Coronary Sinus Oxygen Tension Research Articles

Mechanisms of a reduced cardiac output and the effects of milrinone and levosimendan in a model of infant cardiopulmonary bypass

A low cardiac output state is an important cause of morbidity after pediatric cardiopulmonary bypass. The objectives of our study were to define the early precipitants of the reduced cardiac output and to investigate the effects on these of milrinone and levosimendan in a model of pediatric cardiopulmonary bypass. Experimental study. : Research laboratory at a university-affiliated, tertiary pediatric center. Eighteen piglets. Piglets, instrumented with systemic, pulmonary arterial, and coronary sinus catheters, pulmonary and circumflex arterial flow probes, and a left ventricular conductance-micromanometer-tipped catheter, underwent cardiopulmonary bypass with aortic cross-clamp and cardioplegic arrest. At 120 mins, they were assigned to control, milrinone, or levosimendan groups and studied for a further 120 mins. In controls, between 120 and 240 mins, cardiac output decreased by 15%. Systemic vascular resistance was unchanged, but pulmonary vascular resistance increased by 19%. Systemic arterial elastance increased by 17%, indicating increased afterload. End-systolic elastance was unchanged, and coronary sinus oxygen tension decreased by 4.0 +/- 1.7 mm Hg. In animals receiving milrinone cardiac output was preserved, and in animals receiving levosimendan cardiac output increased by 14%. Both drugs prevented an increase in arterial elastance and pulmonary vascular resistance after cardiopulmonary bypass. Systemic vascular resistance decreased by 31% after levosimendan, and end-systolic elastance increased by 48%, indicating improved contractility. Both agents prevented a decrease in coronary sinus oxygen tension. Increased afterload, which is not matched by an equivalent elevation in contractility, contributes to the reduced cardiac output early after pediatric cardiopulmonary bypass in this model. This increase is prevented by milrinone and levosimendan. Both agents exert additional beneficial effects on pulmonary vascular resistance and myocardial oxygen balance, although levosimendan has greater inotropic properties.

Myocardial tissue oxygen during coronary artery constriction and hypotension in dogs.

Sodium nitroprusside (SNP) may decrease myocardial tissue oxygenation in dogs with normal coronary arteries. We compared SNP- with desflurane-induced hypotension on myocardial tissue oxygen and pH in dogs with left anterior descending artery constriction. Twenty-four dogs were anesthetized with 8% desflurane for baseline anesthesia. Catheters were inserted into the femoral artery and vein and the coronary sinus. A flow probe and flow restriction device was placed on the left anterior descending (LAD) artery. A probe that measured myocardial oxygen pressure was inserted into the middle myocardium in the LAD region. Baseline measures were made of LAD artery flow, arterial and coronary sinus blood gases, and myocardial tissue gases. A 30% decrease in blood pressure was induced with SNP with unrestricted LAD flow (n=6) or when LAD artery flow was restricted by 30% from baseline (n=6). In separate dogs, a 30% decrease in blood pressure was produced with 14 +/- 1% desflurane with unrestricted LAD flow (n=6) or with baseline LAD artery flow restricted by 30% (n=6). During SNP-induced hypotension with no LAD constriction, LAD artery flow and coronary sinus oxygen tension increased but myocardial tissue oxygen tension (PmO2) decreased by 40%. When baseline artery flow was decreased by 30% by LAD constriction, SNP-induced hypotension decreased tissue oxygen pressure by 80%, and ischemic acidosis was produced. During unrestricted LAD artery flow or with a 30% flow restriction, desflurane-induced hypotension produced no significant change from baseline myocardial tissue oxygen tension or pH. During coronary artery constriction, desflurane-induced hypotension maintained myocardial tissue oxygenation and pH better than did SNP-induced hypotension. The divergence between tissue and coronary sinus oxygen tension during SNP suggests that arteriovenous shunting may occur.

