A rat model for predicting orthostatic hypotension during acute and chronic antihypertensive drug therapy

An experimental model has been developed to determine postural hypotension in chloralose-urethane-pentobarbital (CUP) anesthetized rats. Using this technique, mean arterial pressure, heart rate, and blood pressure compensation to 60 degree tilt were examined in rats treated acutely and chronically with a spectrum of standard antihypertensive agents. The results closely parallel the orthostatic profiles seen clinically with these drugs. Significant orthostatic hypotension was seen with the acute intravenous administration of the alpha-adrenergic antagonists phenoxybenzamine, phentolamine, and prazosin, the neuronal suppressant guanethidine, and the ganglionic blockers hexamethonium and chlorisondamine. The central antihypertensive clonidine displayed mild, acute orthostasis that dissipated by 1 hr. The vasodilator minoxidil was entirely free of postural effects. Chronically, guanethidine, the ganglionic blocker mecamylamine, and a high dose of reserpine all resulted in significant postural hypotension after 4 days of oral administration. Prazosin's acute orthostasis had largely dissipated by this time. Chronic minoxidil resulted in slight overcompensation to tilt. Based on the consistency to these data relative to the clinical profiles of these standard antihypertensive agents, it would appear that the CUP anesthetized rat is an accurate, efficient test model for identifying orthostasis in novel hypotensive agents under acute and chronic drug treatment conditions.