Cardiovascular Activity of A-74283, a 5-Hydroxytryptamine1A Agent, in the Spontaneously Hypertensive Rat

A-74283, (+,-)trans-2-(4-(3a,4,4a,6a,7,7a-hexahydro-4,7-etheno-1H cyclobut [f] isoindol-1,3-dionyl)-butyl)-9-methoxy-2,2,2a,4,5,9b-hexahydro-1H-benz[e]isoindol HCl, was studied in receptor binding assays and in the spontaneously hypertensive rat (SHR). In radioligand binding to rat cortex, A-74283 had high affinity (equipotent to 8-OH-DPAT) and high selectivity for 5HT 1A receptors compared to 5HT 1B sites. In conscious SHR, A-74283 lowered mean arterial pressure (MAP) in a dose-related fashion with a prolonged effect after oral administration of higher doses, but heart rate (HR) was not changed. In anesthetized SHR, i.v. administration of A-74283 decreased MAP and total peripheral resistance, but not cardiac output. Pretreatment of conscious SHR with the selective 5TH 1A receptor antagonists spiroxatrine or BMY 7378 reduced the hypotensive effect of A-74283 significantly, but pretreatment with adrenergic antagonists phenoxybenzamine or idazoxan or the 5HT 2 receptor blocker ketanserin did not alter the effect of A-74283. Intracisternal administration of A-74283 also decreased MAP; however, A-74283 had no effect on blood pressure in pithed SHR in which blood pressure was supported with vasopressin, in contrast to nitroprusside. These data demonstrate that A-74283 exerts a potent hypotensive effect in SHR via systemic vasodilation originating from a central 5HT 1A receptor mechanism. A-74283 may be useful for studying 5HT 1A receptors and cardiovascular function.