Coronary Sinus PO2 Research Articles

Hydrogen Peroxide

We tested the hypothesis that hydrogen peroxide (H2O2), the dismutated product of superoxide (O2*-), couples myocardial oxygen consumption to coronary blood flow. Accordingly, we measured O2*- and H2O2 production by isolated cardiac myocytes, determined the role of mitochondrial electron transport in the production of these species, and determined the vasoactive properties of the produced H2O2. The production of O2*- is coupled to oxidative metabolism because inhibition of complex I (rotenone) or III (antimycin) enhanced the production of O2*- during pacing by about 50% and 400%, respectively; whereas uncoupling oxidative phosphorylation by decreasing the protonmotive force with carbonylcyanide-p-trifluoromethoxyphenyl-hydrazone (FCCP) decreased pacing-induced O2*- production. The inhibitor of cytosolic NAD(P)H oxidase assembly, apocynin, did not affect O2*- production by pacing. Aliquots of buffer from paced myocytes produced vasodilation of isolated arterioles (peak response 67+/-8% percent of maximal dilation) that was significantly reduced by catalase (5+/-0.5%, P<0.05) or the antagonist of Kv channels, 4-aminopyridine (18+/-4%, P<0.05). In intact animals, tissue concentrations of H2O2 are proportionate to myocardial oxygen consumption and directly correlated to coronary blood flow. Intracoronary infusion of catalase reduced tissue levels of H2O2 by 30%, and reduced coronary flow by 26%. Intracoronary administration of 4-aminopyridine also shifted the relationship between myocardial oxygen consumption and coronary blood flow or coronary sinus pO2. Taken together, our results demonstrate that O2*- is produced in proportion to cardiac metabolism, which leads to the production of the vasoactive reactive oxygen species, H2O2. Our results further suggest that the production of H2O2 in proportion to metabolism couples coronary blood flow to myocardial oxygen consumption.

Phenotypic adaptation of the late preconditioned heart: Myocardial oxygen consumption is reduced

Although the signalling pathways of late preconditioning have been extensively investigated, its consequence for myocardial metabolism remains unknown. Thus, myocardial oxygen consumption (MVO2) was evaluated before and under late preconditioning. In 7 chronically instrumented dogs, we measured MVO2 in vivo at baseline and during inotropic stimulation with dobutamine (10 and 20 microg/kg/min, i.v.) before (Day 0) and 24 h after (Day 1) a 10-min circumflex coronary artery occlusion. At Day 0, dobutamine dose-dependently increased the triple product (heart ratexleft ventricular systolic pressurexleft ventricular maximum dP/dt), MVO2, coronary blood flow, and coronary sinus pO2. At Day 1, the triple product was similar at baseline and at each dose of dobutamine but MVO2 was significantly blunted as compared to Day 0 (-15+/-4%, -22+/-3% and -19+/-4% at baseline, dobutamine 10 and 20 microg/kg/min, respectively). Importantly, the relationship between MVO2 and triple product was significantly rightward shifted with late preconditioning, i.e., MVO2 was reduced for any level of triple product. At Day 1, the relationship between coronary blood flow and MVO2 was not altered as compared to Day 0 but coronary sinus pO2 was significantly increased vs. Day 0 for any level of coronary blood flow, suggesting that late preconditioning exerted no vasomotor effect but rather changed myocardial oxygen handling. These effects were abolished by administration of S-methyl-isothiourea (1.5 mg/kg, i.v.), a iNOS inhibitor. This study demonstrates that ischemic late preconditioning is characterized by a major reduction in MVO2, both at baseline and under inotropic stimulation. NO from iNOS contributes to this modification of metabolic phenotype.

Effect of fentanyl on baroreflex control of circumflex coronary conductance.

