H. Fred Downey

Coronary hemodynamics during reperfusion following acute coronary ligation in dogs

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

Transmural Gradient of Retrograde Collateral Blood Flow in Acutely Ischemic Canine Myocardium

The contribution of retrograde coronary flow to total collateral flow was examined transmurally in anesthetized, open-chest dogs subjected to acute obstruction of the left anterior descending coronary artery. Regional coronary flow in normal and ischemic tissue was reflected by the tissue content of radioisotopes of potassium and rubidium and by radioactive microspheres. To measure total collateral flow, one isotope was administered when the retrograde cannula was clamped. The other isotope was administered when the cannula was opened to divert retrograde coronary flow away from acutely ischemic myocardium. Significant quantities of this isotope reached the ischemic region despite diversion of retrograde flow at an average rate of 3.5 ml/min. These results confirm earlier, but disputed, reports that total coronary collateral flow exceeds retrograde flow and are indicative of collateral pathways associated more closely with the microcirculation than with the larger epicardial arteries. Furthermore, the transmural distribution of myocardial blood flow in the ischemic tissue was altered nonuniformly by diversion of retrograde flow: 42K or 86Rb uptake was reduced to 25% of control in subepicardial tissue but only to 70% of control in subendocardial tissue. The transmural distribution of radioactive microspheres was similarly affected by diversion of retrograde flow. The results suggest that collateral pathways differ transmurally and may include significant luminal connections. Retrograde coronary flow is not a sensitive index of collateral flow to acutely ischemic subendocardial tissue.

Functional significance of microvascular collateral anastomoses after chronic coronary artery occlusion.

Abstract A portion of canine left ventricular free wall was rendered collateral dependent by gradual occulsion of the left anterior descending coronary artery (LAD) with a surgically implanted ameroid constrictor. Six to nine weeks after implantation of the constrictor, regional myocardial blood flow was measured with 9-μm microspheres in 12 dogs under control conditions and during diversion of collateral flow retrogradely by venting the LAD to atmospheric pressure. In four dogs, flow measurements during retrograde diversion were also made with 25-μm microspheres. Under control conditions, flow in the collateral-dependent region was similar to that in the normally perfused left ventricular myocardium. Retrograde diversion of collateral flow caused mean aortic pressure to decrease 10%, but did not change heart rate, left atrial blood pressure, or flow in the normally perfused region. Despite diversion of collateral flow from the LAD and the accompanying decrease in aortic pressure, flow in the collateral-dependent region averaged 0.55 ± 0.09 ml/min/g, 67% of the control flow. The 9- and 25-μm microspheres were distributed similarly in transmural sections of the collateral-dependent region, whereas the large microspheres were distributed preferentially toward the endocardium in transmural sections of the normally perfused region. The findings of a large volume of residual, nondivertible collateral flow and of similar transmural distributions of 9- and 25-μm microspheres indicated that a significant portion of the collateral flow traversed microscopic, intramural pathways. A model describing the source of flow to collateral-dependent myocardium was developed. It predicts that approximately one-half of the flow reaches the collateral-dependent region through microvascular pathways.

Coronary reperfusion: effects of vasodilators (papaverine and adenosine).

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

Myocardial Oxygen Consumption and Blood Flow During Nicotine Infusion: Effect of Combined α- and β-adrenergic Blockade

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

Arteriovenous shunts in dilated or reperfused canine coronary vasculature.

