Central 5-HT(1A) receptors and the mechanism of the central hypotensive effect of (+)8-OH-DPAT, DP-5-CT, R28935, and urapidil

This study investigated the central hypotensive effects of drugs that possess a high affinity for central 5-hydroxytryptamine (5-HT(1A)) binding sites; (+)8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), N,N-dipropylcaboxamidotryptamine (DP-5-CT), erythro-1-{1-[2(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl}- -benzimidazolinone (R28935) and urapidil proved to possess high affinity and selectivity for central 5-HT(1A) binding sites, labeled by [3H]8-OH-DPAT. (+)8-OHDPAT (0.1-10 μg/kg) given through the left vertebral artery of choralose-anesthetized cats, lowered blood pressure by a biphasic dose-response curve. When given systemically, 10- to 100-fold higher doses of (+)8-OH-DPAT were necessary to obtain the same hypotensive effect when compared with central administration. Besides 8-OH-DPAT, R28935, DP-5-CT and urapidil also lowered blood pressure by a central mechanism in doses that were ineffective when given systemically. The central hypotensive effect of 0.3 μg/kg (+)8-OH-DPAT, 3 μg/kg DP-5 CT, and 3 μg/kg R28935 could be blocked by 100 μg/klg (-)pindolol, indicating that central 5-HT(1A) receptors are involved. High doses of (+)8-OH-DPAT (3-10 μg/kg) can also lower blood pressure by activating central α2-adrenoceptors. The hypotensive effect of 300 μg/kg urapidil given through the vertebral artery could not be blocked by (-)pindolol. These results indicate the involvement of central 5-HT(1A) receptors in the mechanism of the central hypotensive activity of (+)8-OH-DPAT, DP-5-CT, and R28935