1. Fentanyl, a synthetic mciro-opioid receptor agonist, is the preferred induction and maintenance anaesthetic agent in cardiac surgery. 2. Its actions on myocardial blood flow are poorly understood. There are reports of intra-operative myocardial ischaemia. Its reported actions on cardiorespiratory control vary widely, but do involve hypertension, bradycardia and peripheral vasoconstriction. 3. Accordingly, the postulate that fentanyl would cause coronary vasoconstriction and myocardial disadvantage was examined in awake dogs with a continuous wave Doppler flow probe mounted on the circumflex coronary artery. 4. Continuous intravenous infusion of fentanyl citrate (550 ng/kg per min) raised plasma concentrations of fentanyl to 3.37 ng/mL in a linear fashion at 20 min. There was a fall in core temperature of 0.7 degrees C and, although no apparent depression of ventilation or fall in arterial or coronary sinus PO2, there was a rise in PCO2 and H+ concentration. Some dogs salivated and panted transiently. Thus, fentanyl may reset temperature regulation in low doses but, at higher doses, is associated with metabolic acidosis. 5. In sinus rhythm, the arterial pressure of the dogs fell slightly, then rose to 115% of resting control. Circumflex flow and conductance rose early, then conductance steadily declined to 83%. Heart rate fell, then rose before returning to pre-infusion levels. The early circumflex coronary vasodilator effects, but not the later vasoconstrictor effects, were reduced in dogs with paced hearts. 6. In dogs with paced hearts, a dose-effect study using 138, 275, 550 and 1100 ng/kg per min fentanyl suggested that, at low plasma concentrations of 1-2 ng/mL, vasodilatation does occur in both coronary and systemic circulations; however, at higher doses, intense coronary and systemic vasoconstriction supervenes. 7. The dose-response effect of fentanyl on arterial baroreflex control of circumflex conductance was examined during the immediate 8 s circumflex vasodilator response to a step rise in aortic pressure caused by inflation of an intra-aortic balloon. At low plasma concentrations of fentanyl, baroreflex control of circumflex conductance appears to be enhanced but, with increasing plasma concentrations of fentanyl, appears to be depressed. 8. Therefore, the effects of fentanyl are dose dependent. At low plasma concentrations, left ventricular blood flow and its baroreflex control is enhanced but, at higher concentrations, it is depressed.

Perioperative Myocardial Ischemia: Pathophysiology and Does it Really Matter

Perioperative Myocardial Ischemia: Pathophysiology and Does it Really Matter

Phosphodiesterase type 5 inhibition enhances vasorelaxation caused by nitroprusside in guinea pig intact heart and isolated aorta.

Increased vascular smooth muscle cyclic guanine monophosphate (cGMP) results in vascular relaxation. The vascular effects of stimulating cGMP production with 10(-8)-10(-4) M nitroprusside (NP) and inhibiting cGMP hydrolysis with 10(-8)-10(-4) M zaprinast (ZAP), a selective type V inhibitor of cGMP phosphodiesterase (PDE), were assessed in isolated guinea pig hearts and aortic rings. Coronary flow (CF) IC50 values for NP and ZAP, respectively, were 0.8+/-0.1 x 10(-6) M and 3.6+/-0.1 x 10(-6) M; for coronary sinus pO2 IC50 values were 0.7+/-0.1 x 10(-6) M and 3.7+/-0.1 x 10(-6) M. CF increased by 13+/-2% with 10(-6) NP, and by 12+/-2% with 10(-5) M ZAP; percentage O2 extraction (%O2E) decreased by 17+/-3% with NP and 28+/-4% with ZAP. Together, 10(-6) M NP + 10(-5) M ZAP augmented the increased in CF to 23+/-3% of control, and the decrease in percentage O2 extraction (%O2E) to 40+/-4% of control. Other cardiac effects of NP and ZAP were minimal. In norepinephrine preconstricted aortic rings, the IC50 for relaxation was elicited at 0.4+/-0.1 x 10(-6) M NP and 6.1+/-0.1 x 10(-6) M ZAP. NP given with ZAP gave a logarithmic relation so that IC50 [NP] = -(57 log10 [ZAP]) + 416; R2 = 0.95. NP, 3 x 10(-7) M; ZAP, 3 x 10(-6) M; and NP + ZAP combined increased aortic tissue cGMP by eight-, nine-, and 15-fold, respectively. Inhibiting cGMP hydrolysis may be an effective approach to augment vasorelaxation elicited by cGMP synthesis in the heart.

