Lipid and Carbohydrate Metabolism of Myocardium During the Biphasic Inotropic Response to Epinephrine

Ethanol in saline solution (15!b, v/v) was infused into anesthetized rabbits at a rate of 0.494 ml/min for the first 12 minutes and then at 0.247 ml/min for 108 minutes. Three hours after the infusion, heart triglyceride and lipoprotein lipase were assayed. Oxidation and esterification of fatty acids (palmitate-14 C as an indicator) were assessed by using either tissue homogenates or perfused hearts taken from the rabbits. Oxidation-reduction states of the perfused hearts were examined by measuring the tissue levels of dehydrogenase-linked substrates. The infusion of ethanol resulted in 180% increase in heart triglyceride content, but the infusion of norepinephrine (3 /Ltg/kg/min) did not change the content. No change in plasma free fatty acids and triglyceride or heart lipoprotein lipase activity was detected. Addition of ethanol had little effect on the distribution of palmitate-1 4C in the lipids of tissue slices and homogenates. On the other hand, prior infusion of ethanol resulted in depression of 14 COj production (70 and 50%) and enhanced fatty acid esterification into triglyceride (270 and 170$) both in homogenates and perfused hearts. Mitochondrial and cytoplasmic redox states were shifted to more oxidized states by ethanol infusion. It is postulated from these results that an accumulation of triglyceride in the rabbit heart in response to ethanol administration is a result of decreased fatty acid oxidation rather than of increased tnglyceride uptake or increased fatty acid synthesis.

Section: Resultscontrasting

confidence: 99%

Metabolic Effects of Ethanol on the Rabbit Heart

Kikuchi

Kako

1970

“…An hypoxic mechanism with either an oxygen supply deficit or "oxygen wasting" has been postulated in the pathogenesis of the catecholamine induced cardiac lesions (11,(21)(22)(23). The recent metabolic studies of Regan during epinephrine and norepinephrine infusions do not support an ischemic theory (24,25). Furthermore, dissimilarities between catecholamine lesions (5, 9, 17, 18) and the morphologic (26) and biochemical (27) lesions of ischemic necrosis raise serious doubt about the traditionally postulated hypoxic mechanism.…”

Section: Discussionmentioning

confidence: 98%

Cardiovascular Effects of Sustained Norepinephrine Infusions in Dogs

Moss

Schenk

1970

Sustained infusions of norepinephrine (NE) are known to produce deleterious pathophysiologic effects on the circulatory system. The mechanisms responsible for these effects were investigated in 25 dogs; 17 were treated with selective block of alpha receptors by phenoxybenzamine or of beta receptors by propranolol, or by both agents, and then infused with NE (4 /ig-kg-1 -min-1 ) for 4 hours; 8 control animals were given only adrenergic blocking agents. Left ventricular and systemic pressure, cardiac output and arterial blood gases were measured at selected intervals throughout the infusion period, and histologic examinations of the heart and other vital organs were performed at the conclusion of each study. In animals with alpha-receptor blockade, NE infusions were associated with extensive subendocardial hemorrhage and focal myofiber fatty degeneration, yet blood pressure, cardiac output, and derived cardiac work parameters were well maintained. In animals with beta-receptor blockade, NE caused minimal pathologic changes in the heart despite significant reduction in cardiac output, minute and stroke work, and significant increase in left ventricular end-diastolic pressure (LVEDP) and peripheral vascular resistance. In animals receiving combined alpha-and beta-receptor blockade, NE infusions were not associated with significant hemodynamic or morphologic abnormality. These findings indicate: (1) the hemodynamic abnormalities are the result of the action of NE mediated primarily through alpha receptors; (2) the morphologic changes are produced by NE mediated mostly through beta receptors; and (3) the reductions in cardiac output and minute and stroke work and the increase in LVEDP produced by sustained NE infusions are not necessarily a consequence of the pathologic changes which develop in the heart muscle. This work was supported in part by U. S. Public Health Service Grants HE 10465-03 and HE 10251-05 from the National Heart Institute, a General Research Support grant and by the Ernest L. Woodward Research Fund.Received July 11, 1969; accepted for publication October 17, 1970. tory abnormalities were correlated with the development of extensive myocardial lesions (5, 6) and it was postulated that the myocardial lesions accounted in large part for the low cardiac output that developed during NE administration (4).Norepinephrine, by stimulating both alpha and beta receptors, produces constriction of the peripheral resistance vessels and a positive inotropic effect on the myocardium. To define more clearly the mechanisms responsible for the deterioration in cardiac function and for the cardiovascular lesions that develop during sustained NE infusions, selective adrenergic blocking agents were administered before NE

“…This raised the possibility that NE causes direct injury to the myocyte, and possibly interstitial cells, independent of concurrent hemodynamic or metabolic changes (Ferrans, 1969). Indeed, myocardial lipid accumulation is one of the earliest biochemical changes in canine myocardium following catecholamine injury, and occurs with no reduction in coronary flow or its transmural distribution (Regan et al, 1966(Regan et al, , 1971(Regan et al, , 1972.…”

Section: Discussionmentioning

confidence: 99%

Contribution of alpha-adrenoceptor activation to the pathogenesis of norepinephrine cardiomyopathy.

Downing¹,

Lee²

1983

Graded doses of norepinephrine and methoxamine were given to rabbits over a standard 90-minute infusion period to assess their potential for inducing myocardial injury. Lesions of myofiber necrosis and leukocytic infiltration were graded semiquantitatively in animals killed 2 days later. A close correlation was found between the dose of norepinephrine and the histological score (r = 0.912, P less than 0.001). Mean arterial pressure rose from 100 mm Hg to a maximum of 129 mm Hg, and averaged 115 mm Hg during infusion of 2 micrograms/min per kg. However, heart rate fell from 287 beats/min to average 208 beats/min. The pressure-rate product, an index of metabolic demand, showed no significant change and did not differ from saline-infused controls. Beta-adrenergic blockade with practolol (4 mg/kg) or propranolol (1 mg/kg) failed to significantly reduce cardiac injury with norepinephrine. However, alpha-adrenoceptor blockade with phentolamine (10 mg), alone or in combination with either of the beta-antagonists, markedly reduced lesion formation as reflected by the histological score (P less than 0.02). Administration of the alpha-agonist methoxamine produced dose-related increases in the intensity of myocardial injury (r = 0.938, P less than 0.01), morphologically identical with those resulting from norepinephrine. Hemodynamic changes also were comparable. Phentolamine markedly reduced methoxamine injury. It may be concluded from these studies that norepinephrine cardiomyopathy results in large part from activation of the alpha-adrenergic system in the rabbit model. Ischemia or a supply-demand mismatch are unlikely mechanisms. We speculate that alterations in myofiber Ca++ translocation, uptake, and binding induced by alpha 1-receptor activation may contribute to membrane damage.