No abstract

A B S T R A C T Coronary responses to adrenergic stimuli were determined in the intact beating heart before and after administration of practolol, 4-(2-hydroxy-3-isopropylaminoproproxy) acetanilide, which in low doses blocks myocardial but not vascular beta receptors. The left circumflex coronary artery of dogs was perfused with arterial blood at constant flow, and coronary perfusion pressure was measured.Before practolol, intracoronary injections of isoproterenol and norepinephrine and electrical stimulation of left cardiac sympathetic nerves caused reductions in perfusion pressure or vasodilatation associated with increases in left ventricular dp/dt, heart rate, and systolic pressure.After practolol, the coronary vasodilator response to isoproterenol was reduced by about 30% and occurred without significant changes in dp/dt, heart rate, and pressures. The addition of propranolol blocked completely the coronary responses to isoproterenol. Vascular responses to isoproterenol in the paw were not altered by practolol.Practolol antagonized the increases in dp/dt, heart rate, and systolic pressure and reversed coronary responses to norepinephrine and nerve stimulation from dilatation to constriction. The constriction, in turn, was reduced or reversed by phentolamine, an alpha receptor antagonist. Propranolol did not augment the constriction seen in response to norepinephrine and nerve stimulation after practolol.These results indicate that the coronary vasodilator action of norepinephrine and sympathetic nerve stimulation is indirect and caused by stimulation of myocardial

Direct effects of adrenergic stimuli on coronary vessels in dogs were compared with effects on vessels to skin (hind paw) and skeletal muscle (gracilis muscle) after intravenous administration of practolol (2 mg/kg), a selective myocardial beta receptor blocker which minimized indirect effects of myocardial stimulation on coronary vascular resistance. The left circumflex coronary, cranial tibial, and gracilis arteries were perfused separately but simultaneously at constant flow.Perfusion pressures, left ventricular pressure and dP/ dt, and heart rate were recorded. Changes in perfusion pressure to each bed reflected changes in vascular resistance.The direct constrictor effects of sympathetic nerve stimulation, norepinephrine and phenylephrine on coronary vessels were minimal compared with effects on cutaneous and muscular vessels. Subsequent blockade of vascular beta receptors did not augment the constrictor responses. Angiotensin, a nonadrenergic stimulus, produced striking coronary vasoconstriction which exceeded that in skin and approximated that in muscle. These results suggest that there is a paucity of alpha adrenergic receptors in coronary vessels compared to cutaneous and muscular vessels.Direct dilator responses to isoproterenol were similar in coronary and cutaneous vessels, but were greater in muscular vessels. Responses to glyceryl trinitrate, a nonadrenergic dilator, also were greater in skeletal muscle. Therefore, differences in effects of isoproterenol on the three beds may reflect differences in reactivity to dilator stimuli rather than differences in the density of beta receptors.This work was presented in part at the 43rd Scientific Sessions of the American Heart Association, Atlantic City, 13 November 1970. A preliminary report has appeared in abstract form (1).Received for publication 3 May 1971 and in revised form 27 September 1971. In contrast to norepinephrine, the predominant direct effect of epinephrine on coronary vessels was dilatation mediated through activation of vascular beta receptors. A constrictor effect caused by stimulation of alpha receptors was unmasked by propranolol.Finally, the order of potency of agonists in stimulating coronary vascular beta receptors and the demonstration of selective beta receptor blockade with practolol suggest that beta receptors in coronary vessels resemble those in peripheral vessels more than those in myocardium.

