The Neurogenic Vasoconstrictor Effect of Digitalis on Coronary Vascular Resistance

Abstract

A B S T R A C T The coronary vasoconstrictor properties of digitalis were evaluated in 61 anesthetized, openchest dogs after coronary sinus cannulation and under conditions of a constant heart rate (atrioventricular pacing) and near-constant blood pressure. The contribution of alpha adrenergic receptor stimulation to the digitalisinduced increase in coronary vascular resistance (CVR) was examined. With Na pentobarbital anesthesia (16 dogs), intravenous acetylstrophanthidin (0.5 mg) caused a significant (P < 0.05) rise in CVR from 1 through 9 min after injection. The peak increase was + 11±2% SE of the control of 1.8±0.2 mm Hg/cm3/min. The mean time to peak effect was 3 min, and to recovery was 21 min. Prior alpha adrenergic receptor blockade with phenoxybenzamine in 11 animals reduced (P < 0.05) the acetylstrophanthidin-induced peak of CVR and substantially decreased (P < 0.05) the time to recovery (5 min). Intravenous digoxin (1.0 mg) with Na pentobarbital anesthesia (five dogs) had no significant effect on CVR. However, with chloralose and urethane anesthesia (nine dogs) the same dose of digoxin produced a significant rise in CVR from 3 through 30 min. The peak increase was +20±3% of control (1.4±0.1 mm Hg/cm3/ min). One-third the dose of intravenous digoxin (0.35 mg) produced a 9.5±1.0% increase in CVR (five additional dogs). Myocardial oxygen consumption did not change significantly in nine dogs after intravenous digoxin. In 10 additional dogs pretreated with phenoxybenzamine and in 7 dogs pretreated with mecamylamine, the increase in CVR did not occur after 1.0 mg of intravenous digoxin. Thus there is a coronary vasoconstrictor effect of intravenous acetylstrophanthidin and digoxin, Preliminary report of data presented at the 56th Annual Meeting of the Federation of American Societies for Experimental Biology, 1972. (Fed. Proc. 31: 597. Abstr.) Received for publication 28 February 1973 and in revised form 10 August 1973.of rapid onset, which is mediated through alpha adrenergic receptor stimulation. INTRODUCTIONA direct vasoconstrictor effect of digitalis has been established in a number of organ systems (1, 2) and has been postulated for the heart (3). Recently, a neurogenic vasoconstrictor effect of digitalis, mediated through alpha adrenergic receptor stimulation, has been described in resting skeletal muscle (4); the magnitude of this effect is substantially greater than the direct effect of the drug (4). These findings coupled with the demonstration of the existence of alpha adrenergic receptors in the coronary vasculature (5, 6) suggest that digitalis might have a neurogenic vasoconstrictor effect in the heart. The purpose of this communication is to present data documenting the existence of a neurogenic coronary vasoconstriction produced by both acetylstrophanthidin and digoxin. The data also characterize the time course and magnitude of this effect.

Effects of a cardiac glycoside in combination with propranolol on the ischemic heart of conscious dogs.

“…The effects of occlusion and subsequent propranolol were not significantly different in these animals from the changes observed in dogs subsequently treated with ouabain. However, there were important differences following ouabain from the propranololocclusion baseline which are covered in detail above in 15 17 that the increase in flow was not a spontaneous occurrence over this time period of coronary occlusion, since nontreated control dogs did not demonstrate a further increase in flow after propranolol (table 2). There are several mechanisms which could be responsible for the improvement in blood flow.…”

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

“…Nerve recordings, however, have provided evidence that the digitalis glycosides exert significant effects on the afferent and efferent autonomic nervous system (5)(6)(7). Recent studies in our laboratory have demonstrated that the greatest portion of digoxin-induced coronary vasoconstriction and of acetylstrophanthidin-induced vasoconstriction in skeletal muscle is neurogenically mediated and occurs through stimulation of alpha adrenergic receptors (8,9). This effect appears to be due to the action of digitalis at or proximal to the sympathetic ganglia.…”

Effect of ouabain on total vascular capacity in the dog.

“…The elevation of transhepatic resistance is primarily mediated through stimulation of alpha adrenergic receptors, Similarly, stimulation of alpha receptors is the major mechanism whereby intravenous digitalis administration elevates arterial vascular resistance as noted in Figs. 2 and 3 and our previous work (9)(10)(11). The work by Garan et al (12) suggests that the central nervous system is the site of action of the increase in arterial resistance after digitalis administration.…”

“…Cotten and Stopp (2) studied the effects of the gly-coside ouabain on peripheral capacity in dogs. They hypothesized increases in intravascular volume in the splanchnic vasculature within 10 min of the administration of ouabain based on findings of diminished venous return associated with a decrease in left and right atrial pressures; however, they did not make observations beyond 10 min after drug administration. Furthermore, they did not directly assess the effects of the drug on total vascular capacity, nor did they investigate whether changes in transhepatic resistance might influence splanchnic and total intravascular volume.…”