Nitroglycerin-induced hypoxemia does not produce myocardial ischemia

Objective: Nitroglycerin has been the drug of choice for relieving myocardial ischemia for more than a hundred years. Several studies have indicated that a significant reduction in arterial oxygen tension (PaO 2) occurs after the administration of sublingual nitroglycerin to patients with coronary artery disease breathing room air. Because available oxygen in arterial blood is reduced, it would be reasonable to assume that oxygen delivery to the myocardium would also be impaired. The purpose of this study was to investigate whether nitroglycerin-induced arterial desaturation results in compromised oxidative metabolism of myocardium assessed by coronary sinus lactate concentration and oxygen content in patients with coronary artery disease undergoing coronary artery bypass surgery. Participants: Ten randomly selected patients undergoing coronary bypass surgery. Setting: All studies were performed at Siyami Ersek Cardiovascular and Thoracic Surgery Center. Methods: A catheter was inserted into the radial artery to measure blood gases and arterial lactate concentration. After sternotomy, and aortic and venous cannula placement, a coronary sinus catheter was introduced into the coronary sinus to measure oxygen content and lactate concentration. Control coronary sinus and arterial blood samples were obtained before nitroglycerin infusion. Nitroglycerin was then given in a dose of 2 μg/kg/min for a period of 5 minutes. At the end of 5 minutes, second samples were obtained from the coronary sinus and arterial catheters. Main Results: It was found that arterial and coronary sinus oxygen tension decreased significantly. Arterial lactate concentration did not change, coronary sinus lactate concentration decreased. Despite a substantial fall in arterial oxygen tension after administration of nitroglycerin, a significant reduction in coronary sinus lactate concentration occurred. Conclusion: Nitroglycerin-induced hypoxia does not compromise oxidative metabolism of myocardium as can be assessed by a concomitant decrease in coronary sinus lactate concentration.

The comparative effects of equimolar sevoflurane and isoflurane in isolated hearts.

The aim of this study was to compare the direct effects of equivalent molar concentrations of sevoflurane (SEVO) and isoflurane (ISO) on electrophysiology, mechanical function, metabolism, and perfusion in isolated hearts, independent of neuronal, humoral, or hemodynamic influences. Three equimolar concentrations of SEVO or ISO were administered randomly in each of 14 guinea pig hearts perfused by the Langendorff technique. Spontaneous heart rate (HR), atrioventricular (AV) conduction time, left ventricular pressure (LVP), and coronary flow (CF) were measured directly. To differentiate a direct vasodilatory effect from an indirect metabolic effect due to autoregulation of CF, arterial and coronary sinus oxygen tension were measured continuously to calculate oxygen delivery (Do2), myocardial oxygen consumption (MVo2), percent O2 extraction, and cardiac efficiency. Linear slope analysis (cardiac effect as a function of 0.1 mM anesthetic concentration) was used to compare anesthetic effects. Only AV time was increased more (P < 0.05) by ISO (+1.8 ms per 0.1 mM) than by SEVO (+1.1 ms per 0.1 mM). CF tended to be higher with ISO (+0.7 mL.g-1.min-1 per 0.1 mM) than SEVO (0.4 mL.g-1.min-1 per 0.1 mM) but this was not significant. HR (ISO, -1.4% per 0.1 mM; SEVO, -1.7% per 0.1 mM), LVP (ISO, -5.8% per 0.1 mM; SEVO, -5.1% per 0.1 mM), and percent O2 extraction (ISO, -6.1% per 0.1 mM; SEVO, -5.8% per 0.1 mM) were decreased similarly by both anesthetics and these effects were accompanied by proportional decreases in MVo2 (ISO, -34% +/- 4%, SEVO, -37% +/- 6%) at the highest concentrations (0.53 mM). Neither anesthetic altered cardiac efficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue oxygenation with graded dissolved oxygen delivery during cardiopulmonary bypass

