Experimental studies on the neurocardiovascular effects of urapidil

The major purpose of our study was to determine whether urapidil acts in the central nervous system (CNS) to lower arterial blood pressure. Once demonstrating a CNS antihypertensive action of urapidil we further set out to determine: (1) the relative role of a CNS antihypertensive action to the total antihypertensive effect of urapidil; (2) the brain site of action for the antihypertensive effect of urapidil; and, (3) the receptor mechanism whereby urapidil acts in the CNS to lower arterial blood pressure. Studies were conducted in chloralose-anaesthetised cats, and arterial blood pressure and heart rate were monitored. Drugs were administered intravenously (IV), into the cerebral ventricles (ICV), topically by application to the ventral surface of the medulla and by microinjection into specific nuclei. Receptor binding studies were also conducted using rat cerebral cortex homogenates. We found that injection of urapidil into the fourth ventricle decreased arterial pressure. Local application of urapidil to the ventral medullary surface also decreased arterial blood pressure. Microinjection of urapidil into one of the nuclei associated with the ventral surface of the medulla, the rostral part of the nucleus reticularis lateralis (rLRN), produced a similar degree of antihypertensive effect. The effect of urapidil was not altered by alpha 1-receptor blockade. Instead, the urapidil effect resembled that produced by drugs that stimulate serotonin (5-hydroxytryptamine)-1A receptors (B695-40 and 8-OH-DPAT). Furthermore, urapidil was found to have the highest potency for binding to serotonin-1A receptor sites (as compared to alpha 1- and alpha 2-receptor sites). Urapidil administered IV was shown to lower arterial blood pressure in part by blocking peripheral alpha 1-adrenoceptors but also, in high doses, by acting in the CNS to decrease central sympathetic outflow. These data indicate that urapidil is a unique drug, possessing both peripheral and CNS actions which contribute to its antihypertensive effect. Urapidil may also be unique in that its central action may involve activation of serotonin-1A receptors.