Abstract Arteriovenous shunts in the coronary circulation were investigated by measuring the passage of microspheres, 7–10 μm in diameter, through the coronary vascular bed of anesthetized open-chest dogs. In Group I (12 dogs), the left common coronary artery was cannulated and perfused with arterial blood at aortic pressure. Venous blood was collected from the coronary sinus. In Group IA (six dogs), the following measurements of percentage shunt flow were made: control, 2.0 ± 0.2%; reactive hyperemia following 20-sec coronary artery occlusion, 1.8 ± 0.2%; coronary dilation with adenosine, 2.0 ± 0.1%. In Group IB (six dogs), the following observations were made: control, 1.8 ± 0.7%; coronary dilation with adenosine and perfusion pressure elevated to 170 mm Hg, 2.4 ± 0.5%; systemic hypoxia due to inhalation of nitrogen and perfusion pressure elevated to 170 mm Hg, 4.2 ± 0.9%. Only under the hypoxic condition was the percentage shunt flow significantly elevated above the control condition. In Group II (six dogs), the left anterior descending coronary artery (LAD) was cannulated and perfused, and the ascending coronary vein was cannulated for collection of venous blood. For 2 hr, the LAD perfusion line was clamped. Upon reperfusion of the LAD vasculature, the following observations of shunt flow were made: at 5 min, 2.2 ± 0.7%; at 1 hr, 2.5 ± 0.8%; at 2 hr, 2.8 ± 2.0%. These values did not significantly differ among themselves or from the control observations in Group I.

Binding of (3H)Dihydroalprenolol to Beta Adrenoceptors of Cells Isolated from Adult Rat Heart

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

Myocardial blood flow and oxygen consumption during moderate cardiac tamponade: role of reflex vasoconstriction.

Summary The influence of reflex vasoconstriction on aortic pressure and myocardial oxygen supply and demand during moderate cardiac tamponade was examined in anesthetized, open-chest dogs by comparing responses before and after systemic alpha adrenergic blockade. After α blockade, aortic pressure fell more during cardiac tamponade but there was no change in the ability of myocardium to satisfy its oxygen demand. The data suggest that although peripheral vasoconstriction attenuates the fall in aortic pressure during cardiac tamponade, adequate oxygen supply to myocardium depends on local metabolic vasodilatory systems that couple metabolism to coronary vascular tone, and not on this reflex adjustment.

Measurement of Nicotine in Plasma by High-Performance Liquid Chromatography

Abstract A new procedure has been developed to measure nicotine in blood plasma by high-performance liquid chromatography (HPLC). Nicotine is extracted from plasma by elution with cholorform. Final determination is achieved by isocratic HPLC with ultraviolet detection. Twenty microliters of plasma extract is deluted over a silica column at a flow rate of 1.0 ml/min with a dioxane:isopropanol:NH4OH (80:3.0:0.4) mobile phase. The procedure is sensitive to 0.05 ug of nicotine per ml of plasma and is linear within the range of 0.05 to 10.0 ug/ml of plasma. When a known amount of nicotine was added to plasma, the concentration of nicotine measured averaged 99.9 + 3.9 (S.D.)% of the known concentration. The within-sample coefficient of variation was 3.9%

Coronary reperfusion: effects of hyperosmotic mannitol.

Abstract The purpose of this study was to determine the effects of hyperosmotic mannitol on coronary hemodynamics, regional myocardial contractility, and the distribution of myocardial blood flow during coronary reperfusion in anesthetized, thoracotomized dogs. A portion of the left ventricle was rendered ischemic by occlusion of the left anterior descending coronary artery for two hours. During reperfusion, mannitol was infused intravenously at a rate which increased serum osmolality by approximately 40 mOsm./Kg. Coronary resistance in the reperfused vasculature increased progressively during reperfusion, in spite of mannitol treatment increasing by 45 per cent above the pre-occlusion control value after four hours of reflow. Minimal resistance in the reperfused coronary vascular bed, representing the passive or structural component of resistance, also increased progressively during reperfusion. Regional myocardial blood flow was measured with radiolabelled microspheres at five minutes, two hours, and four hours of reperfusion. At five minutes of reperfusion, myocardial blood flow was elevated in all regions of the left ventricle. After two hours of reperfusion, in spite of mannitol treatment, blood flow to the reperfused region was more severely reduced, and a transmural gradient of flow favoring the subepicardium existed. Blood flow in the reperfused region was further reduced at four hours of reperfusion, and the transmural flow gradient persisted. Regional contractility in the superficial and deep myocardial fibers, measured with Walton-Brodie strain gauges, diminished during reperfusion. However, contractility in the deep fibers was more severely depressed than that in the superficial fibers. This study demonstrated that treatment with hyperosmotic mannitol did not prevent the progressive increase in coronary vascular resistance or the selective underperfusion of the subendocardium during coronary artery reperfusion.