Bovine polymerized hemoglobin increases cardiac oxygen consumption and alters myocardial substrate metabolism in conscious dogs: role of nitric oxide.

We investigated the effect of bovine polymerized hemoglobin-based oxygen carrying (HBOC) solution on myocardial oxygen consumption (MVO2) and substrate use. At 15 min after the end of HBOC infusion (20% blood volume, i.v.) in nine permanently instrumented conscious dogs, mean arterial pressure and coronary blood flow were both increased by 41+/-5% and 93+/-20% (p<0.01) without affecting late diastolic coronary resistance and left ventricular dP/dtmax. Administration of HBOC did not affect arterial PO2 or O2 content, but significantly decreased coronary sinus PO2 and O2 content by 21+/-3% and 36+/-3%, respectively. MVO2 was increased from 7.2+/-0.8 to 15+/-1.8 ml O2/min (p<0.01). Despite an increase in triple product from 44+/-2 to 56+/-3 (p<0.01) 15 min after HBOC, the ratio of MVO2 and triple product was markedly elevated by 62+/-19%. Myocardial free fatty acid consumption was decreased from 14+/-1 to 4.5+/-2.2 microEq/min, whereas consumption of lactate increased from 19+/-6 to 69+/-10 micromol/ min and that of glucose increased from 1.0+/-0.5 to 10+/-3 mg/min (all p values, <0.05). These metabolic changes were not observed in dogs that received angiotensin II at a dose used (20-40 ng/kg/min, i.v.) to match those hemodynamic effects of HBOC. These results suggest that administration of HBOC increases coronary blood flow and MVO2 and shifts cardiac metabolism from using free fatty acid to using lactate and glucose in conscious dogs at rest. These metabolic changes are independent of the HBOC-induced change in hemodynamics.

Effect of inhibition of nitric oxide formation on coronary blood flow during exercise in the dog.

The aim was to test the hypothesis that nitric oxide (or a related compound) contributes to the coronary vasodilatation during physiological increases of myocardial O2 consumption that occur with exercise. Active hyperaemia associated with graded treadmill exercise and coronary reactive hyperaemia were examined in chronically instrumented awake dogs during control conditions and after administration of the nitric oxide synthase inhibitor, N-nitro-L-arginine (LNNA). LNNA blunted the response to intracoronary acetylcholine, with an 80(SEM 6)% decrease in the maximum acetylcholine induced coronary vasodilatation, but did not alter the response to sodium nitroprusside. Increases of myocardial oxygen requirements during treadmill exercise were associated with progressive increases of coronary blood flow. LNNA caused a significant increase in arterial pressure at rest and during exercise, and this was associated with slightly but significantly higher myocardial oxygen consumption. Coronary blood flow-during exercise was also slightly higher after LNNA, while coronary vascular resistance was unchanged. Coronary sinus PO2 was slightly but significantly lower during exercise after LNNA, indicating that coronary vasodilatation in response to the increased myocardial oxygen demands during exercise was slightly blunted by LNNA. LNNA did not alter the peak increase in blood flow during reactive hyperaemia following a 15 s coronary occlusion, but decreased the duration of the response and decreased reactive hyperaemia debt repayment from 300(56)% during control conditions to 182(36)% after LNNA (p < 0.01). LNNA antagonised coronary vasodilatation in response to acetylcholine and blunted coronary reactive hyperaemia, but did not substantially impair the coronary vasodilatation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support an essential role for nitric oxide in coronary resistance vessel dilatation during exercise in the dog.

Increased oxyhemoglobin affinity by carbamylation: coronary autoregulation and O2 transport.