Background: Intravascular perfluorochemical emulsions together with a high oxygen tension may increase the delivery of dissolved oxygen to useful levels. The hypothesis of this study is that increasing the dissolved oxygen content of blood with incremental doses of a perfluorochemical emulsion improves tissue oxygenation during cardiopulmonary bypass in a dose-related fashion. Methods and Results: Oxygen utilization was studied in a profoundly anemic canine model of hypothermic cardiopulmonary bypass. Forty-two dogs (mean ± standard error of the mean). Cardiopulmonary bypass was begun and resulted in a hematocrit of 9.4% + 0.6%. A standard primng solution was used in the control group ( n = 12), and the test groups received 1.35 gm perfluorochemical · kg -1 ( n = 10 dogs), or 5.4 gm perfluorochemical · kg -1 ( n = 10 dogs), 2.7 gm perfluorochemical · kg -1(n = 10 dogs) through the venous return cannula. Each animal underwent a series of randomized pump flows (0.25,0.5, 1.0, 1.5, 2.0, and 3.0 L · min -1 · m -2 ) at 32° C. After the randomized flows were completed at 32° C, the temperature was raised to 38° C and cardiopulmonary bypass was discontinued. Mortality from cardiac failure on separation from cardiopulmonary bypass was 42% in the control group and 20% in perfluorochemical-treated groups. The mean perfluorochemical dose was higher in surviviors than in nonsurvivors (2.9 + 0.4 versus 1.3 + 0.5 gm perfluorochemical · kg -1; p < 0.05). No differences in oxygen consumption or transbody lactate gradient were found between groups during cardiopulmonary bypass. Analysis of mixed venous oxygen tension (a surrogate measure for tissue oxygenation) as a function of cardiopulmonary bypass flow normalized to body surface area showed that the control group had significantly lower mixed venous oxygen tension ( p < 0.05) than the perfluorochemical emulsion-treated groups. Furthermore, the differences were related to the perfluorochemical emulsion dose. These differences in mixed venous oxygen tension continued after termination of cardiopulmonary bypass. The coronary sinus oxygen tension and cardiac arterial-venous oxygen content differences during and after cardiopulmonary bypass were similar among the control and perfluorochemical emulsion-treated animals. Dissolved oxygen consumption during and after cardiopulmonary bypass was calculated. Dissolved oxygen consumption increased in the perfluorochemical-treated animals in a perfluorochemical dose-related manner and was significantly higher in perfluoro-chemical-treated animals than in the control animals ( p < 0.05). Conclusions: Graded increases in mixed venous oxygen tension during cardiopulmonary bypass were observed in response to graded increases in the dissolved oxygen delivery. These data suggest that enhancing oxygenation with perfluorochemical-dissolved oxygen is an effective temporary substitute for the use of hemoglobin-bound oxygen during cardiopulmonary bypass. Perfluorochemical-dissolved oxygen may be particularly beneficial in the setting of multiple hypoxic stresses. (J T HORAC C ARDIOVASC S URG 1995;110: 774-85) J T HORAC C ARDIOVASC S URG 1995;110:1-85.

Hemodynamic and Coronary Vasodilative Properties of a Selective and Full β1-Adrenoceptor Agonist, T-0509, in Comparison with Isoproterenol in Anesthetized Dogs

Recently, the beta 1-adrenoceptor was shown to mediate direct coronary vasodilation independent of metabolic demand in canine arrested heart preparation. To investigate the beta 1-adrenoceptor-mediated direct vasodilation in a beating heart preparation, we compared coronary blood flow (CBF) and coronary sinus oxygen tension (PO2) in anesthetized open-chest dogs using a beta 1-selective agonist, T-0509. T-0509 (0.005-0.05 microgram/kg intravenously, i.v.) increased the maximal rate of increase in left ventricular pressure (LVdp/dtmax) and heart rate (HR) to an extent similar to that induced by isoproterenol (ISO) without decreasing diastolic blood pressure (DBP). A beta 1-adrenoceptor antagonist, (-)-bisoprolol (10 micrograms/kg), but not a beta 2-adrenoceptor antagonist, ICI 118,551 (30 micrograms/kg), inhibited the T-0509-induced increase in LVdp/dtmax and HR. Thus, T-0509 showed selective beta 1 stimulation at the doses used. T-0509 also caused beta 1-selective relaxation in isolated coronary arteries. ISO increased both CBF and PO2. The early phase of the increase in CBF and the concurrent increases in PO2 were inhibited by ICI 118,551, whereas the late phase of the increase in CBF was inhibited by (-)-bisoprolol. T-0509 increased CBF, and this increase was inhibited by (-)-bisoprolol. A slight but significant increase in PO2 induced by T-0509 was not altered by these doses of the antagonists. Our results indicate that the T-0509-induced increase in CBF is due mainly to an indirect effect on myocardial beta 1-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial Oxygen Supply/Demand Relations During Phenylephrine Infusions in Dogs

