Herbert C. Wenger

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.

Pharmacological antagonism of the toxic manifestations of amitriptyline and protriptyline in dogs

Abstract In unanesthetized dogs intoxication with amitriptyline produced tachycardia and neurologic changes characterized chiefly by agitation and restlessness. The chronotropic actions of such intoxication were reduced by inhibitors of cholinesterase (physostigmine, pyridostigmine), by mecamylamine, a ganglionic blocking agent, and by propranolol, a β-receptor blocking agent. Neurologic patterns were favorably influenced only by physostigmine. Protriptyline, given in toxic doses, produced a lesser degree of tachycardia, did not cause neurologic disturbances and was less susceptible to physostigmine reduction of heart rate changes than amitriptyline. The data suggest that the weak anticholinergic activities of amitriptyline and protriptyline may be responsible for some of the toxic manifestations. Activation of the sympathetic nervous systems may participate to some extent in the tachycardia.

Central antihypertensive properties of muscimol and related structures

Abstract The central antihypertensive properties of four γ-aminobutyric acid (GABA) analogs were characterized in anesthetized cats with implanted intracerebroventricular cannulae. An intracerebroventricular infusion (ICV) of muscimol, 0.1-0.5 μg/min (total dose: 1–5 μg ICV), substantially reduced mean arterial pressure and slightly reduced heart rate. The compound was not hypotensive at 5 μg IV (total dose) and only slightly hypotensive after an intracisternal injection (5 μg). Kojic amine (2-aminomethyl-5-hydroxy-4H-pyran-4-one) and baclofen were also hypotensive following an intracerebroventricular infusion, but they were less active than muscimol. GABA, at 15–150 μg/min ICV (total dose, 150–1500 μg ICV), was not hypotensive by itself and unlike muscimol its activity was not enhanced in cats pretreated with nipecotic acid, an uptake inhibitor of GABA. The ability of muscimol to interfere with baroreceptor reflexes was considered in experiments in which reflex vasoconstrictor (carotid occlusion) and reflex vasodilatation (acute elevation in mean arterial pressure with norepinephrine) was measured in the perfused hindlimb of cats previously prepared with intracerebroventricular cannulae. Muscimol significantly attenuated the response to bilateral carotid occlusion and completely abolished reflex vasodilatation. These results suggest that GABA agonists and analogs may regulate blood pressure centrally and, through an interaction with the central nervous system, may attenuate baroreceptor reflexes.