S.Evans Downing

Coronary vasoconstriction and catecholamine cardiomyopathy

Norepinephrine (NE) causes extensive myocardial injury in the rabbit. To investigate a potential mechanism we measured coronary blood flow with radioactive microspheres. Coronary resistance and oxygen demand (heart rate-blood pressure double product) were calculated. Severity of injury was determined by semiquantitative histologic evaluation. Changes resulting from NE infusion were determined in animals with or without alpha-receptor blockade with phentolamine (10 mg). In all animals oxygen demand remained constant. Coronary blood flow (ml/gm/min) was 2.66 at the beginning of the experiment, rose to 3.46 after 3 minutes of NE infusion (p less than 0.05), then declined to baseline values (2.33) after 10 minutes. However, coronary blood flow was sharply lower than baseline (1.51; p less than 0.05) after 40 minutes of infusion. Coronary resistance rose progressively from baseline values of 40.9 (units) to 74.8 at 40 minutes (p less than 0.05). Animals given phentolamine manifested none of these changes. Control subjects infused with saline solution showed no significant changes in coronary blood flow or coronary resistance. Animals pretreated with phentolamine had minimal histologic damage at 48 hours compared with NE alone (p less than 0.01). We conclude that NE induces sustained coronary vasoconstriction in the rabbit and that reduced coronary blood flow may contribute to the pathogenesis of NE cardiomyopathy in this species.

Myocardial injury following endogenous catecholamine release in rabbits

Catecholamines (CAT) given in large doses produce cardiomyopathic changes in several animal species. This study was designed to determine if endogenous release can also induce cardiac injury. Rabbits were infused with doses of tyramine (TYR), ranging from 200 to 500 micrograms/min/kg, i.v. for 90 min. Arterial pressure and heart rate were measured, as were total CAT concentrations, blood gases, pH and glucose. Two days later the animals were killed and cardiac injury assessed using a histological scoring system. All data were compared with controls given saline. Initial CAT averaged 452 pg/ml, rose to 2890 pg/ml after starting TYR, 500 micrograms/min/kg, and remained elevated for the duration of infusion. Circulating CAT levels were a function of TYR dose, and bore a linear relationship to the histological score (P less than 0.001). Development of lesions was unaltered by beta 1 blockade with practolol, but sharply reduced by alpha blockade with phentolamine (P less than 0.01). Pretreatment with insulin also reduced lesion formation, but diabetic (alloxan) rabbits showed no greater CAT injury. It is concluded that endogenous release of CAT induces myocardial injury in the rabbit in a dose-dependent manner. This is unrelated to myocardial O2 demand, and microvascular pathology was absent. Activation of alpha adrenergic pathways is likely the dominant or exclusive mechanism.

Inotropic responsiveness of the heart in catecholamine cardiomyopathy

Inotropic responsiveness to norepinephrine (NE) or Ca2+ was studied in 15 rabbits with catecholamine cardiomyopathy (CM) and the results were compared with 11 controls. The former group was prepared by infusing NE (2 micrograms/min/kg) for 90 minutes, 2 to 3 days prior to study, and injury was confirmed and quantified histologically. Comparison of NE dose-response curves relating percent increase of left ventricular (LV) dP/dt max to NE dose in six controls and 10 CM hearts revealed significant depression of CM contractility. Responses to graded infusions of Ca2+ were also determined in five controls and in five CM animals. With the increases in serum Ca2+ identical in the two groups, the percent increases in dP/dt max were less in CM hearts. Further, NE dose-response curves obtained during continuous CaCl2 infusion were sharply attenuated in CM hearts and initial LV end-diastolic pressure (LVEDP) in the CM hearts was considerably higher than in the controls. It is concluded that inotropic sensitivity to NE is reduced in CM hearts. This cannot be ascribed to altered beta-receptors alone, because responsiveness to Ca2+ was also reduced. Myocardial damage was indicated by histology and elevated LVEDP. Moreover, the normalized percent data suggest tht the remaining viable fibers in the CM hearts were functioning subnormally and thus reduced performance was not due solely to the decreased number of contracting units.

Mechanical and metabolic effects of insulin on newborn lamb myocardium.

The effects of insulin on myocardial contractility (MC) and metabolism were studied in 18 newborn lambs. Cardiac work and rate were kept constant. Following insulin (80 units, intravenously), contractility increased and remained elevated for 1 hour. This was not prevented by beta blockade or glucose infusion. Myocardial extraction and uptake of glucose and nonesterified fatty acid (NEFA) increased, the arterial concentration of both decreased. But after glucose fell to less than 20 per cent of control, uptake of both glucose and NEFA declined as did MC. It is concluded that in the neonate insulin increases MC as well as substrate uptake.