Hemoglobin carbamylation with sodium cyanate was used to study myocardial O2 delivery during increased oxyhemoglobin affinity. A group of control dogs was compared with a group of dogs, in which their hemoglobin had been carbamylated by daily ingestion of sodium cyanate over a period of 6-8 wk. The O2 tension at 50% saturation of hemoglobin (P50) averaged 23 mmHg in the carbamylated group compared with an average P50 of 31 mmHg in the control group. The left main coronary artery was cannulated and perfused via an extracorporeal, pressure-controlled reservoir. Coronary pressure, coronary flow, and blood gas measurements were made at coronary perfusion pressures spanning the autoregulatory range. The increased oxyhemoglobin affinity produced no significant difference in convective O2 transport to the coronary capillaries, although the carbamylated group had a significantly higher arterial O2 content and significantly lower coronary flow. The autoregulatory process was not significantly altered by carbamylation-induced shifts in the O2 dissociation curve. Despite a significantly lower coronary sinus PO2 in the carbamylated group, the increase in oxyhemoglobin affinity was associated with significantly lower O2 extractions in the carbamylated group. Significant extraction reserve was present in both the control and carbamylated groups as demonstrated by the fact that O2 extraction could still increase well above control levels when perfusion pressure was lowered. We conclude that there is no significant vasodilatory compensation for moderate increases in oxyhemoglobin affinity, despite the continued presence of autoregulatory vasodilatory reserve.

Phenylephrine does not limit myocardial blood flow or oxygen delivery during isoflurane-induced hypotension in dogs.

Experiments were performed on seven fentanyl-pentobarbital-anesthetized, open-chest dogs to determine whether stimulation of coronary alpha 1-adrenergic receptors by phenylephrine causes coronary vasoconstriction and impaired myocardial oxygen delivery when phenylephrine is infused to correct isoflurane-induced hypotension. Myocardial blood flow was measured with radioactive microspheres, and myocardial oxygen and lactate extraction were determined. The Fick equation was used to calculate myocardial oxygen consumption. Measurements were obtained (a) under control conditions, (b) after a 30-min inhalation of isoflurane sufficient to decrease mean aortic pressure by 30%, and (c) while maintaining administration of isoflurane, 5-10 min after restoration of mean aortic pressure by intravenous infusion of phenylephrine. Isoflurane-induced hypotension was accompanied by a baroreceptor-mediated increase in heart rate and by a decrease in myocardial oxygen consumption; however, myocardial blood flow was maintained, resulting in decreased oxygen extraction and increased coronary sinus PO2, thus implying a direct coronary vasodilating effect for isoflurane. Lactate extraction was unaffected. Phenylephrine infusion during inhalation of isoflurane returned mean aortic pressure and heart rate to their respective control values, and it did not change myocardial oxygen consumption, myocardial blood flow, myocardial oxygen extraction, coronary sinus PO2, or lactate extraction from values obtained during isoflurane alone. These latter findings are consistent with undiminished coronary vasodilation by isoflurane in the presence of phenylephrine. In conclusion, infused phenylephrine to restore aortic pressure during isoflurane administration had no vasoconstrictor effect in the coronary circulation and did not impair myocardial oxygen delivery. Apparently, the direct coronary vasodilating action of isoflurane completely nullified phenylephrine-induced vasoconstriction via local alpha 1-adrenergic receptors.

Changes in oxygen-haemoglobin affinity and myocardial function during extracorporeal perfusion in immature pigs

An alteration in oxygen-haemoglobin affinity, as indicated by the partial pressure of oxygen at 50% haemoglobin saturation (P50), may theoretically affect oxygen delivery to the myocardium and, thus, alter myocardial tissue PO2 and possibly myocardial function. We studied the effect of changes in P50 on heart function, metabolism, and coronary sinus PO2 in 10 anaesthetized immature domestic pigs. To facilitate exchange transfusions and control of preload (left ventricular end diastolic pressure, LVEDP), afterload (mean arterial pressure), cardiac output, and heart rate, the animals were placed on right heart bypass. Stroke work (SW), myocardial oxygen consumption (MVO 2), coronary blood flow (CBF), arterial-coronary sinus O2 content difference (CaO2 -CcsO2), and P50 were measured with a control blood prime and after an exchange transfusion with blood having either a low (Group I) or high (Group II) affinity for oxygen. Results (Mean ± SEM, Control versus Test): P50 (mmHg) at 37°C and pH 7.4 increased in Group 1 (35.5 ± 0.7 versus 40.1 ± 1.2, p &lt;0.01) and decreased in Group II (34.7 ± 1.3 versus 26.3 ± 0.5, P &lt;0.001). At 8mmHg LVEDP, SW (gram·metres, g.m) remained constant in Group I (12.2 ± 1.1 versus 11.7 ± 0.8 g·m), but decreased (p &lt;0.05) in Group II (11.7 ± 0.9 versus 8.6 ± 0.61 g.m). In addition, Starling curves relating SW to LVEDP between 4 and 18mmHg were uniformly depressed in Group II but not Group I. No significant change in MVO2 occurred in either group. Group II demonstrated decreased CaO2- CcsO2 (9.3 ± 0.8 versus 6.0 ± 0.3ml O2/dl, p &lt;0.05) and increased CBF (121.6 ± 16.5 versus 188.9 ± 16.9ml/min/1 00gm, p &lt;0.01). PcsO2 increased significantly in Group I (26.6 ± 4.2 versus 36.1 ± 2.7, P &lt;0.02) but not Group II. In conclusion, a decrease in P50 appeared to decrease myocardial function despite a lack of change in PcsO2 or MVO2. A decrease in P50 also led to an increase in CBF. An increase in P50 did not alter function, but did increase coronary sinus and, presumably, tissue PO2.