A B S T R A C T Ascorbic acid is a required cofactor in the conversion of dopamine to norepinephrine in vitro, and the deficiency of this vitamin in guinea pigs is associated with degeneration of autonomic ganglion cells and with cardiac supersensitivity to norepinephrine. Because of these findings, we tested the hypothesis that ascorbic acid deficiency in man alters autonomic cardiovascular reflexes and vasomotor responses to adrenergic stimuli. We studied five normal volunteers who had been deprived of ascorbic acid for a period of 3 months; they had developed symptoms and signs of scurvy and their plasma levels of ascorbic acid averaged 0.178 +SE 0.07 mg/100 ml. We repeated the studies after giving the subjects vitamin C for a period of 4 months; they had become asymptomatic and their plasma ascorbic acid had increased to an average of 1.68 ±0.151 mg/100 ml.Blood flow to the left forearm (plethysmograph), arterial and central venous pressures, and heart rate were measured before and after exposure of the lower half of the body to subatmospheric levels of pressure and before and after intravenous and intra-arterial (left brachial artery) infusions of norepinephrine and tyramine.Average values of blood flow (7.9 ±1.4 ml/min per 100 ml), arterial pressure (91.2 ±4.6 mm Hg), heart rate (68 ±4.4 beats/min), central venous pressure (6.1 ±1.1 mm Hg), and plasma catecholamines (0.68 ±0.20 /Ag/liter) obtained during ascorbic acid deficiency were not altered significantly after correction of the deficiency. Vasoconstrictor responses to intra-arterial norepinephrine and tyramine were augmented after vitamin repletion. During ascorbic acid deficiency, four subjects had

Choline acetyltransferase activity, which is rate limiting in acetylcholine biosynthesis, was measured in the four heart chambers of guinea pigs subjected to (1) sham surgery, (2) constriction of the ascending aorta, (3) constriction of the descending thoracic aorta, and (4) constriction of the pulmonary artery. After 30 days when hypertrophy and heart failure were fully established, choline acetyltransferase was quantified in vitro by a radiochemical assay. In the sham-operated group, enzyme activity expressed in terms of unit weight of cardiac tissue was greatest in the right atrium and the right ventricle and lower in the left atrium and the left ventricle (3.62 ± 0.30, 2.96 ± 0.52, 1.64 ± 0.15, and 1.67 ± 0.22 nmoles/min g~\ respectively). Enzyme activity was reduced (P < 0.05) in the right atria and the right ventricles of guinea pigs with constriction of the pulmonary artery (1.68 ± 0.37 and 1.31 ± 0.29 nmoles/min g" 1 , respectively). Enzyme activity also tended to be reduced in the left atria and the left ventricles of guinea pigs with constriction of the aorta. These changes represented a relative dilution of enzyme activity per unit weight but not an absolute depletion, since, choline acetyltransferase activity per ventricle was not reduced. The absence of significant changes in the total amount of the neuronal enzyme, choline acetyltransferase, per ventricle contrasted with the observed increases in the myocardial enzyme, carnitine acetyltransferase. These results confirm the presence of significant parasympathetic innervation of the ventricles as well as the atria but do not demonstrate alterations in parasympathetic neurotransmitter biosynthesis in hypertrophied and failing myocardium. The absence of absolute reductions in choline acetyltransferase activity in hypertrophied and failing ventricle contrasts strikingly with the previously reported reductions in tyrosine hydroxylase, which is rate limiting in sympathetic neurotransmitter biosynthesis. KEY WORDSparasympathetic neurotransmitter cardiac chambers carnitine acetyltransferase cardiac hypertrophy parasympathetic innervation of the heart choline acetyltransferase• In hypertrophied and failing hearts, defects in neurogenic control involve both sympathetic and parasympathetic abnormalities. These sympathetic defects are characterized by decreases in catecholamine biosynthesis and depletion of the sympathetic neurotransmitter (1-4), but the nature of the parasympathetic defects is uncertain (5). Depletion of the parasympathetic neurotransmitter, acetylcholine, has been postulated but not confirmed (6). Technical difficulties in the bioassay of acetylcholine emphasize the need for alternative assessments of cardiac parasympathetic innervation (7). Measuring the activity of choline acetyltransferase, the enzyme that catalyzes the This study was supported by U. S. Public Health Service Grants NS 11310, HL 02644, and HL 014388 from the National Institutes of Health and by a grant from the Veterans Administration.Received August 29, 1974. Accep...