Comparison of hypotensive, orthostatic and sympathetic inhibitory actions of antihypertensive drugs in rats.

Hypotensive and orthostatic activities of a variety of orally administered antihypertensive drugs were concurrently evaluated in conscious spontaneously hypertensive rats and attempts were made to relate these responses to effects on peripheral sympathetic function. The alpha-adrenergic blockers phentolamine and prazosin and the adrenergic neuron blocker guanethidine inhibited compensatory responses to upright tilt at antihypertensive doses. The ganglionic blocker mecamylamine produced milder inhibition. The centrally active agents methyldopa and clonidine and the vasodilator minoxidil did not alter tilt responses appreciably. In contrast, the vasodilator hydralazine exerted marked postural effects. Autonomic interactions were evaluated in pithed rats. alpha-Adrenergic receptor, adrenergic neuron and ganglionic blockers inhibited pressor responses to i.v. phenylephrine and/or to sympathetic nerve activation. Vasodilators did not produce specific effects. The tilt and pithed rat models, when used in conjunction, are very useful in predicting orthostatic potential of drugs in humans although absolute correlation cannot be expected.