Myocardial and Systemic Hemodynamics During Isovolemic Hemodilution Alone and Combined With Nitroprusside-Induced Controlled Hypotension

Myocardial and systemic effects of isovolemic hemodilution alone and combined with controlled hypotension induced with sodium nitroprusside (SNP) were studied in halothane-anesthetized, open-chest dogs. Regional blood flow was measured with radioactive microspheres and used to compute regional oxygen (O2) supply. Values for regional blood flow in myocardium were used to compute myocardial O2 (MVO2) and lactate uptake (MVLAC) using the Fick equation. Hemodilution to hematocrit 50% of baseline increased aortic blood flow and decreased systemic vascular resistance, although other systemic hemodynamic values were not changed. Twofold increases in myocardial blood flow were accompanied by no change in MVO2, MVLAC, or coronary sinus PO2. Hemodilution increased regional blood flow sufficiently in the pancreas, liver, duodenum, skeletal muscle, skin, and brain to preserve O2 supply whereas unchanged blood flow in the spleen and kidney reduced O2 supply. Under hemodilution, 15 min of intravenous SNP sufficient to reduce mean arterial pressure by 50% caused parallel reductions in aortic blood flow, dP/dt max, and left ventricular end-diastolic pressure; systemic vascular resistance was unaffected. Myocardial blood flow and MVO2 decreased proportionally, whereas MVLAC and coronary sinus PO2 did not change. Regional blood flow and O2 supply decreased in the kidney, spleen, liver, and skin. Extending SNP infusion to 60 min increased myocardial blood flow and MVO2, but other hemodynamic values were unchanged. Comparing previous results with adenosine-induced hypotension inferred that coronary vasodilator reserve was greatly reduced at this time. In conclusion, although myocardial O2 supply versus demand balance was well maintained during SNP-induced hypotension under hemodiluted conditions, diminished coronary vasodilator reserve suggests increased vulnerability to ischemia if stresses of augmented cardiac work demand or impaired arterial oxygenation were superimposed. The decrease in O2 supply in the kidney during combined hemodilution and SNP-induced hypotension also warrants concern. These latter findings suggest the need for extensive clinical monitoring when SNP is used for controlled hypotension under hemodiluted conditions.

Myocardial and systemic oxygenation during severe hypoxemia in ventilated lambs

We studied the interrelationships among myocardial oxygenation, cardiac output, and systemic oxygenation during acute progressive hypoxemia in the paralyzed and mechanically ventilated lamb. Fractional inspired concentration of oxygen was reduced in five steps to a minimum of 0.05, decreasing arterial oxygen content (CaO2) from 10.9 +/- 2.4 to 2.8 +/- 0.5 ml/dl. Heart rate and stroke volume did not change at any step so that systemic oxygen transport decreased with CaO2. Systemic oxygen consumption fell at CaO2 less than 6 ml/dl. Left ventricular blood flow at maximal hypoxemia increased 277% (249 +/- 27 to 938 +/- 118 ml.min-1.100 g-1) so that left ventricular oxygen delivery and oxygen consumption were maintained. Evidence of anaerobic metabolism occurred when CaO2 was less than four (increase in arterial lactate and hypoxanthine), whereas at this level there was no evidence of inadequate myocardial oxygenation as determined by normal subepicardial: subendocardial blood flow and absence of net lactate production, although coronary sinus PO2 decreased. Although myocardial, cerebral, and adrenal blood flows increased, there was no redistribution of blood flow away from the viscera and skin.

