CARDIOVASCULAR ACTIVITY OF A-74283, A 5-HYDROXYTRYPTAMINE(1A) AGENT, IN THE SPONTANEOUSLY HYPERTENSIVE RAT

A-74283, rans-2-(4-(3a,4,4a,6a,7,7a-hexahydro-4,7-etheno-1H cyclobut [ f] -dionyl)-butyl)-9-methoxy-2,2,2a,4,5,9b-hexahydro- 1H-benz[e]isoind ol HCl, was studied in receptor binding assays and in the spontaneousl y hypertensive rat (SHR). In radioligand binding to rat cortex, A-7428 3 had high affinity (equipotent to 8-OH-DPAT) and high selectivity for 5HT(1A) receptors compared to 5HT(1B) sites. In conscious SHR, A-7428 3 lowered mean arterial pressure (MAP) in a dose-related fashion with a prolonged effect after oral administration of higher doses, but hear t rate (HR) was not changed. In anesthetized SHR, i.v. administration of A-74283 decreased MAP and total peripheral resistance, but not card iac output. Pretreatment of conscious SHR with the selective 5TH(1A) r eceptor antagonists spiroxatrine or BMY 7378 reduced the hypotensive e ffect of A-74283 significantly, but pretreatment with adrenergic antag onists phenoxybenzamine or idazoxan or the 5HT(2) receptor blocker ket anserin did not alter the effect of A-74283. Intracisternal administra tion of A-74283 also decreased MAP; however, A-74283 had no effect on blood pressure in pithed SHR in which blood pressure was supported wit h vasopressin, in contrast to nitroprusside. These data demonstrate th at A-74283 exerts a potent hypotensive effect in SHR via systemic vaso dilation originating from a central 5HT(1A) receptor mechanism. A-7428 3 may be useful for studying 5HT(1A) receptors and cardiovascular func tion.