Carl T. Ludden

Some cardiovascular effects of ST-91 and clonidine☆

St-91, 2(2,6-diethylphenylamino)-2-imidazoline, is a clonidine derivative which does not penetrate the blood-brain barrier. In spontaneously hypertensive (SH) rats is acutely increased arterial pressure and reduced heart rate while at 8 to 12 h after oral administration, it slightly lowered arterial pressure. In contrast, clonidine had acute antihypertensive activity at all doses used. By intracerebroventricular administration to SH rats, both drugs (St-91 and clonidine) reduced arterial pressure and heart rate; in this respect, clonidine was more potent then St-91. Cardiac acceleration induced by low frequency electrical stimulation of right cardiac sympathetic nerves in anesthetized and vagotomized dogs was reduced by St-91 at the same doses by clonidine. Phenoxybenzamine, phentolamine and desipramine antagonized the inhibitory effects of St-91 on electrically induced cardiac acceleration. It was concluded that St-91, like clonidine, stimulates inhibitory alpha-adrenergic receptors at the sympathetic nerve endings but, unlike clonidine, is substantially devoid of acute antihypertensive activity. This suggests that stimulation of peripheral presynaptic inhibitory alpha-adrenergic receptors is not likely to represent the sole mechanism of antihypertensive action of clonidine.

Hemodynamic Effects of Angiotensin and Renin Inhibition in Dogs with Acute Left Ventricular Failure

The effects of enalaprilat (MK-422), an angiotensin converting enzyme inhibitor, were compared to those of SCRIP, a renin inhibitor, in experimentally induced left ventricular failure. In anesthetized dogs, acute left ventricular failure was induced by repeated embolization, via the left main coronary artery, with 50 microns plastic microspheres. Embolization significantly increased left ventricular enddiastolic pressure from 6 +/- 1 to 14 +/- 1 (p less than 0.05) mm Hg and decreased both left ventricular maximal dP/dt (3,135 +/- 338 to 1,636 +/- 126 mm Hg/second, p less than 0.05) and cardiac output (3.0 +/- 0.3 to 1.6 +/- 0.1 liters per minute, p less than 0.05). Embolization also significantly reduced heart rate and mean arterial pressure. These parameters remained stable after induction of heart failure. Forty-five minutes after embolization, 16 dogs received enalaprilat (100 microns/kg intravenously) and six dogs received SCRIP (100 microns/kg intravenously followed by 10 microns/kg per minute). Both agents caused similar reductions in left ventricular end-diastolic pressure (21 percent versus 26 percent) and total peripheral resistance (25 percent versus 32 percent) and rise in peak positive cardiac contractility, as measured by (dP/dt)/P, (12 percent versus 11 percent). The data suggest that inhibition of angiotensin II formation by two agents, each or which acts at a different point in the cascade, results in similar beneficial hemodynamic effects in dogs with acute left ventricular failure. In addition, angiotensin converting enzyme inhibition failed to further increase sodium excretion and glomerular filtration rate caused by embolization. In summary, inhibition of angiotensin II production by two different inhibitors of the renin system causes an improvement in left ventricular performance in a model of acute experimental left ventricular failure.

Potentiation of the Antihypertensive Action of Hydralazine by Timolol in Spontaneously Hypertensive Rats

Summary Timolol, a new β-adrenergic blocking agent, was found to potentiate the antihypertensive effect of hydralazine in spontaneously hypertensive rats. Propranolol did not have this effect.

Action of angiotensin on isolated guinea pig ileum.

Conclusions 1. Atropine and morphine effectively block angiotensin and nicotine-induced spasm on the isolated guinea pig ileum. 2. Mecamylamine, pempidine, pentolinium and hexamethonium blocked nicotine-induced spasms; however, only mecamylamine and pempidine blocked angiotensin spasms, but very high concentrations were required. 3. It is proposed that angiotensin acts on the post-ganglionic cholinergic mechanism of the ileum and that its site of action is probably peripheral to the ganglion.

Some cardiovascular effects of germine-3-monoacetate

Abstract In anesthetized dogs germine-3-monoacetate (GMA), 40 to 640 μg/kg i.v., increased mean arterial pressure, right ventricular contractile force, left ventricular pressure and left ventricular dp/dt max. At 160 μg/kg i.v., GMA slightly increased the heart rate. The positive inotropic effect of GMA was not prevented by denervation of the carotid sinuses, pithing of the spinal cord, or adrenalectomy; it was blocked or greatly reduced by propranolol, sotalol, reserpine, mecamylamine or tetrodotoxin. When administered to the superior cervical ganglion of cats GMA enhanced contractions of nictitating membrane caused by electrical stimulation of preganglionic fibers with single electrical stimuli. At 6 to 100 μg/ml GMA had dose dependent positive inotropic and chronotropic effects on the isolated guinea pig atria. The in vivo effects of GMA were apparently mediated by the sympathetic nervous system; in addition, at high concentrations, GMA had a direct cardiotonic action on the artrial muscle.

STUDIES ON INTERACTION OF TIMOLOL, HYDROCHLOROTHIAZIDE AND AMILORIDE IN THE RAT

1. The acute effects of hydrochlorothiazide, amiloride, timolol and their combinations on diuresis and arterial pressure were studied in rats.