Experiments were performed on 14 fentanyl-pentobarbital-anesthetized dogs to assess changes in myocardial oxygen supply/demand relations during intravenous infusions of phenylephrine (2.8 micrograms.kg-1.min-1). Myocardial blood flow was measured with radioactive microspheres. Myocardial oxygen and lactate extraction were determined. Myocardial oxygen consumption was calculated with the Fick equation. In series 1, measurements were obtained during phenylephrine-induced pressor responses. In series 2, measurements were obtained with aortic pressure maintained constant with an extracorporeal reservoir during phenylephrine infusion, so that coronary vasomotor responses could be assessed in the absence of increases in ventricular afterload and perfusion pressure. In series 1, the phenylephrine-induced increase in mean aortic pressure (+42%) was accompanied by proportional (60%) increases in myocardial blood flow and myocardial oxygen consumption and with no change in the endocardium-to-epicardium flow ratio, oxygen extraction, coronary sinus oxygen tension and oxygen saturation, or myocardial lactate extraction. In series 2, phenylephrine infusion caused a transmurally uniform 15% decrease in myocardial blood flow combined with a 10% decrease in myocardial oxygen consumption. The coronary arteriovenous oxygen difference increased modestly (+5%), resulting in small decreases in coronary sinus oxygen tension and oxygen saturation, whereas lactate extraction was unaffected. The present findings suggest that phenylephrine has a direct vasoconstrictor effect in the coronary circulation that is weak and completely overridden by metabolic autoregulatory mechanisms in response to pressure-induced augmentations in cardiac workload. The authors conclude that the myocardium is not at risk when phenylephrine is used to treat hypotension in patients with adequate cardiac function and coronary vasodilator reserve.

Myocardial oxygen consumption during exercise in the presence of left ventricular hypertrophy secondary to supravalvular aortic stenosis

The hypothesis that abnormally increased myocardial oxygen demands may contribute to increased vulnerability to ischemia during exercise in the chronically pressureoverloaded hypertrophied left ventricle was tested. Myocardial oxygen consumption was measured during a five stage graded treadmill exercise protocol in eight normal dogs and nine adult dogs in which a 90% increase in left ventricular mass was produced by banding the ascending aorta at 8 weeks of age. Heart rate increased progressively during exercise in both groups of dogs, but was significantly faster than normal in the group with aortic banding. Coronary blood flow increased progressively with exercise in both groups, but was significantly greater than normal in dogs with aortic banding during each exercise stage. Coronary sinus oxygen tension decreased significantly and similarly during exercise in normal and hypertrophied hearts.In dogs with hypertrophy, oxygen consumption per gram of myocardium averaged 52% greater than normal during exercise. This excess myocardial oxygen consumption in dogs with aortic banding resulted from an abnormally large increase in oxygen consumption per beat during exercise and from the faster heart rate in this group of dogs. Measurements of myocardial blood flow with microspheres demonstrated a lower subendocardial/subepicardial blood flow ratio in dogs with hypertrophy; this ratio decreased significantly during exercise in dogs with hypertrophy, but not in normal dogs.These data are consistent with the hypothesis that increased vulnerability to ischemia in the pressure-overloaded hypertrophied left ventricle is the result of both increased myocardial oxygen demands during exercise and abnormalities of myocardial perfusion.

Effects of midazolam on the coronary circulation in patients with coronary artery disease.

The effects of midazolam on coronary sinus blood flow (CSBF), myocardial oxygen consumption (MVO2), and myocardial lactate balance were investigated in eight patients with stable coronary artery disease undergoing cardiac catheterization. Coronary sinus blood flow was measured by continuous thermodilution. Arterial and coronary sinus blood were analyzed for oxygen and lactate content. The determinants of left ventricular (LV) performance were obtained from the cardiac output measured by thermodilution and from left heart catheterization data. All data were obtained before, and 5 and 15 min after midazolam, 0.2 mg X kg-1 iv. Sleep was induced in all patients after administration of midazolam and persisted throughout the entire study period. Mean aortic and LV end-diastolic pressure were decreased from control values (-15 and -44%, respectively), as well as cardiac index and stroke index (-10 and -15%, respectively). Heart rate increased moderately (+8%), while no change in systemic vascular resistance and maximum velocity of shortening (Vmax) were observed. Midazolam administration was followed by a decrease of CSBF (-24%) and of MVO2 (-26%). Coronary vascular resistance did not change, but coronary sinus oxygen tension increased slightly, suggesting a mild alteration in normal autoregulation. However, no evidence of myocardial ischemia occurred, as judged by the absence of changes in the: 1) ECG, 2) myocardial lactate extraction, and 3) relaxation time constant. These results suggest that midazolam may be used safely in patients with coronary artery disease.

Carotid baroreceptor reflex coronary vasodilation in the dog.

