Arterial-coronary Sinus Oxygen Difference Research Articles

Minimal role of nitric oxide in basal coronary flow regulation and cardiac energetics of blood-perfused isolated canine heart.

1. The role of nitric oxide (NO) in the regulation of basal coronary perfusion and ventricular chamber energetics was studied in isovolumetrically contracting isolated blood-perfused canine hearts. Hearts were cross-perfused by a donor animal prior to isolation, and chamber volume controlled by a servo-pump. Coronary sinus flow and arterial-coronary sinus oxygen difference were measured to determine energetic efficiency. 2. NO synthase (NOS) was competitively inhibited by NG-monomethyl-L-arginine (L-NMMA; 0.5 mg kg-1, intracoronary), resulting in a reduction of acetylcholine (50 micrograms min-1)-induced flow augmentation from 143 to 62% (P < 0.001). 3. NOS inhibition had no significant effect on basal coronary flow. Coronary pressure-flow relationships were determined at a constant cardiac workload by varying mean perfusion pressure between 20 and 150 mmHg. Neither the shape of the relationship, nor the low-pressure value at which flow regulation was substantially diminished were altered by NOS inhibition. 4. Myocardial efficiency was assessed by the relationship between myocardial oxygen consumption and total pressure-volume area (PVA), with cavity volume altered to generate varying PVAs. This relative load-independent measure of energetic efficiency was minimally altered by NOS inhibition. 5. These results contrast with isolated crystalloid-perfused heart experiments and suggest that in hearts with highly controlled ventricular loading and whole-blood perfusion, effects of basal NO production on coronary perfusion and left ventricular energetics are minimal.

Rest and exercise cardiovascular effects of terazosin in congestive heart failure

This study investigated the acute effects of the α 1 antagonist terazosin on myocardial circulatory responses at rest and during exercise. Ten patients with congestive heart failure (class III and IV) underwent hemodynamic evaluation before and after a 5-mg oral dose of terazosin. At rest and during exercise, terazosin significantly decreased pulmonary capillary wedge pressure, systemic vascular resistance and mean arterial pressure while cardiac index increased. Stroke volume index increased (p < 0.01) during exercise while left ventricular stroke work index remained unchanged in both experimental conditions. Terazosin administration significantly decreased both rest and exercise myocardial oxygen consumption while exercise coronary sinus oxygen content increased and arterial-coronary sinus oxygen difference diminished (p < 0.05). Parallel with these changes, a blockade decreased the ratio of coronary blood flow to total cardiac output. Coronary vascular resistance remained unaltered with a blockade both at rest and during exercise. Coronary blood flow tended to diminish with decreased myocardial oxygen demand. Alpha 1 blockade induces systemic vasodilation and improves myocardial circulatory parameters with-out inducing coronary dilation or altering metabolic autoregulation.

Improved myocardial oxygen utilization by diltiazem in patients

Calcium entry blocking drugs produce different effects on systemic and coronary hemodynamics and myocardial oxygen extraction. To examine the effects on myocardial oxygen extraction, intravenous diltiazem (100 μg/kg bolus with a continuous 10 μg/kg/min infusion) was administered to 11 patients at rest and during controlled heart rates (100 ± 5 and 120 ± 5 bpm). At rest, diltiazem decreased mean arterial pressure from 109 ± 13 to 99 ± 14 mm Hg ( p < 0.01), increased heart rate from 64 + 12 to 74 ± 14 bpm ( p < 0.01), and decreased coronary sinus resistance (1.02 ± .41 to 0.87 ± .40 U, p < 0.05). Myocardial oxygen extraction was significantly reduced since coronary sinus oxygen content increased (6.0 ± 0.9 to 7.8 ± 1.2 ml/dl, p < 0.01) and the arterial-coronary sinus oxygen difference decreased (12.0 ± 1.7 to 10.6 ± 1.6 ml/dl, p < 0.01). Similar changes occurred with heart rate held constant. There were no significant changes in absolute coronary sinus blood flow, calculated myocardial oxygen consumption, or left ventricular dP dt . Diltiazem decreases mean arterial pressure while reducing both myocardial oxygen extraction and coronary arterial resistance, suggesting that a principal mechanism of a beneficial effect upon the coronary circulation appears to be an improvement in myocardial oxygen extraction relative to myocardial oxygen demand.

