an opposing change in oxygen demand. When right ventricular oxygen consumption was altered by pacing, a linear flow-oxygen consumption relationship was observed (8.2 +/- 0.4 ml/min/100 g per ml O2/min/100 g). Subtraction of flows associated with pressure-induced changes in metabolism revealed a potential autoregulatory capability of the right coronary circulation similar to that manifested by the left coronary circulation.

We examined transmurally the right coronary autoregulatory flow response to varied perfusion pressures in 11 anesthetized, open-chest dogs. Right coronary artery flow was measured electromagnetically, and its transmural distribution was defined with 15-micron radioactive microspheres. Heart rate, mean aortic blood pressure, right ventricular systolic pressure, end-diastolic pressure, and dP/dtmax were constant. At 100 mm Hg, subepicardial flow averaged 0.48 +/- 0.04 ml/min/g, and subendocardial flow averaged 0.56 +/- 0.05 ml/min/g. In contrast to the left coronary circulation, right coronary hypotension did not cause preferential subendocardial ischemia. As right coronary perfusion pressure was decreased from 100 to 40 mm Hg in five dogs, subepicardial and subendocardial flows were reduced similarly by 35-36%. As right coronary perfusion pressure was elevated from 100 to 150 mm Hg in six dogs, right ventricular subepicardial blood flow increased by 31%, whereas subendocardial blood flow increased by 70%. Right ventricular subendocardial-to-subepicardial flow ratios averaged 1.15-1.20 for perfusion pressures of 40 to 120 mm Hg, and they increased to 1.36 +/- 0.05 at 150 mm Hg. Right coronary artery autoregulatory closed-loop gain averaged 0.47 +/- 0.06 between 70 and 100 mm Hg and was greater than zero from 40 to 120 mm Hg. Between 120 and 150 mm Hg, gain fell to -0.15 +/- 0.10. Regional gain varied from 0.59 +/- 0.10 to 0.44 +/- 0.08 in subepicardium as pressure was decreased from 100 to 40 mm Hg. Subendocardial gains were similar to subepicardial gains over this pressure range.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a maximally dilating dose of intracoronary adenosine on total (CBV) and small-vessel blood volume (MSVBV, an index of open-capillary density), hematocrit (MSVHct), and related parameters of O2 supply-demand ratio was examined in left ventricular myocardium of anesthetized open-chest dogs. CBV was measured from washout of 51Cr-labeled red blood cells (RBC) and MSVBV and MSVHct from contents of 51Cr-RBC and plasma label, either 131I-serum albumin or 59Fe-siderophilin, in samples of myocardium and blood. Coronary blood flow (CBF) was measured by electromagnetic flowmeter. Myocardial oxygen consumption (MVO2) was computed with the Fick equation. Myocardial oxygen tension (MPO2) was measured with bare-tipped platinum electrodes. Adenosine raised CBV 75%, CBF, 574%, and MPO2 122%, but did not affect significantly MSVBV, MSVHct, or MVO2. These results indicate that infusion of adenosine into a coronary artery perfused at constant pressure causes relaxation of smooth muscle of arteriolar resistance vessels and of other vessels larger than 100 micrometers diam, but not that of the precapillary sphincters. This may be explained by the opposing action of increased MPO2 on the sphincters when flow increases. MSVHct was consistently much less than large-vessel Hct. This warrants combined use of red blood cell and plasma labels for accurate measurements of MSVBV.

The present study was undertaken to evaluate the influence of respiratory condition [free breathing (FB) vs. controlled ventilation (CV)] and of anesthetic [pentobarbital (PA) vs. chloralose (CA)] on nicotine-induced vasomotor responses in the renal cortex and splanchnic beds. Nicotine (36 micrograms . kg-1 . min-1 iv) was infused in four groups of dogs: group I, PA and CV; group II, PA and FB; group III, CA and CV; group IV, CA and FB. Regional vascular conductances (VC) were calculated from regional blood flows measured with 15-microns radioactive microspheres. In group I, VC fell in renal cortex (-22%) and pancreas (-52%), increased in liver (hepatic arterial bed +130%), and did not change significantly in duodenum and spleen. In group III, VC fell to a greater extent in renal cortex, pancreas, duodenum, and spleen than in group I; VC in hepatic arterial bed did not change. In FB dogs (groups II and IV), nicotine caused marked hyperventilation, but decreases in VC in renal cortex, pancreas, and duodenum were similar to those in CV dogs. Results indicate that during intravenous infusion of nicotine 1) hyperventilation does not attenuate or reverse vasoconstriction in renal cortex, pancreas, or duodenum under either PA or CA, although it does in spleen under CA; 2) vasodilator mechanisms predominate over vasoconstrictor mechanisms in the hepatic arterial bed; and 3) vasoconstrictor responses in renal cortex, pancreas, duodenum, spleen, and liver are more pronounced under CA than under PA.