The hypothesis that neurally mediated coronary vasodilation occurs as part of the carotid baroreceptor reflex was investigated. The left main coronary artery was cannulated and perfused at constant pressure (100 mm Hg) in closed-chest, chloralose-anesthetized dogs. The heart was paced at a constant rate between 60 and 70 beats/min after atrioventricular heart block. Propranolol (1 mg/kg) was given to prevent beta-receptor-mediated alterations in contractility. Aortic blood pressure was stabilized with a blood reservoir. The aortic depressor nerves were cut bilaterally to prevent the buffering influence of aortic arch baroreceptors on the carotid baroreceptor reflex. The carotid sinuses were vascularly isolated and perfused with arterial blood at controlled pressures. Under these conditions, a step change in carotid sinus pressure from 70 to 210 mm Hg produced a 0.29 ml/min per g increase in coronary flow above control and a 10 mm Hg increase in coronary sinus blood oxygen tension. A step in carotid sinus pressure from 70 to 150 mm Hg resulted in a flow increase of 0.13 ml/min per g and a coronary sinus oxygen tension increase of 5.3 mm Hg relative to prestimulation values. Atropine (0.5 mg/kg, iv) blocked most of the reflex coronary vasodilation, indicating a parasympathetic component, and the addition of adrenergic alpha-receptor blockade with phenoxybenzamine (0.25 mg/kg, ic) abolished the remaining response, demonstrating sympathetic participation. The reflex nature of the coronary response was confirmed with carotid sinus denervation and vagotomy. It is concluded that carotid sinus hypertension results in a graded reflex neural coronary vasodilation independent of myocardial metabolic factors. The major component is due to activation of parasympathetic coronary vasodilator fibers, but there is also inhibition of sympathetic vasoconstrictor fibers.

The Effect of Hypocapnia on Coronary Blood Flow and Myocardial Function in the Dog

The effect of hypocapnia on global and regional myocardial function and coronary blood flow (CBF) was studied in dogs anesthetized with halothane before and after critical constriction of the left anterior descending (LAD) coronary artery. Coronary blood flow decreased 29% (P less than 0.05) when hypocapnia was induced in dogs with a normal LAD artery. Critical constriction reduced CBF by 42% (P less than 0.05). In the critically constricted LAD artery, hypocapnia did not reduce CBF. During hypocapnia and with a normal LAD artery, oxygen extraction by the myocardium increased 16% (P less than 0.01) and oxygen tension in the coronary sinus was reduced by 19% (P less than 0.001). After critical constriction of the LAD, hypocapnia was associated with an increase in oxygen extraction of 14% (P less than 0.01) and the coronary sinus oxygen tension was reduced by 21% (P less than 0.001). CBF of the left circumflex coronary artery (LC) increased 36% (P less than 0.05) after critical constriction to the LAD when compared with control values of the preconstriction phase. However, LC flow did not change during hypocapnia when critical stenosis had been applied to the LAD artery. Although oxygen supply (product of CBF and arterial oxygen content) to the myocardium was reduced during hypocapnia, regional myocardial function did not change from control values. Regional function was similarly maintained during hypocapnia and critical constriction of the LAD.

Relationship between sympathetic neural activity, coronary dynamics, and vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion

The relationship between neural sympathetic discharge and vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion was studied in 26 chloralose-anesthetized dogs. Preganglionic cardiac sympathetic impulse activity and ventricular fibrillation thresholds were separately determined before and during a 10-minute period of left anterior descending coronary artery occlusion and during release-reperfusion. Within 2 minutes of occlusion the ventricular fibrillation threshold was significantly decreased (from 25 ± 1.3 to 16 ± 2.3 mA, p < 0.05) corresponding with the period of maximal activation of cardiac sympathetic preganglionic fibers (from 4.4 ± 0.2 to 6.3 ± 0.5 impulses/sec). Coronary sinus blood flow and oxygen tension decreased significantly. All these changes persisted for 5 to 6 minutes, thereafter returning to control levels despite continued obstruction of the coronary artery. A transient but significant reduction in ventricular fibrillation threshold also occurred with release of the occlusion but was unaccompanied by increases in sympathetic neural discharge. Bilateral stellectomy completely prevented the ventricular fibrillation threshold changes observed during coronary artery occlusion. However, there was no change in coronary sinus oxygen tension or blood flow. During reperfusion, stellectomy increased rather than decreased vulnerability to ventricular fibrillation. Stellectomy augmented the reactive hyperemic response to release-reperfusion. These findings indicate that enhanced cardiac sympathetic neural activity contributes to ventricular vulnerability associated with coronary artery obstruction. An opposite action results during release-reperfusion. Cardiac sympathetic neural discharge, by reducing the magnitude of reactive hyperemic response through influence on coronary vascular tone, exerts an antifibrillatory effect.

