James L. Bergey

Effects of atriopeptins I, II and III on atrial contractility, sinus nodal rate (guinea pig) and agonist-induced tension in rabbit aortic strips

The cardiovascular effects of atriopeptins (AP) I, II and III were compared in spontaneously beating or electrically stimulated guinea pig atria and in rabbit aortic strips precontracted by various agonists. Atriopeptins did not significantly affect sinus nodal rate or atrial contractility. AP II and III, although more potent than nitroprusside, exhibited similar vasorelaxant profiles against vascular strips maximally stimulated by norepinephrine, high [K+]0 or Ca2+ ionophore A23187. The ability of atriopeptins and nitroprusside to relax ionophore-induced vascular tension implies an intracellular mechanism of action.

Effects of human ANF-(99-126) on sympathetic nerve function, hemodynamic parameters and plasma cGMP levels in anesthetized, ganglion-blocked dogs

The ability of human ANF-(99-126) (ANF) to affect neuronal function, plasma cGMP levels or various hemodynamic parameters was tested in anesthetized dogs subjected to ganglionic blockade which prevented reflex changes in sympathetic tone. In each group of dogs, heart rate changes due to electrical stimulation of the cardioaccelerator nerve at 0.5, 1, 3 and 10 Hz were measured before and after ANF or vehicle infusion. A possible direct effect of ANF on the beta-adrenoceptor mechanisms was assessed by evaluating changes in heart rate after i.v. administration of isoproterenol (a beta-adrenoceptor agonist). The results showed that i.v. infusion of ANF (200 pmol/kg per min for 60 min), but not vehicle, produced significant inhibition of heart rate responses to low frequency nerve stimulation (0.5-1 Hz) when compared to vehicle 30 min after the end of infusion; high frequency (10 Hz) responses remained unaffected. A significant (P less than 0.05) enhancement in isoproterenol responses was evident in ANF-treated animals at the end of infusion, and 30 min afterward. ANF increased plasma cGMP from pretreatment levels of 28 +/- 4 to 149 +/- 1 pmol/ml at the end of infusion, and falling to 63 +/- 7 pmol/ml 30 min later (t 1/2 = 25.1 +/- 2.2 min). Cardiac output also tended to fall during infusion and remained significantly reduced (-18%) 30 min after infusions end; blood pressure fell without a decrease in total peripheral resistance. Thus, ANF produced a direct, frequency-dependent depressant action on sympathetic nerve function, reduced both cardiac output and blood pressure, and enhanced chronotropic responses to beta-adrenoceptor stimulation. These persistent changes in hemodynamic parameters and neuronal function may contribute to the mechanism of action of ANF.

Direct effects of diltiazem, nifedipine and verapamil on peripheral sympathetic nerve function, cardiac impulse conduction and cardiovascular function in anesthetized dogs subjected to ganglionic blockade

The Ca2+ entry blockers diltiazem, nifedipine and verapamil produced dose-dependent increases in atrioventricular conduction time (A-H interval), while decreasing heart rate and mean arterial pressure in anesthetized dogs previously subjected to ganglionic blockade to prevent hypotension-induced reflex changes in sympathetic tone. Nifedipine and verapamil, but not diltiazem, also reduced (P less than 0.05) the tachycardia produced by electrical stimulation of the cardioaccelerator nerve at doses which did not alter the heart rate response to direct beta-adrenoceptor stimulation by isoproterenol (0.1 microgram/kg i.v.). The lowest doses of nifedipine (0.03 mg/kg) and verapamil (0.3 mg/kg) that produced decreases in mean arterial blood pressure were the same as or greater than those which selectivity reduced the tachycardiac effects of low frequency (1 Hz, 25-35 V, 5 ms), but not high frequency (10 Hz, 25-35 V, 5 ms) cardiac nerve stimulation. These data suggest that threshold vasodilator doses of some Ca2+ blockers may selectively reduce low level (or basal) sympathetic neurotransmission and this additional pharmacologic action may contribute to the antihypertensive mechanism. The failure to inhibit the high frequency nerve response may also help to explain the relatively low incidence of orthostatic hypotension associated with the clinical use of Ca2+ blockers as compared to other direct-acting vasodilators.