Myocardial oxygen transport during leftward shifts of the oxygen dissociation curve by carbamylation or hypothermia.

An isolated dog heart preparation was used to study the effect of left-shifting the O2 dissociation curve by carbamylation or hypothermia. The two interventions had a similar effect on the variables of O2 delivery. There were significant decreases in myocardial O2 consumption, coronary sinus PO2, and O2 extraction. There was no compensatory increase in O2 transport. Coronary flow autoregulation was somewhat blunted by hypothermia but not by carbamylation. We conclude that an increase in hemoglobin-O2 affinity is capable of limiting myocardial O2 delivery and that increases in convective O2 transport play a minor role at best in the coronary adaptation to small decreases in P50.

Myocardial Blood Flow and Oxygen Consumption during Isovolemic Hemodilution Alone and in Combination with Adenosine-Induced Controlled Hypotension

Recent reports have proposed combining isovolemic hemodilution and controlled hypotension to limit blood loss during surgery. Before such a technique can be considered for clinical use, it must be demonstrated that it does not endanger maintenance of adequate myocardial oxygenation. Accordingly, measurements of left ventricular myocardial blood flow and oxygen consumption were obtained during isovolemic hemodilution alone and in combination with adenosine-induced controlled hypotension in ten pentobarbital-anesthetized, open chest dogs with normal coronary circulation. Hemodilution to a hematocrit of 21.7% was produced by isovolemic exchange of whole blood for 5% dextran. In the presence of hemodilution, adenosine was infused intravenously at a rate sufficient to decrease mean aortic pressure to 51 mm Hg. Myocardial blood flow was measured with radioactive microspheres and used to calculate global left ventricular myocardial oxygen consumption and oxygen supply. Hemodilution alone increased aortic blood flow (+43%) but had no effect on aortic pressure, left atrial pressure, heart rate, or left ventricular dP/dtmax; an increase in myocardial blood flow (+130%) maintained oxygen supply and consumption at the baseline level. Adenosine-induced hypotension during hemodilution decreased heart rate (-35%), left ventricular dP/dt max (-28%), and aortic blood flow (-14%). These systemic responses were accompanied by reduced myocardial oxygen consumption (-29%) and increased myocardial blood flow (+54%) and myocardial oxygen supply (+72%). These latter effects resulted in reduction in the coronary arteriovenous oxygen content difference and in an attendant rise in coronary sinus Po2 (+66%), which are signs of luxuriant myocardial perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of beta-adrenergic receptor blockade on responses to acute hypoxemia in lambs.

We studied the effects of beta-adrenergic receptor blockade on general circulatory and metabolic responses to moderate (FIO2 = 0.09) acute hypoxemia in newborn (protocol 1) and 3-wk-old (protocol 2) lambs, and on regional blood flow distribution in newborn lambs (protocol 1). Via a left thoracotomy we placed an electromagnetic flow transducer around the ascending aorta and inserted various vascular catheters. After 2 days of recovery, the lambs were studied. In protocol 1, we measured cardiovascular variables and regional blood flow distribution during control conditions, after 45 min of acute hypoxemia, and after 0.5 mg/kg of propranolol during acute hypoxemia. In protocol 2, we measured cardiovascular variables during control conditions and after 45 min of acute hypoxemia with and without propranolol pretreatment. In both groups, propranolol limited the increase in cardiac output and heart rate caused by hypoxemia, and thus decreased oxygen delivery. However, propranolol also decreased oxygen consumption so that pulmonary arterial pO2 was either higher (protocol 1) or the same (protocol 2) as during acute hypoxemia alone. Neither metabolic acidosis nor hypothermia ensued. In protocol 1, propranolol decreased renal, carcass, and most importantly, myocardial blood flows. However, myocardial O2 consumption also fell, coronary sinus pO2 increased, and blood was redistributed toward the subendocardium, suggesting that myocardial perfusion improved. Thus, beta-adrenergic receptor blockade during acute moderate hypoxemia may have a beneficial effect by reducing total body and myocardial oxygen demand in excess of the reduction in oxygen delivery.