Mechanism of action of hyaluronidase in decreasing myocardial ischemia post coronary occlusion in the isolated perfused rabbit heart

The influence of hyaluronidase (H) on subacute experimental myocardial ischemia was studied in isolated perfused rabbit hearts. Changes in ischemic area were assessed by epicardial nicotinamide adenine dinucleotide (NADH) fluorescence photography, an intrinsic high-resolution display of myocardial ischemia. Computerized determination of ischemic area was made from standardized photographs. Hyaluronidase was begun 20 minutes after coronary artery occlusion at 4 units/ml perfusate. NADH fluorophotographs were taken at 10-minute intervals up to 60 minutes of ischemia. Coronary sinus oxygen tension (P csO 2), myocardial oxygen consumption (MV̇O 2), and coronary flow were determined. After 70 minutes, the hearts were perfused with rhodamine solution to identify areas of myocardial perfusion. In 13 H-treated hearts 54.3% ± 3.7% (mean ± SEM) of the nonperfused area (rhodamine stained) was ischemic (NADH fluorescent). In 14 untreated hearts 79.8% ± 3.2% of the nonperfused area was ischemic ( p < 0.0001) and the ischemic areas were uniform. The distance between perfused and ischemic tissue was 952 ± 78 μm in the H hearts and 504 ± 35 μm in the untreated hearts ( p < 0.0001). In the H treated hearts P csO 2 increased to 155% of the post-ligation control while it decreased to 79% in the untreated hearts ( p < 0.0001). MV̇O 2 decreased in the H-treated hearts to 62%; the untreated hearts had no further change. In the H-treated hearts, coronary flow increased to 146% of the post-ligation control while it fell to 91% in the untreated group ( p < 0.0001). We conclude that H increases coronary flow while decreasing MV̇O 2 during subacute ischemia. In H-treated hearts, significant amounts of myocardium remain normoxic within the nonperfused areas, and may potentially be salvaged after prolonged myocardial ischemia.

Alpha-Adrenergic control of oxygen delivery to myocardium during exercise in conscious dogs.

alpha-Adrenergic control of the oxygen delivery to the myocardium during exercise was investigated in eight conscious dogs instrumented for chronic measurements of coronary blood flow, left ventricular (LV) pressure, aortic blood pressure, and heart rate and sampling of arterial and coronary sinus blood. After alpha-adrenergic receptor blockade a standard exercise load elicited a significantly greater increase in heart rate, rate of change of LV pressure (LV dP/dt), LV dP/dt/P, and coronary blood flow than was elicited in the unblocked state. In contrast to the response pattern during control exercise, there was no significant change in coronary sinus oxygen tension (PO2), myocardial arteriovenous oxygen difference, and myocardial oxygen delivery-to-oxygen consumption ratio. It is concluded that the normal relationship between myocardial oxygen supply and oxygen demand is modified during exercise after alpha-adrenergic blockade, whereby oxygen delivery is better matched to oxygen consumption. These results indicate that the increase in coronary blood flow and oxygen delivery to the myocardium during normal exercise is limited by alpha-adrenergic vasoconstriction.

Relationships between adenosine and coronary resistance in conscious exercising dogs.

The relation between myocardial adenosine content, coronary sinus plasma concentration, and coronary vascular resistance was studied in conscious dogs during rest or treadmill exercise. Exercise at 5 mi/h for 7 min on a 20% slope had a significant threefold increase in cardiac work over that of dogs at rest. Exercise increased myocardial adenosine content from 1.35 +/- 0.54 to 8.18 +/- 0.60 nmol/g and decreased coronary vascular resistance from 1.07 +/- 0.13 to 0.69 +/- 0.08 mmHg.ml-1.min.100 g; the former correlated negatively with the latter (r = -0.74, P less than 0.01). The adenosine concentration in coronary sinus plasma increased from 108 +/- 16 to 184 +/- 18 nmol/l plasma and correlated negatively with coronary vascular resistance (r = -0.83, P less than 0.01). Myocardial adenosine content correlated positively with coronary sinus plasma adenosine concentration (r = 0.77, P less than 0.05). Low myocardial lactate content, continued lactate uptake, lack of change in the lactate-pyruvate ratio, and stable coronary sinus oxygen tension values indicated no myocardial hypoxia. These findings demonstrate the release of adenosine into coronary sinus blood and show significant correlations between myocardial adenosine content, coronary sinus adenosine concentration, and coronary vascular resistance during physiological exercise in the dog. The results support the hypothesis that adenosine regulates coronary blood flow during increased metabolic activity.