Preservation of Ventricular Function by Adrenergic Influences during Metabolic Acidosis in the Cat

Although metabolic acidemia reduces the contractility of cardiac muscle in isolated preparations, it does not do so to the same extent in intact animals or those with a functioning sympathoadrenal system. The present study was designed to determine if the resistance of the heart to acidemia is the consequence of concurrent adrenergic influences on the myocardium. The function of the cats left ventricle was examined in a preparation that allowed control of aortic pressure, cardiac output, heart rate and temperature. The arterial blood pH, Po2, Pco2, and temperature were continuously measured. Acidemia was produced either endogenously by temporarily diminishing perfusion of peripheral tissues, or by infusion of 0.5N lactic acid. Studies were made before and after beta-receptor blockade with propranolol, 0.25 to 0.5 mg/kg iv or im. In eight control animals, reduction of pH from 7.34 to 7.08 failed to diminish contractility. In 14 animals with beta-receptor blockade, reduction of pH to 7.02 reduced contractility by about 25% (P<.001). Correction of the acidemia by infusion of tris(hydroxymethyl)aminomethane returned contractility to approximately 95% of control. Rapid reduction of pH transiently diminished contractility in control animals and severely depressed those with beta-receptor blockade. These data support the position that sympathoadrenal activity is necessary to preserve ventricular function in the presence of severe metabolic acidemia.

Influence of Sympathetic Nerve Stimulation on Ventricular Function in the Newborn Lamb

Cardiac responses to supramaximal electrical stimulation of postganglionic sympathetic nerve fibers were studied in 17 lambs, 10 hours to 3 days of age. In all lambs left ventricular contractility increased within 3 seconds and was unaltered by atropine, ganglionic blockade, or nerve sectioning proximal to the stimulating electrodes but was abolished by beta-receptor blockade. The responses were repeatedly demonstrated in two lambs subjected to bilateral adrenalectomy. Acidemia (pH 6.9) produced by lactic acid infusion failed to diminish the inotropic responses. Intravenous or leftatrial injections of tyramine produced chronotropic and inotropic responses comparable to sympathetic nerve stimulation. Glucagon, 50 to 200 µg/kg, failed to elicit cardiac responses in lambs from 1 to 60 days of age. It is concluded that sympathetic neural mechanisms may strongly influence myocardial contractility in the newborn lamb and that these responses are independent of adrenal medullary release of catecholamines. These findings further suggest that the lamb possesses a myocardial adenyl cyclase system that responds only to catecholamines and may be blocked with propranolol.

Contributions of Coronary Perfusion Pressure, Metabolic Acidosis and Adrenergic Factors to the Reduction of Myocardial Contractility during Hemorrhagic Shock in the Cat

The contributions of metabolic acidosis, coronary perfusion pressure (CPP) and adrenergic support to left ventricular performance during hemorrhagic shock at aortic pressure (AP) of 30 ± 5 mm Hg were evaluated in cats in which AP, cardiac output (CO), and heart rate (HR) were controlled, and arterial pH, Po2 and Pco2 were continuously monitored. After 2 hours of shock, the stroke volume (SV), ejected at end-diastolic pressure of 10 cm H2O (SV10), was irreversibly reduced to 46 ± 4% (P < .001) of initial values (arterial pH 6.93 ± .05). In control animals SV10 after 2 hours was 86 ± 6% (pH 7.32 ± .07). Eight animals were subject to shock, but their CPP was held at 100 mm Hg. These showed no difference in SV10 from controls after 2 hours, although the pH had fallen to 6.90 ± .05. Reduction of CPP in these animals without correction of pH resulted in a rapid fall of SV10. In 10 animals subjected to shock for 2 hours, the arterial pH was maintained near 7.40 by infusion of Tris buffer. Five showed no greater reduction of SV10 than the controls, and five became severely depressed. In five cats subjected to beta-receptor blockade, hemorrhagic shock (pH 7.40) produced a rapid fall of SV10 which initially could be reversed by reelevation of AP. In less than 15 minutes, the SV10 depression became irreversible. Thus, shock (2 hours) and associated metabolic acidosis is detrimental to ventricular contractility only if CPP is also reduced. The contribution of acidosis may be related to the amount of sympathetic support during shock. With beta-receptor blockade, shock results in a marked reduction in SV10, even in the absence of metabolic acidosis.