Cardiac Effects of Phytic Acid Induced High P50with Free and Limited Coronary Blood Flow

A blood preparation with a large increase in P50, obtained by a new technique to encapsulate inositol hexaphosphate (IHP) in erythrocytes was evaluated on an isolated heart model. Each heart was alternatively perfused with control stored human blood (P50 = 2.12.+/- 0.9 mmHg) and IHP-treated human blood (P50 = 42.5 +/- 9.33 mmHg). Changes of perfusates were performed when coronary blood flow (CBF) was free and adapted to a constant perfusion pressure (FREE CBF). Changes of perfusates were also performed at a constant but restricted CBF corresponding to 55% of basal value (RESTRICTED CBF). Both bloods were oxygenated and equilibrated to achieve the same acid-base balance, arterial PO2 and O2 content. When CBF was not restricted, switching from control blood to IHP-treated blood, induced a decrease in CBF (-23%), an increase in coronary sinus PO2 (57%) and a decrease in coronary sinus O2 content associated with an increase in myocardial O2 consumption (14%). These metabolic changes were associated with a decrease in left ventricular developed pressure (LVDevP) (-15%) and its maximal positive derivative (-12%). When CBF was restricted, switching from control blood to IHP-treated blood, induced an increase in perfusion pressure (59%). This vasoconstriction was associated with the same changes in the blood gas measurements as those observed when CBF was not restricted, while LVDevP increased significantly (7%). It is concluded that the beneficial effects on myocardial metabolism from the increase in P50 with IHP, are lessened by the cardiodepressive effect of the blood preparation which is predominant when CBF is not restricted.

Coronary response to large decreases of hemoglobin-O2 affinity in isolated rat heart.

In this study, the consequences of large increases of P50 (O2 partial pressure at 50% oxyhemoglobin saturation) on coronary blood flow (CBF) were investigated in isolated Wistar rat heart. Rightward shifts of the O2 dissociation curve (ODC), obtained by lysing and resealing erythrocytes to encapsulate inositol hexaphosphate (IHP), led to a very large increase in P50 without side effects. Each heart was perfused alternatively with control stored human blood [P50 = 18.8 +/- 0.3 (SE) mmHg] and IHP-treated human blood (P50 = 47.1 +/- 1.7 mmHg), according to the technique of Langendorff (mean perfusion pressure 80 mmHg; hematocrit 25%). Arterial PO2 of 180 mmHg was maintained to keep arterial O2 content identical for both types of blood. When hemoglobin affinity was lowered, CBF decreased from 5.32 +/- 0.20 to 3.40 +/- 0.14 ml X min-1 X g-1, coronary sinus PO2 (PcsO2) rose from 39.9 +/- 0.9 to 69.9 +/- 4.2 mmHg, and myocardial O2 consumption (MVO2) rose slightly from 0.125 +/- 0.005 to 0.149 +/- 0.010 ml O2 X min-1 X g-1 (P less than 0.05). A significant negative correlation was found between CBF and P50 (r = -0.90; n = 32) and a significant positive correlation between PcsO2 and P50 (r = +0.84; n = 28). The coronary blood flow response to high P50 values was not abolished when maximal dilation was induced by adenosine, so this response seems independent of metabolic needs. These experiments have demonstrated that if O2 uptake by erythrocytes remains constant, in the presence of a high P50, sufficient O2 supply may be achieved with substantially less blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