Decrease in acute myocardial ischemia by hyaluronidase in isolated, perfused, rabbit hearts

Hyaluronidase has been reported to reduce infarct size and cellular damage after coronary artery occlusion. The influence of hyaluronidase (H) on experimental myocardial ischemia was studied in isolated perfused rabbit hearts. Changes in ischemic area were assessed by epicardial NADH fluorescence photography, an intrinsic, high-resolution display of myocardial ischemia. Computerized determination of ischemic area was made from standardized photographs. H was begun 5 min after coronary artery ligation at 4 units/ml perfusate. NADH fluorophotographs were taken at 10-min intervals up to 40 min of ischemia. Coronary sinus oxygen tension ( P esO 2) myocardial oxygen consumption (MV̇ O 2) and coronary flow were determined. After 40 min, the hearts were perfused with a rhodamine solution to indicate areas of myocardial perfusion. In 18 H-treated hearts 55 ± 6% (mean ± SE) of the nonperfused area was ischemic (NADH fluorescent) and the ischemic areas had a patchy distribution. In 26 untreated hearts 86 ± 2% of the nonperfused area was ischemic and the ischemic areas were uniform, ( P < 0.001). The distance between perfused and ischemic tissue was 861 ± 76 μm in the H-treated and 359 ± 19 μm in the untreated hearts, ( P < 0.001). In the H-treated hearts P esO 2 increased to 154% of the postligation control while it decresed to 77% in the untreated hearts ( P < 0.001). MV̇ O 2 decreased to 87% of control after ligation in both groups. The H-treated hearts had a further decline of 37% while the untreated hearts had no further change. In the H-treated hearts, coronary flow increased to 150% of the postligation control while it fell to 80% in the untreated group ( P < 0.001). We conclude that hyaluronidase increases P esO 2 and coronary flow while it decreases MV̇ O 2 during acute ischemia. In hyaluronidase-treated hearts, significant amounts of myocardium remain normoxic within the nonperfused areas.

Myocardial blood flow and its distribution in anesthetized polycythemic dogs.

SUMMARY Decreased cardiac output, coronary blood flow, and systemic oxygen transport in polycythemia are attributed to increased blood viscosity and regarded as potentially harmful. We studied the effects of isovolemic polycythemia on these variables as well as on myocardial oxygen consumption and regional myocardial blood flow in 31 anesthetized dogs, seven with cannulated left main coronary arteries. Measurements were made at rest, during hypoxemia or adenosine infusions, and with aortic stenosis, pacing, or an aorto-atrial fistula. When hematocrit increased from 42% to 66%, it reduced cardiac output by 36% and systemic oxygen transport by 8%; with hypoxemia, cardiac output rose in polycythemic dogs. Normoxemic polycythemia decreased myocardial blood flow by 46% and increased mean coronary resistance by 54%, slightly decreased myocardial oxygen transport and consumption, and did not alter coronary sinus oxygen tension or myocardial oxygen extraction. Cardiac stress, hypoxemia, and adenosine infusion lowered coronary resistance in polycythemic dogs. Left ventricular myocardial oxygen transport was dependent on pressure work and not on arterial oxygen content or hematocrit. With maximal coronary vasodilation, coronary vascular resistance at hematocrits of 66% was 1.5 times that at 42%. Polycythemia per se did not alter the even distribution of flows across the left ventricular wall, but subendocardial underperfusion began at higher perfusion pressures in polycythemic than in normocythemic dogs. We conclude that autoregulation plays a role in regulating flows and oxygen transport in polycythemia. With maximal coronary vasodilation, however, the increased viscosity of polycythemic blood could be an important factor reducing the amount of myocardial blood flow and oxygen transport. THE EFFECTS of polycythemia on the circulation depend in part on whether there is an associated increase in blood volume 1 which is usually elevated in most forms of polycythemia in man. 2 5 Because of the raised blood volume, cardiac output is usually increased, unless there is heart failure. Systemic oxygen transport (cardiac output times arterial oxygen content) is therefore increased above normal when arterial oxygen saturation is normal 4 and may be normal or only moderately reduced when

Coronary vascular sympathetic beta-receptor innervation.