R013-6438, a new inotrope-vasodilator: Systemic and coronary hemodynamic effects in congestive heart failure

Systemic and coronary hemodynamics and transmyocardial norepinephrine release were determined before and after oral administration of RO13-6438, a new inotrope-vasodilator agent, in 12 patients with severe chronic heart failure unresponsive to conventional and vasodilator therapy. improvement in left ventricular (LV) function was evident from a marked increase in cardiac index (from 2.09 ± 0.45 to 3.30 ± 0.73 liters/min/m2, p <0.01), stroke volume index (from 23 ± 7 to 36 ± 11 ml/m2, p <0.01), and stroke work index (from 23 ± 11 to 36 ± 14 g-m/m 2, p <0.01), and concomitant fall in pulmonary capillary wedge pressure (from 26 ± 7 to 16 ± 8 mm Hg, p <0.01). Myocardial oxygen consumption did not change significantly (from 15.3 ± 6.8 to 14.9 ± 6.8 mi/min), but the ratio of minute work/myocardial oxygen consumption, an index of LV efficiency, Increased significantly (p <0.05). Although average coronary sinus flow did not change, coronary sinus oxygen increased (from 3.2 ± 0.8 to 4.2 ± 1.5 vol%, p <0.05), and arterial-coronary sinus oxygen difference decreased (from 11.8 ± 2.1 to 10.4 ± 1.9 vol%, p <0.05), suggesting a primary vasodilating effect of R013-6438 on the coronary vascular bed. Net transmyocardial norepinephrine release did not change despite the marked hemodynamic improvement. These findings suggest that R013-6438 has the potential to cause marked improvement in LV function and LV efficiency in patients with severe, refractory congestive heart failure.

Variability in coronary hemodynamics in response to ergonovine in patients with normal coronary arteries and atypical chest pain

Because an increase in coronary vascular resistance in response to ergonovine maleate has been suggested as a possible diagnostic aid for variant angina, changes were evaluated in coronary hemodynamics and serial myocardial thallium-201 perfusion scans in 15 patients without angina and with normal coronary arteries in response to ergonovine (0.05, 0.10 and 0.20 mg intravenously). For the group, heart rate-blood pressure product increased significantly (p less than 0.001) without any change in coronary sinus flow, coronary vascular resistance, myocardial oxygen extraction, arterial-coronary sinus oxygen difference and lactate extraction. In 7 of 15 patients, however, coronary vascular resistance increased (mean 39%, range 11 to 75%, probability [p] less than 0.001), and coronary sinus flow decreased (14%, p less than 0.001), despite an increase in heart rate-blood pressure product (36%, p less than 0.02). No electrocardiographic, metabolic or thallium-201 scan abnormalities occurred. Therefore, significant increases in coronary vascular resistance in response to ergonovine may occur in patients with normal coronary arteries and atypical chest pain.

Effects of hydralazine on coronary blood flow and myocardial energetics in congestive heart failure.

The acute effects of oral hydralazine, 1 mg/kg, on coronary vascular resistance, coronary blood flow (estimated using the coronary sinus thermodilution technique), and myocardial oxygen consumption were evaluated in 10 patients with chronic (New York Heart Association class III and IV) nonischemic congestive heart failure. Central hemodynamic responses demonstrated a modest decrease in mean arterial pressure, pulmonary capillary wedge pressure and systemic vascular resistance (12%, 15% and 29%, respectively), while the cardiac index increased from 2.3 +/- 0.1 to 3.1 +/- 0.3 and left ventricular stroke work index from 24 +/- 3.7 to 28 +/- 3.4 (p less than 0.01). Heart rate and diastolic filling time did not change. Coronary blood flow increased approximately 50%, from 144 +/- 17 to 218 +/- 30 ml/min, and coronary vascular resistance decreased from 0.55 +/- 0.09 to 0.36 +/- 0.08 mm Hg/ml/min (both p less than 0.01). Oral hydralazine increased myocardial oxygen consumption by 33%, from 15 +/- 1.6 to 20 +/- 2.7 ml/min. Despite this moderate augmentation in myocardial oxygen consumption, the arterial-coronary sinus oxygen difference decreased from 104 +/- 6.2 to 94 +/- 7.5 and the myocardial oxygen extraction ratio decreased from 71% to 64% (both p less than 0.05). The ratio of coronary vascular resistance to systemic vascular resistance decreased with hydralazine therapy, while coronary blood flow increased from 3.5% to 4.3 % of total cardiac output. In this group of patients with nonischemic cardiomyopathy, hydralazine had a favorable effect on the coronary circulation and improved the critical myocardial oxygen supply-demand ratio.