Oxidative metabolism and mechanical function in reperfused neonatal pig heart

Oxidative metabolism in reperfused neonatal myocardium has not been characterized. A blood-perfused isovolumic heart preparation was used to quantify metabolic and mechanical responses of the neonatal left ventricle to global normothermic ischemia and reperfusion. Hearts from piglets aged 2-7 days were subjected to either 2 hrs of total ischemia at 37 degrees C followed by 1 hr of reperfusion or 3 hrs of perfusion alone; glucose and palmitate oxidation were measured in separate experiments by incorporation of the appropriate [14C]-labeled substrate into the perfusate. In the pre-ischemic period, glucose, palmitate, and lactate contributed 10%, 41%, and 36%, respectively, to oxidative metabolism. After 2 hrs of total normothermic ischemia, oxidation of exogenous glucose was 165% and 229% of control values at 30 and 60 minutes of reperfusion, respectively; palmitate oxidation was 110% and 143% of control values at these times. Despite increased glucose oxidation, palmitate oxidation accounted for 69% of myocardial oxygen consumption after 1 hr of reperfusion, with glucose responsible for 25%. Lactate use was minimal during reperfusion. Reperfusion was accompanied by rapid and parallel recovery of oxygen utilization, mechanical function, and high-energy phosphates. The neonatal piglet heart demonstrates significant metabolic and mechanical tolerance to prolonged ischemia. Although glucose utilization increased markedly, palmitate was the primary substrate for energy production in the post-ischemic neonatal heart.

Coronary vascular responses to hypoxia in the diabetic lamb: independence from adenosine and autonomic mechanisms.

We have previously found that the coronary dilator response to infused adenosine is attenuated in diabetic (alloxan) lambs. Adenosine responsiveness is restored by administration of insulin. The present studies tested the hypothesis that coronary flow changes with hypoxia, if mediated by adenosine, would also be modified. Studies were carried out in eight control and six diabetic lambs. The animals were anesthetized and prepared to maintain constant arterial pressure (reservoir), cardiac output (pump), and heart rate (paced). Atropine and practolol were given. Forced inspired oxygen was reduced in steps. Arterial and coronary sinus blood samples were analyzed for Po2, oxygen content, pH, hematocrit, and glucose. Myocardial oxygen delivery and uptake (MVO2) were calculated. Coronary flow increased identically in both control and diabetic animals as PaO2 was reduced below 60 Torr. Oxygen delivery and MVO2 fell equally in both groups. Acidosis potentiated hypoxic coronary flow changes. Alpha blockade (phentolamine) was without effect in control lambs but caused coronary flow to increase in diabetic lambs. Changes in coronary flow with hypoxia were unaffected, however. Insulin caused no change in the coronary dilator response to hypoxia in either control or diabetic lambs. It is concluded that coronary alpha tone is increased in diabetes but does not modify changes in coronary flow during hypoxia. As coronary flow responses to hypoxia were unaltered in diabetic lambs, and unaffected by insulin, adenosine may not be the primary mediator of coronary vascular dilatation. Potentiation of adenosine by tissue acidosis is apparently insufficient to explain these findings. The mechanism for coronary dilatation during hypoxia is unclear but may involve direct effects of reduced oxygenation of coronary vascular smooth muscle.

Ventricular responses to hypoxemia following chemoreceptor denervation and adrenalectomy.

Abstract The sensory system responsible for increased ventricular contractility (VC) during hypoxemia is not fully established. Previous studies have demonstrated that isolated carotid body hypoxia is not associated with an increase of VC.8 However, reflexly increased VC may result from pharmacologic stimulation of the aortic chemoreceptors.9 In order to evaluate their contribution during hypoxia, VC was studied in atropinized cats before and following denervation by bilateral vagotomy. VC was measured under conditions of constant aortic pressure, cardiac output, and heart rate. Arterial blood gases and pH were continuously monitored. With hypoxemia (P o 2 27 to 46 mm. Hg), all cats showed an increase of VC, manifested by an increase of dP dt for a given end-diastolic pressure. The responses were unaltered by bilateral vagotomy. Similar findings were obtained in animals with bilateral carotid body denervation. The increase of VC during hypoxia was not significantly less following adrenalectomy. Beta-adrenergic blockade completely abolished these responses. It is concluded that the increase in VC associated with systemic hypoxia cannot be entirely attributed to aortic or carotid chemoreceptor reflex activity. The influence of stimulation of structures within the central nervous system must also be considered.