John M. Stavorski

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.

Effect of clonidine on cardiac acceleration in vagotomized dogs

Abstract In anesthetized dogs, clonidine, 3, 10 and 30 μg/kg, i.v., antagonized cardiac acceleration induced by electrical stimulation of right post-ganglionic sympathetic fibers. In dogs with vagi intact, the effect of clonidine was not dependent on the frequency of electrical stimulation. In vagotomized dogs, clonidine antagonized cardiac acceleration induced by low (1.58 or 5 Hz) but not high (15.8 Hz) frequency electrical stimulation. Clonidine-induced antagonism of cardiac acceleration cannot be explained by enhancement of vagal activity only. It is likely to involve also a peripheral inhibitory action at the sympathetic nerve endings.

Effects of phentolamine, phenoxybenzamine and desipramine on clonidine-induced blockade of cardiac acceleration in the dog.

Clonidine reduced cardiac acceleration induced by low frequency electrical stimulation of cardiac sympathetic nerve fibers in anesthetized and vagotomized dogs. This effect of clonidine was abolished by short periods of high frequency electrical stimulation. The inhibitory effect of clonidine was observed with 10- as well as with 90-sec periods of electrical stimulation of sympathetic nerve fibers; it was antagonized by phentolamine, phenoxybenzamine and desipramine. This suggests the presence of alpha-adrenoceptors at the peripheral sympathetic nerve ending in the dog.

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.