Wm. John Powell

Improvement in Myocardial Function and Coronary Blood Flow in Ischemic Myocardium after Mannitol

The purpose of this study was to evaluate the effect of hyperosmolality on the performance of, and the collateral blood flow to, ischemic myocardium. The myocardial response to mannitol, a hyperosmolar agent which remains extracellular, was evaluated in anesthetized dogs. Mannitol was infused into the aortic roots of 31 isovolumic hearts and of 15 dogs on right heart bypass, before and during ischemia. Myocardial ischemia was produced by temporary ligation of either the proximal or mid-left anterior descending coronary artery. Mannitol significantly improved the depressed ventricular function curves which occurred with left anterior descending coronary artery occlusion. Mannitol also significantly lessened the S-T segment elevation (epicardial electrocardiogram) occurring during myocardial ischemia in the isovolumic hearts and this reduction was associated with significant increases in total coronary blood flow (P < 0.005) and with increased collateral coronary blood flow to the ischemia area (P < 0.005).THUS, INCREASES IN SERUM OSMOLALITY PRODUCED BY MANNITOL RESULT IN THE FOLLOWING BENEFICIAL CHANGES DURING MYOCARDIAL ISCHEMIA: (a) improved myocardial function, (b) reduced S-T segment elevation, (c) increased total coronary blood flow, and (d) increased collateral coronary blood flow.

Effects of Intra-Aortic Balloon Counterpulsation on Cardiac Performance, Oxygen Consumption, and Coronary Blood Flow in Dogs

The effect of intra-aortic Counterpulsation (IACP) with a balloon upon myocardial oxygen consumption (MV·o2), coronary blood flow (TCF), and left ventricular performance was studied in 23 anesthetized canine right heart bypass preparations at constant heart rate and cardiac output. In nonhypotensive, nonTCF-limited preparations, IACP produced a fall in left ventricular peak systolic pressure (LVP) and a decrease in MV·o2 (-1.1 ± 0.2 (SE) ml/min/100 g LV). In these animals there was little steady state change in TCF (-5.6±5.9 ml/min), secondary to autoregulation by the coronary vascular bed. Left ventricular end-diastolic pressure (LVEDP) fell if elevated but exhibited little change if initially normal. However, in hypotensive preparations, in which left ventricular performance was substantially limited by a decreased TCF, IACP produced a striking increase in TCF (+40.9 ± 8.6 ml/min) accompanied by an increase in MV·o2 (+1.2±0.3 ml/min/100 g LV). Elevated LVEDPs fell substantially toward normal. Directiona...

The Central Nervous System as a Site of Action for the Coronary Vasoconstrictor Effect of Digoxin

Digitalis is known to have a vasoconstrictor effect in the coronary circulation. Recent studies have demonstrated that the coronary vasoconstrictor effects of acetylstrophanthidin and digoxin are neurally mediated via alpha adrenergic fibers. In the present study, experiments were done in 20 dogs anesthetized with chloralose and urethane to study the central nervous system as a possible site of action for this vasoconstrictor effect of digoxin. After the intravenous administration of 1.0 mg digoxin, cerebrospinal fluid concentrations of digoxin rose to a peak of 2.3+/-0.4 (SEM) ng/ml at 15 min, temporally corresponding to the peak in coronary vascular resistance change of +20.0+/-2.5% of control in the paced canine heart. Submicrogram digoxin injections into the lateral cerebral ventricle produced a significant increase in coronary vascular resistance, the latter injection producing a peak increase in coronary vascular resistance of 12.4+/-1.2% of control. Cross-perfusion experiments, where the isolated head of the operative dog was perfused from a donor dog receiving digoxin, thus keeping digoxin levels in the remainder of the operative dog very low, showed a similar degree of coronary vasoconstriction. Thus, the central nervous system appears to be an important site of action for the early coronary vasoconstrictor effect of digoxin.