Extending the limits of hemodilution on cardiopulmonary bypass using stroma-free hemoglobin solution

Ten swine were subjected to exchange transfusion to a hematocrit level of 5% with either stroma-free hemoglobin solution (SFHS) or 7% albumin solution. Myocardial performance, oxygen kinetics, and myocardial metabolism were subsequently examined using a perfused, in situ, right heart bypass, swine heart model with control of preload, afterload, and heart rate. Animals were tested during a control period (hematocrit = 30%) and following exchange transfusion with either solution to a hematocrit level of 5%. We found that myocardial performance following albumin solution exchange could not be sustained on right heart bypass, and these animals had a stroke volume of zero at a left ventricular end-diastolic pressure of 14 torr. SFHS animals had a significant drop in stroke volume at 14 torr following exchange (20 +/- 3 versus 10 +/- 4, p < 0.025), but this 50% performance level could be sustained. Coronary blood flow rose and myocardial oxygen consumption fell in both groups, although the statistically nonsignificant mean differences were less with SFHS. Arterial-coronary sinus oxygen difference fell significantly (p < 0.05) with albumin solution (7.3 +/- 0.8 versus 2.2 +/- 0.2) and nonsignificantly with SFHS (5.6 +/- 0.4 versus 4.1 +/- 0.7). Lactate production occurred in both groups, but was greater with albumin (34% +/- 6%) than with SFHS (3% +/- 16%). No changes in myocardial tissue gasses were noted in either group. Although myocardial performance decreased and some lactate production occurred with SFHS, we believe these comparative results provide promise in the eventual utilization of an oxygen-carrying agent such as SFHS to extend the limits of hemodilution to a hematocrit value of 5% or less.

Comparative effects of intravenous dipyridamole and sublingual nitroglycerin on coronary hemodynamics and myocardial metabolism at rest and during atrial pacing in patients with coronary artery disease

The effects of intravenous dipyridamole (20 mg) and sublingual nitroglycerin (0.6 mg) were compared at rest and during rapid atrial pacing in patients with significant coronary obstruction. Dipyridamole, which had no significant effect on resting systolic blood pressure, caused a significant increase in coronary sinus flow (CSF) and reduction of coronary vascular resistance (CVR) and arterial-coronary sinus oxygen difference (AO2-CSO2δ), whereas nitroglycerin reduced resting systolic pressure but had no significant effect on CSF, CVR, or AO2-CSO2°. Although these effects of dipyridamole and nitroglycerin on resting systolic pressure, CSF, CVR, and AO2-CSO2° were qualitatively similar during rapid atrial pacing, the onset of chest pain and ischemic ECG changes occurred at a lower heart rate following dipyridamole (136±5 beats/min) than following nitroglycerin (149±6 beats/min, p<0.01). However, maximal double product and myocardial oxygen consumption achieved during pacing were similar following both dipyridamole and nitroglycerin and were less than control pacing values. Coronary dilatation following dipyridamole appears to reduce tolerance to pacing-induced ischemia probably by maldistribution of coronary flow away from ischemic myocardium. Nitroglycerin differs from dipyridamole by improving tolerance to pacing; however, this difference appears to be due to systemic vasodilator effects of nitroglycerin rather than to enhancement of flow to ischemic myocardium.

Effects of disopyramide on systemic and coronary hemodynamics and myocardial metabolism in patients with coronary artery disease: Comparison with lidocaine