Recent studies indicate that coronary vessels have alpha- and beta-2-adrenergic receptors and that the alpha receptors are functionally innervated. We studied whether the beta-2-vasodilator receptors are functionally innervated, using a dog in situ modified Langendorff preparation with constant coronary perfusion pressure. The beating, nonworking heart and systemic circulation were supported with a pump oxygenator. Stimulation of the left stellate ganglion increased coronary blood flow and decreased coronary sinus oxygen tension from prestimulation control values. After beta-1-receptor blockade (practolol, 10 mg/kg), stellate stimulation decreased coronary blood flow and decreased coronary sinus oxygen tension from prestimulation control values, revealing alpha-receptor vasoconstriction. After the addition of alpha-receptor blockade (Dibozane, 5 mg/kg), stellate stimulation increased coronary blood flow and coronary sinus oxygen tension a small amount from prestimulation values. Finally, after the addition of beta-2-receptor blockade (propranolol, 2 mg/kg), stellate stimulation increased flow and coronary sinus oxygen tension slightly from prestimulation control values. Direct intracoronary injections of isoproterenol, norepinephrine, and epinephrine gave results consistent with the presence of beta-1 myocardial receptors and alpha and beta-2 coronary receptors. We conclude that there is little functional innervation of coronary vascular beta-2 receptors. Intracoronary injections of isoproterenol and epinephrine activated beta-2-receptor coronary vasodilation after beta-1-receptor blockade, but norepinephrine did not.

Cardiovascular effects of nucleoside analogs.

Short-chain aliphatic esters and amides of adenosine-5'-carboxylic acid caused marked increases in coronary sinus oxygen tension (PO2) in the dog; the amides were generally more potent, causing additionally marked hypotension and tachycardia. The hypotensive effect was observed also in the spontaneously hypertensive rat. That the increase in coronary sinus PO2 paralleled an increase in coronary flow was verified with ethyl adenosine-5'-carboxylate hydrochloride. This compound also increased the reactive hyperemic response. Aminophylline blocked the increase in coronary flow. A representative amide and ester were very poor substrates for adenosine and adenylate deaminase in vitro; the amide exhibited a weak inhibitor effect on the enzymic activities while the ester was inactive. The observations that the compounds (1) cause marked pharmacological effects within seconds after intravenous administration, (2) are blocked by aminophylline like adenosine, (3) are not deaminated significantly in vitro by either adenosine or adenylate deaminase, and (4) cannot be phosphorylated at the 5' terminus because the 5'-OH has been removed chemically, support the hypothesis that they are acting directly on an "adenosine receptor" and have a prolonged duration of action because they are not metabolized significantly by the normal physiological pathways of adenosine degradation.

Control of myocardial oxygen tension by sympathetic coronary vasoconstriction in the dog.

The effect of sympathetic alpha-receptor coronary vasoconstriction on myocardial oxygen tension was studied in open- and closed-chest, chloralose-anesthetized dogs. Blood oxygen tension in the coronary sinus and blood flow in the circumflex coronary artery were continuously measured in a three-part experiment. With stimulation of the left stellate ganglion (15 Hz, 3 msec, 4-7 v, 90-second train) under vagotomy control conditions (part 1), heart rate, blood pressure, and coronary blood flow increased, but coronary sinus oxygen tension decreased from 19 mm Hg to 15 mm Hg. In part 2, beta-receptor blockade with propranolol (2.0 mg/kg. iv) in the same dogs blunted the positive inotropic and chronotropic effects of sympathetic stimulation; coronary alpha-receptor vasoconstriction was unmasked, and coronary sinus blood oxygen tension fell from 17 mm Hg to 11 mm Hg. Since increases in oxygen metabolism were blunted, it appeared that the decrease in coronary sinus oxygen tension was caused by alpha-receptor coronary artery vasoconstriction. This hypothesis was tested in part 3 by the addition of alpha-receptor blockade with Dibozane (3.0 mg/kg, iv). Sympathetic stimulation no longer resulted in a change in either coronary vascular resistance or coronary sinus oxygen tension. These results indicate that the fall in oxygen tension during beta-receptor blockade in part 2 was due to alpha-receptor coronary vasoconstriction. Thus, myocardial oxygen tension may be regulated by coronary sympathetic vasomotion as well as by myocardial oxygen metabolism and local vascular control mechanisms.