Effect of Hypoxia on Myocardial Relaxation in Isometric Cat Papillary Muscle

A B S T R A C T Myocardial relaxation is an important energy-dependent process. Hypoxia, unlike ischemia, has not been shown to impair myocardial relaxation. This difference may be because (a) the traditional index to assess isometric muscle relaxation (halftime to relaxation or RT,/2) reflects both changes in developed tension as well as relaxation and (b) the relaxation process is highly sensitive to temperature and previous papillary muscle studies have been conducted under hypothermic conditions. The present study examines the effect of hypoxia on the relaxation process of 31 isometrically contracting kitten papillary muscles at hypothermic (29°C) and euthermic (38°C) conditions using RT112, the peak rate of tension fall (-dT/dt) and -dT/dt normalized for tension ([peak -dT/dt]/T and max [-dT/dt per T]). Hypoxia at 29°C resulted in a fall in RT,/2 from 278±11 (SEM) to 230±17 ms (P < 0.01) and no change in (peak -dTIdt)/T and max (-dTldt per T). However, at 38°C, hypoxia impaired relaxation as reflected in a prolongation of RTI/2 from 101±6 to 126±8 ms (P < 0.01) in spite of a substantial fall in peak tension. Moreover, (peak -dTIdt)IT decreased from -15.4±0.7 to -11.0±0.8/s (P <0.01) and max (-dT/dt per T) decreased from -25.1±1.8 to -13.8±0.9/s (P < 0.01). In conclusion, the present study demonstrates that hypoxia impairs the relaxation process of cardiac muscle.

Detection of edema associated with myocardial ischemia by computerized tomography in isolated, arrested canine hearts.

SUMMARYThis study was undertaken to determine if computerized tomograph (CT scanning) with an EMI cranial scanner could detect edema associated with myocardial ischemia in canine hearts. A localized area of decreased density in the posterior papillary muscle and surrounding myocardium was detected on serial 8 mm CT scan slices of each heart after 60 min of circumflex artery occlusion and 45 min of reflow of blood. The wet/dry weight ratios and previous electron microscope studies of the ischemic posterior papillary muscles revealed edema accumulation. After 1 hour of arterial occlusion and 12 hours of reflow (which produces extensive necrosis and a decrease in the wet/dry ratio)lesions were still discernibl but were less consistently as severe. Permanent ligation of the left anterior descending coronary artery and major collateral arteries for 6 hours also resulted in a lesion of decreased density in the distribution of the occluded arteries.Thus, CT scanning can detect, and is a potential means for sequential noninvasive quantitation of myocardial edema associated with ischemia.

beta-Adrenergic regulation of total systemic intravascular volume in the dog.

While it is known that β-adrenergic receptor stimulation is associated with an increase in venous return, the mechanism by which this increase is mediated has not been well defined. A total of 55 dogs were anesthetized, placed on cardiopubnonary bypass, and perfused at a constant rate. In 23 of these animals, changes in total systemic intravascular volume were measured as reciprocal changes in extracorporeal reservoir volume during isoproterenol (6 /ig/min) or norepinephrine infusion (30 μ/ min). At central venous pressures of 3, 8, and 13 cm H2O, isoproterenol was associated with decreases in intravascular volume of 70 ± 20 (standard error of the mean) (P < 0.02), 50 ± 20 (P < 0.05), and 20 ± 30 (NS) ml, respectively, and norepinephrine was associated with decreases of 300 ± 60 (P < 0.001), 230 ± 30 (P< 0.001), and 190 ± 40 (P< 0.001) ml, respectively. The splanchnic vasculature was perfused selectively at a constant rate and drained separately in another 18 animals. In these dogs, an isoproterenol-associated decrease in splanchnic volume occurred concomitantly with a decrease in postsinusoidal hepatic vascular resistance from 38 ± 5 to 18 ± 3 cm H2O«min/liter (P< 0.001). A norepinephrine-associated decrease in splanchnic volume occurred simultaneously with a decrease in hepatic vascular resistance from 33 ± 6 to 18 ± 2 cm H2O«min/liter (P < 0.001). The decreases in total intravascular volume obtained with either isoproterenol or norepinephrine were abolished after the splanchnic vasculature had been removed in two other animals. Decreases in hepatic resistance, splanchnic volume, and total volume were abolished after propranolol. Thus, β-adrenergic receptor stimulation with either isoproterenol or norepinephrine is associated with a decrease in transhepatic vascular resistance and subsequent decreases in splanchnic and total systemic intravascular volume. Circ Res 48:112-120, 1981