In two groups, each comprising 10 patients with advanced coronary artery disease, disopyramide, 2 mg/kg over a period of 5 minutes, or lidocaine, 100 mg as a bolus dose, was injected intravenously. Disopyramide increased diastolic and mean arterial pressures significantly because of its vasoconstrictive properties. Cardiac index decreased from 3.7 ± 0.3 to 3.2 ±0.1 liters/min per m 2 at 10 minutes and to 3.1 ± 0.2 30 minutes after the injection was begun. After lidocaine no changes in hemodynamic variables were observed. Disopyramide revealed potent coronary constrictive activity, whereas lidocaine was a mild coronary vasodilator. Coronary blood flow increased significantly from 68.2 ± 4.3 ml/ min × 100 g to 74.8 ± 4.1 directly after injection of 100 mg lidocaine and to 75.5 ± 5.0 25 to 30 minutes later. Disopyramide decreased coronary blood flow significantly from 73.8 ± 3.8 to 67.8 ± 2.7 ml/ min × 100 mg during the 5 minute period after drug infusion. Coronary vascular resistance increased very significantly from 0.94 ± 0.1 to 1.14 ± 0.1 units. Because of an extreme increase in the arterial-coronary sinus oxygen difference, myocardial oxygen consumption (MVO 2) increased at the same time from 9.9 ± 0.6 to 10.6 ± 0.5 ml/ min × 100 g. At 25 to 30 minutes after the start of the dlsopyramide infusion MVO 2 increased significantly to 11.9 ± 0.6 because the coronary blood flow increased to 79.1 ± 2.8. However, the arterial-coronary sinus oxygen difference remained significantly elevated and coronary vascular resistance declined only moderately. Myocardial lactate extraction did not change. Apparently a metabolism-induced dilatation in coronary vasculature actually overcomes the vasoconstriction by disopyramide and prevents serious myocardial ischemia, but a vasoconstrictive effect of disopyramide is still present. The potent coronary constrictive activity of intravenous disopyramide in the presence of increased myocardial oxygen need may be hazardous in specific clinical situations.

Carotid sinus reflex coronary vasoconstriction during controlled myocardial oxygen metabolism in the dog.

We studied carotid baroreceptor reflex coronary vasoconstriction in closed-chest dogs with controlled aortic blood pressure and myocardial oxygen metabloism. The dogs were anesthetized with morphine and chloralose. Left coronary blood flow was measured by a cannula-tip flowmeter, and myocardial oxygen metabolism was calculated by measuring the arterial-coronary sinus oxygen difference. A bilateral vagotomy was performed in all animals and they were treated with propranolol. Reduction of carotid sinus pressure to 40 mm Hg caused an increase in aortic pressure that was limited to 15 mm Hg by means of a pressure-control reservoir. During carotid hypotension, heart rate and myocardial oxygen metabolism were unchanged but diastolic conronary vascular resistance increased by 21%. Intracoronary artery infusion of norepinephrine had similar effects. After interruption of the reflex are with the alpha-adrenergic receptor antagonist, dibozane, carotid sinus hypotension and the same increase in aortic pressure (15 mm Hg) resulted in only a 5% increase in diastolic coronary resistance. Dibozane also reduced the coronary responses to norepinephrine. It is concluded that carotid sinus hypotension results in reflex sympathetic alpha-receptor coronary vasoconstriction and that this reflex vasoconstriction is independent of changes in myocardial oxygen metabolism or changes in aortic pressure.

Hemodynamic and metabolic effects of isosorbide dinitrate in chronic congestive heart failure

To assess the potential beneficial effects of a nonparenteral vasodilator, sublingual isosorbide dinitrate (5 to 15 mg.) was administered in 12 patients with chronic congestive heart failure refractory to conventional therapy. Hemodynamic measurements were performed before and at 15 minute intervals after drug administration for 90 minutes. Venous capacitance was measured at 5 minute intervals. Myocardial metabolism was also studied in five patients before and after drug administration. Hemodynamic effects were characterized by a modest decrease in mean arterial pressure (85 ± 3 to 78 ± 2 [S.E.M.] mm. Hg) and substantial decrease in right atrial (10 ± 1 to 6 ± 1), pulmonary arterial (39 ± 4 to 30 ± 4) and pulmonary capillary wedge pressures (28 ± 2 to 21 ± 2). These changes were accompanied by an increase in venous capacitance (2.46 ± 0.16 to 3.99 ± 0.24 c.c./100 c.c. of tissue). Along with a decrease in left ventricular filling pressure, cardiac index increased (1.99 ± 0.13 to 2.37 ± 0.15 L./min./M. 2). No significant effect on heart rate was seen. ΔP Δt , an index related to left ventricular dp dt , increased in all but one patient (253 ± 31 to 298 ± 39 mm. Hg/sec.) (p < 0.02 for all changes) in the face of decreased preload and afterload and unchanged heart rate, suggesting improved contractile state. A decrease in coronary blood flow (165 ± 13 to 131 ± 15 c.c./min.) and myocardial oxygen consumption (18.1 ± 1.6 to 14.5 ± 1.6 c.c./min.) was noted (p < 0.02). No change in arterial-coronary sinus oxygen difference or lactate extraction was observed. These data demonstrate that the objectives of therapy in congestive heart failure, namely improved forward output and decreased ventricular filling pressures, can be achieved without metabolic deterioration by using sublingual isosorbide. The mechanisms responsible are related to diminished impedance to ventricular ejection and peripheral pooling of blood. Since the duration of action does not usually exceed 90 minutes, frequent drug administration may be a source of patient inconvenience.