143 MYOCARDIAL METABOLIC AND HEMODYNAMIC CHANGES DURING ACUTELY INDUCED ASPHYXIA IN FETAL LAMBS

Two days after instrumentation, we measured heart rate (HR), arterial blood pressure (BP), left ventricular myocardial blood flow (MBF), and myocardial consumption of oxygen, glucose and lactate in 6 fetal sheep (118-128 days gestation) in utero during acute progressive asphyxia induced by gradual constriction of a common uterine artery snare. Ascending aortic blood oxygen content decreased by 70% from 7.5 to 2.2 ml/dl. Ascending aortic blood oxygen saturation fell from 60% to 15%. pH fell from 7.40 to 7.04, while PCO2 increased from 46 to 72 torr. Coronary sinus PO2 fell from 11.6 to 6.6 torr. MBF increased 317% above the control of 239 ml/100g/min. Hemoglobin concentration was maintained from 9.3 to 10.8 g/dl during the study. HR, BP, and rate-pressure product remained unchanged. Myocardial oxygen consumption and extraction were maintained until an arterial oxygen saturation of 20-25%, after which they decreased. During hypoxemia, myocardial glucose consumption markedly increased and net lactate uptake by the myocardium occurred until an arterial PO2 of 12 torr (O2 saturation of 21%) was reached. Below this level lactate production occurred in 3 of 6 fetuses. Thus the fetal lamb has a marked reserve to increase myocardial blood flow and maintain myocardial oxygenation and substrate delivery during acute severe asphyxia.

Limitations of tracer oxygen uptake in the canine coronary circulation.

Theoretical models of oxygen transport in the myocardium have failed to account for low average tissue pO2 relative to to coronary sinus pO2, measured with pO2 electrodes and myoglobin saturation, and for hypoxic contractile failure at relatively high coronary sinus pO2 levels. These findings could be explained by either arteriovenous diffusional shunting or a limiting rate of transfer of oxygen from blood to tissue, or both. To gain new insights, we performed multiple indicator dilution tracer experiments across the coronary circulation in the dog, with 18O2 as the oxygen tracer and 51Cr-labeled red cells as the reference tracer for oxygen. 125I-Albumin and 22Na+ were included to provide the relative plasma flow rate. The tracer oxygen outflow curve consisted of a large early peak related to its reference red cell curve. No tracer emerged before the labeled red cells. The downslope, which contains the returning component of the tracer curve, decreased less steeply when oxygen consumption was reduced by propranolol. Fitting the tracer oxygen outflow curve with a distributed model including irreversible sequestration behind a resistance gave a transfer rate constant which was relatively small, and a relatively large rate constant for sequestration. Relative oxygen consumption (estimated from the arteriovenous difference) correlated closely with the rate constant for sequestration. Estimated average tissue oxygen concentrations were of the order of one-third blood concentration. Dimensional analysis indicates that the low transfer rate constant derives from hemoglobin-oxygen binding; this decreases fractional tracer oxygen transfer in proportion to the ratio of plasma:red cell oxygen pools.

Lidoflazine in the early stages of acute myocardial ischaemia.

1 Pretreatment of anaesthetized rats with intravenously administered lidoflazine (an antianginal agent) reduced the incidence and severity of ventricular arrhythmias which resulted from acute coronary artery ligation. Ventricular fibrillation was completely prevented by doses of 50 micrograms/kg and 2 mg/kg and no animal so treated died ( contrast 50% incidence of fibrillation in the controls and 30% mortality). 2 In anaesthetized greyhound dogs, lidoflazine (2 mg/kg) administration resulted in transient reductions in systemic arterial pressure, LV dP/dt max and cardiac output. Coronary sinus Po2 was markedly increased, indicating pronounced coronary vasodilatation. 3 Lidoflazine pretreatment inhibited the increase in epicardial ST-segment elevation which resulted, in dogs, from short (3 min) occlusions of the left anterior descending coronary artery. This effect was especially marked at sites where, in control occlusions, ST-segment elevation was most pronounced. 4 Lidoflazine greatly reduced the number of ventricular ectopic beats which usually resulted from more prolonged (30 min) periods of acute coronary artery occlusion. There was no ventricular fibrillation in these dogs (contrast 25% incidence in the controls). 5 Lidoflazine did not modify the ventricular fibrillation which results from reperfusion of a previously ischaemic area of the left ventricular wall.