Cardiovascular Activity of A-74283, a 5-Hydroxytryptamine_1A Agent, in the Spontaneously Hypertensive Rat

Abstract

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 5HT₂ 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.

Influence of Intraventricular Application of Baclofen on Arterial Blood Pressure and Neurotransmitter Concentrations in the Hypothalamic Paraventricular Nucleus of Rats

“…Activation of these neurons leads to an increase in blood pressure [20]. A decrease is mediated by 5HT type-2 receptors in the nucleus tractus solitarius [21] and also by 5HT type-1A receptors [9]. To prove the effect of baclofen on the PVN, a reverse microdialysis study should be carried out.…”

“…A lack of dopamine [7] and glutamate [8] has been shown to lead to hypertonia. Studies demonstrated that there was a decrease in and increase in blood pressure mediated by 5-hydroxytryptamine (5HT)1 and 5HT2 receptors, respectively [9]. Aspartate [10] and glycine [11] have been shown to lead to a decrease in blood pressure.…”

LB50053: A 5-Hydroxytryptamine_1A Agent with a High Binding Affinity and a Potency Evoking a K⁺ Current

“…5-HT 1A receptors are widely distributed both in nonneuronal and neuronal tissues; it couples to multiple effector systems, including the stimulation of a certain type of K + channel, and thus mediates a variety of physiological and behavioral actions [for a review see 2]. Recently, many new ligands for 5-HT 1A receptor binding sites have been developed [3,4]. Most of them represent relatively small derivatives of 5-HT.…”