Cardiovascular effects of diazepam and chlordiazepoxide

In open-chest dog preparations i.v. administration of diazepam and chlordiazepoxide caused increases in coronary blood flow and cardiac output while reducing blood pressure, heart rate, and myocardial contractile force. The decrease in force was independent of the alteration in coronary flow. Arterial-coronary sinus oxygen difference narrowed and myocardial oxygen consumption decreased. These data show that both diazepam and chlordiazepoxide exert an oxygen conserving action along with an increase in myocardial oxygen delivery and suggest that these drugs may be of benefit to the patient with coronary insufficiency by a direct effect on the cardiovascular system as well as through CNS-mediated antianxiety effects.

Mechanical increase of vascular resistance in experimental myocardial infarction with shock.

The hemodynamic and cardiac metabolic effects of increasing central aortic pressure by obstructing the abdominal aorta with a balloon catheter introduced via a femoral artery were determined in 28 anesthetized dogs with acute myocardial infarction and shock produced by coronary embolization with plastic spheres. Following coronary embolization, aortic pressure, cardiac output, and left ventricular mechanical efficiency declined in all animals; left ventricular "excess lactate" appeared in about one-half. With abdominal aortic obstruction for 1 hour, there were significant elevations of postembolic aortic pressure, coronary flow, cardiac output, left ventricular oxygen consumption and mechanical efficiency. Left atrial pressure rose slightly but not beyond normal limits. Arterial-coronary sinus oxygen difference diminished, and left ventricular excess lactate diminished or disappeared in 60% of the animals in which it was noted in the postembolic state. After 1 hour of abdominal aortic obstruction, cardiac output, central aortic pressure, and coronary flow diminished moderately. It is concluded that mechanical increase of vascular resistance for periods up to 1 hour may improve myocardial performance in acute myocardial infarction with shock. The increased left ventricular oxygen needs are met adequately by the increase of coronary flow associated with the increase of perfusion pressure.

The effect of coronary vasodilatation (dipyridamole-induced) on the myocardial distribution of tritiated water.

The uptake of tritiated water in the left ventricle has been studied during constantly increasing concentrations of tritium in two groups of normal dogs, one of which received dipyridamole intravenously while the other acted as control. Dipyridamole administration was associated with a 1.6 times greater coronary flow and an appropriate reduction in arterial coronary sinus oxygen difference. As judged by the concentrations of indicator in different myocardial samples the perfusion of the myocardium of the normal dog is relatively homogeneous. No differences were detected between the inner and outer half of the ventricular wall or between the apical region and the free wall of the left ventricle. Comparison of myocardial and coronary sinus concentrations of tritium indicated that the increased coronary flow following dipyridamole was the result of an increase in the effective capillary flow rather than a shunting through diffusion-limited pathways, such as would occur in functional or anatomical arterio–venous shunts.

Effect of a peripheral arteriovenous fistula on coronary blood flow and cardiac oxygen metabolism.

In anesthetized open-chest dogs, the mean blood pressure, cardiac output and coronary sinus flow were measured before and after opening of a unilateral or bilateral femoral arteriovenous fistulae. The opening of an A-V fistula was accompanied by a decrease in mean blood pressure and an increase in cardiac output and coronary sinus flow. Approximately 20 seconds after the fistula was opened, the coronary sinus flow established itself at a level independent of the per cent change in mean blood pressure and cardiac output. Opening of an arteriovenous fistula was also followed by a significant increase in myocardial oxygen consumption, work, and in most experiments by an increase in cardiac efficiency. During periods of opened-fistula the augmented myocardial oxygen consumption was accompanied by a spread of the arterial-coronary sinus oxygen difference.