Mechanism of antihypertensive activity of orally administered prazosin in spontaneously hypertensive rats

Abstract

In conscious, spontaneously hypertensive rats (SHR) oral prazosin (0.03-3.0 mg/kg) resulted in dose-related reductions of systolic blood pressure measured with a tail cuff. In SHR whose tail artery blood pressure was continuously monitored the antihypertensive effect of prazosin (1.0 mg/kg, p.o.) was accompanied by a significant increase in heart rate. Several groups of SHR were pithed 2 hr after oral prazosin (1.0 mg/kg) or placebo. In this preparation the mean carotid blood pressure increases following i.v. injections of angiotensin II or 5-hydroxytryptamine and the positive chronotropic responses to i.v. norepinephrine or electrical stimulation of the spinal cord were similar in control and prazosin-pretreated animals. However, the dose-pressor response curves to i.v. norepinephrine or electrical stimulation of the spinal cord from prazosin-pretreated SHR lay to the right of the control curves. In addition, the slopes of the linear portion of these curves were flatter after prazosin and remained so even after i.v. propranolol was given alone or with cocaine. Prazosin-pretreated SHR responded to phenylephrine with a fall followed by a rise in carotid blood pressure. The depressor effect was abolished and the pressor phase enhanced by i.v. propranolol. The pressor responses to i.v. cirazoline or clonidine were significantly inhibited by prazosin. Finally, prazosin failed to significantly modify the negative chronotropic effects of clonidine observed in pithed SHR whose heart rate was raised by continuous electrical stimulation of the thoracic spinal cord. These results indicate that oral prazosin exerts pronounced antihypertensive effects in the SHR. This action apparently results from impairment of the sympathetic nervous system at the level of vascular postsynaptic alpha-adrenoceptors.