Synergistic Effect of Propranolol and Nicotinic Acid on the Inhibition of Plasma Free Fatty Acid Release in the Dog

Abstract

Fatty acid mobilization was effected in 24 anesthetized dogs by infusion of norepinephrine over a four-hour period. Infusions of propranolol and nicotinic acid at various doses, individually and in combination, were added and free fatty acid levels were serially determined. Synergistic action of the two agents was apparent in that minimally effective concentrations of the two agents when used in combination suppressed the release of free fatty acids to 29 percent of levels achieved with norepinephrine (1,186 ju,Eq/L) and 70 percent of levels in saline control animals (501 /j.Eq/L). Large individual doses were no more effective than low doses used in combination. The synergistic action of propranolol and nicotinic acid in the suppression of free fatty acid mobilization may be explained by the action of these two agents on the inhibition of the adenyl cyclase system of the adipose tissue cell. This synergistic action in reducing plasma free fatty acids and their effect on lipid synthesis would allow the use of smaller doses that could reduce the risk of side effects. KEY WORDSlipid synthesis atherosclerosis plasma lipoproteins norepinephrine adenyl cyclase inhibition • This report describes a synergistic effect of low doses of propranolol and nicotinic acid on the suppression of the release of plasma free fatty acids. Each of these agents is known to cause plasma free fatty acids to fall when used in full concentrations (1-4). It has also been shown that under the influence of these agents plasma levels of cholesterol and triglyceride fall (3-7). Recent evidence indicates that the inhibitory mechanism of action of both propranolol and nicotinic acid on the release of plasma free fatty acids at the cellular level is mediated through inhibition of adenyl cyclase (8,9). Methods PROCEDUREMongrel dogs were anesthetized with pentoFrom the New England barbital (30 mg/kg) with a single intravenous dose. Occasionally, 60-mg doses of pentobarbital were given subsequently to maintain anesthesia. A Harvard pump respirator, an arterial catheter, blood pressure recording equipment, and an intravenous catheter were connected to the animals. Continuous blood pressure and electrocardiographic recordings were made. Blood samples were taken at frequent intervals from the arterial catheter as indicated below. The first 5 ml of blood drawn from the arterial catheter was discarded. When several agents were infused, they were combined in the same bottle. In each experiment, there was a 15-minute baseline period during which two blood samples were drawn. Then a norepinephrine infusion was started and continued in all the dogs for 4 hours. At various times during this infusion of norepinephrine, a single dose of propranolol or nicotinic acid was given intravenously and was followed by an intravenous infusion of these agents. Norepinephrine infusion was continued throughout die experiments in all dogs except the saline control animals. In some groups of dogs, both propranolol and nicotinic acid were included in the final infusion mixture.In...

Low-dose propranolol for the protection of the left ventricle from ischaemic damage.

“…22 All these energy-sparing activities of beta-blockers may be augmented by the inherent negative inotropic qualities of the propranolol group of drugs.65 66 During the reperfusion period, the supply of energy is enhanced by beta-blocking drugs, which reduce inequalities of myocardial blood-flow distri-bution67 68 and limit microvascular injury during ischaemia.69 7I( The glucose extraction of the myocardium is increased and there is a peripheral antilipolytic action71 which reduces the rise in free fatty acids (FFA) usually associated with myocardial ischaemia36 72 and beta-adrenergic stimulation.' 73 High concentrations of FFA depress contractility and lead to arrhythmias.5 7 74 There is thus much theoretical rationale for the use of beta-blockade to miiinimise intraoperative ischaemic damage; we have confirmed this promise and have shown that though low-dose propranolol has a temporary effect on the heart during operation it does not impair postoperative contractility. We acknowledge gratefully the technical assistance of John Kitchen, AB McMillan, C Wilson, and Miss J Spoors, the statistical help of W Armstrong and A Murray, and the typing of Miss G Shaw and Miss V Jamieson.…”