Action of Diazoxide on Skeletal Muscle Vascular Resistance

Controversy exists as to whether arteriolar dilation after diazoxide (DZ) administration is due to a prolonged vascular effect that outlasts the presence of circulating levels of DZ or to equilibrium of arteriolar sites with circulating DZ. To resolve this question, the direct effects of DZ on the vascular resistance (VR) of the isolated blood-perfused (constant-flow) gracilis muscle were evaluated in 44 anesthetized dogs. Intra-arterial infusions of DZ resulted in falls in vascular resistance (−35.9±5.5 SEM %) which returned to control levels after the infusions, thus indicating that irreversible binding to arterioles or a prolonged arteriolar effect independent of plasma levels of the drug did not obtain. Decreases (− 16% to −35%) in VR could also be achieved by premixing DZ in the blood perfusion reservoir at concentrations between 40 and 100 mg/L (which may be achieved clinically); thus albumin binding does not abolish the activity of DZ. Decreases in VR by DZ were not related to stimulation of beta-adrenergic receptors, alteration in Na+ or K+ balance, or changes in venous levels of glucose, lactate, pO2, pCO2, or pH. When norepinephrine and angiotensin II were infused during diazoxide infusions their vasoconstrictor response was attenuated. Thus DZ has a direct effect in lowering VR which is independent of measurable changes in gracilis muscle metabolism. Moreover, the VR effect of DZ is not dependent on a prolonged arteriolar effect independent of plasma concentrations of the drug.

Effect of changes in ventricular relaxation on early diastolic coronary blood flow in canine hearts.

Since the gradient between aortic pressure and left ventricular diastolic pressure is a major determinant of coronary blood flow, a change in left ventricular relaxation by its effect on early diastole could diminish early diastolic coronary flow. Two interventions that resulted in impaired left ventricular relaxation, hypothermia, and reperfusion following a left anterior descending coronary artery occlusion were studied to evaluate whether there were associated changes in coronary blood flow. With both interventions, there was a significant prolongation of left ventricular relaxation (p<0.01) accompanied by a significant decrease in early diastolic coronary blood flow (p<0.01). Verapamil did not have a significant effect on these hemodynamic changes during hypothermia. However, verapamil significantly blunted the effects of reperfusion following ischemia on ventricular relaxation (p<0.002) and early diastolic coronary blood flow (p<0.01). Thus, impaired left ventricular relaxation has an adverse impact on early diastolic coronary blood flow, which, under the condition of reperfusion following regional myocardial ischemia, can be alleviated with calcium channel blockade. (Circulation Research 1987;61:747-756)

Neurogenic histaminergic vasodilation in canine skeletal muscle: mediation by alpha 2-adrenoceptor stimulation.

This study examines the neurogenic effect of α2-adrenoceptor stimulation on skeletal muscle vascular resistance and its relation to the level of background sympathetic activity. The isolated, separately perfused, neurally intact canine gracilis muscle preparation was used since it permits deliberate and quantifiable alterations in background sympathetic activity, as measured by skeletal muscle vascular resistance. Systemic intravenous UK-14304, a highly selective α2-adrenoceptor agonist, produced a precipitous, neurogenic vasodilation that lowered vascular resistance below the subsequently denervated resistance, thus indicating that an active vasodUation was involved. The overall magnitude of the vasodilation was much greater in animals that had been hemorrhaged to elevate background sympathetic activity than in animals that had been transfused to lower background activity. The neurogenic vasodUation was unaffected by baroreceptor and cardiopulmonary receptor denervatlon and by prior cholinergic-receptor blockade of the gracilis muscle. Prior H1- and H2-histaminergic-receptor blockade, on the other hand, eliminated the active vasodUation but not a vasodUation down to the subsequently denervated resistance. Prior α1-adrenoceptor blockade lowered resistance down to the subsequently denervated resistance and greatly attenuated the active vasodilation. The present study demonstrates that withdrawal of sympathetic activity by α2-adrenoceptor stimulation produces an active vasodilation resulting from histamine release in skeletal muscle as well as a passive vasodUation resulting from lysis of peripheral vasoconstrictor tone.

Hyperosmotic mannitol and collateral blood flow to ischemic myocardium

Elevation of extracellular osmolality reduces the extent of myocardial and endothelial cell swelling that accompanies acute ischemia, and the reduction of cell swelling is associated with an increase in collateral blood flow to the ischemic area. However, little is known about the effects of hyperosmolality on the vascular resistance of the collateral coronary vasculature. We compared the effects of hyperosmolar mannitol with those of nitroglycerin and dipyridamole on the vascular resistance of large collateral coronary vessels and of the small arterial vasculature in an isolated heart model of regional ischemia. Elevation of osmolality by mannitol increased collateral blood flow to the ischemic region through at least two mechanisms. First, increasing osmolality resulted in dilation of large arterial conductance vessels, similar to that produced by nitroglycerin. In addition, mannitol produced an effect on the coronary circulation at a microvascular level which, per se or in combination with its effect on larger collateral conductance vessels, increased collateral blood flow to ischemic regions.