Experiments were performed in 23 open-chest, anesthetized dogs to evaluate 1) the extent of coronary vasodilation during nonischemic hypoxia and 2) whether this dilation is associated with changes in cardiac concentrations of adenosine, inosine, and hypoxanthine. Three minutes of nonischemic myocardial hypoxia caused by selective perfusion of the left anterior descending coronary artery (LAD) with hypoxic blood (PO2 = 11.7 Torr) increased coronary flow 623%, an increase that was not significantly different from that at the peak hyperemic response following 3 min of ischemic hypoxia secondary to LAD occlusion (+534%). Concentrations for adenosine and inosine (nmol/g) in myocardium sampled during nonischemic hypoxia [0.8 +/- 0.2 (SE) and 0.8 +/- 0.2, respectively] were significantly less than values during control conditions (1.7 +/- 0.3 and 1.4 +/- 0.2). Hypoxanthine concentrations did not differ for nonischemic hypoxia and control conditions. During ischemic hypoxia concentrations for adenosine (31.2 +/- 4.9), inosine (91.0 +/- 13.6), and hypoxanthine (44.0 +/- 15.3) were considerably greater than values during nonischemic hypoxia and during control conditions. The results indicate that nonischemic hypoxia induced pronounced coronary vasodilation similar to that during ischemic hypoxia, with reduced rather than with increased tissue concentrations of adenosine and inosine. These findings suggest that reduced myocardial oxygen tension may cause dilation of coronary resistance vessels by a direct relaxant effect on arteriolar vascular smooth muscle.

The coronary hemodynamic effects of re-establishing blood flow to ischemic myocardium and the regional distribution of myocardial flow during reperfusion were studied in anesthetized open-chest dogs. A large portion of the left ventricular wall was rendered ischemic by occlusion of the left anterior descending coronary artery for 2 hours. During reperfusion of the LAD, coronary resistance in the reperfused vasculature increased progressively for the first 3 hours, while resistance in the intact LC vasculature was unchanged. Minimal resistances in the reperfused vascular bed, calculated from mean aortic pressure and peak coronary reactive hyperemic blood flow following a 90 sec. LAD occlusion, were elevated significantly during reperfusion. The increased minimal resistance values, which reflect the passive physical component of resistance, indicate structural changes in the reperfused vascular bed which were evident shortly after the initiation of reperfusion and persisted throughout the experimental period. Coronary resistances (RH) in the reperfused (LAD) and intact (LC) vasculatures during the reactive hyperemia following 10 sec. coronary occlusions were evaluated. During reperfusion, RH in the reperfused vasculature increased progressively while RH in the intact bed was unchanged. The marked increase in RH in the LAD indicates that the reactive hyperemic flow response to a consistent period of coronary occlusion progressively diminished, and reflects a gradual reduction in the vasodilatory potential of the reperfused coronary circulation. The regional distribution of myocardial blood flow following 5 minutes, 2 hours, and 4 hours of reperfusion was measured with multiple injections of radioactive microspheres. These measurements demonstrated a progressive reduction of blood flow to the reperfused myocardium with no significant change in flow to the control myocardium. In contrast to the uniform transmural distribution of flow in the normal myocardium, the reperfused region showed a distinctly nonuniform distribution of flow after 2 hours and 4 hours of reperfusion, with more severe reduction of flow to the endocardial layer. These studies would suggest that rechannelling blood flow distal to an acute coronary occlusion in human subjects might not in itself be capable of reversing the myocardial injury. It is hoped that additional therapeutic measures might be applied to salvage the injured myocardium.