ly-53857 and Hypertension

Intracerebroventricular administration of serotonin (5-HT) to conscious rats increases mean arterial pressure (MAP) and decreases heart rate. To determine the mechanisms involved, 5-HT (2.5 micrograms) was injected intracerebroventricularly into conscious rats pretreated with various neurotransmitter and hormone antagonists. The selective 5-HT2 antagonist LY 53857 abolished the increase in MAP and the bradycardia elicited by 5-HT. The increase in MAP produced by 5-HT was potentiated by chlorisondamine (a ganglionic antagonist), unaffected by prazosin (an alpha 1-antagonist) or a vasopressin V1 antagonist alone, but eliminated by the combined pretreatment with prazosin plus the vasopressin antagonist. In contrast, the bradycardia was eliminated by either the vasopressin V1 antagonist or chlorisondamine. In conclusion, 5-HT injected into the lateral cerebral ventricle of conscious rats induces sympathoexcitation and the release of vasopressin, which results in an increase in MAP; 5-HT also elicits a bradycardia mediated through an interaction of the autonomic nervous system with circulating vasopressin.

Topics: Animals; Autonomic Nervous System; Blood Pressure; Bradycardia; Chlorisondamine; Ergolines; Heart Rate; Hypertension; Injections, Intraventricular; Male; Prazosin; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Vasopressins

The mode of action of i.v. injected ketanserin, LY 53857 and other 5-hydroxytryptamine (5-HT2) receptor antagonists in lowering blood pressure was examined in anesthetized and pithed spontaneously hypertensive rats (SHR). In pithed SHR, LY 53857 (1 mg kg-1) had no effect on alpha-1 or alpha-2 adrenoceptors, but ketanserin (1 mg kg-1) had some potency as an alpha-1 adrenoceptor antagonist, being approximately 100 times less potent than prazosin. Both ketanserin and LY 53857 (0.01 mg kg-1) markedly antagonized the pressor response to 5-HT. In pentobarbitone-anesthetized SHR, ketanserin and LY 53857 (1 mg kg-1) were equieffective at lowering diastolic blood pressure (DBP) subsequent to prazosin (1 mg kg-1), although ketanserin (1 mg kg-1) was more effective at lowering DBP in the absence of prazosin. The blood pressure lowering effects of LY 53857 were unaffected by the peripherally acting 5-HT2 receptor antagonist BW 501C. Neither LY 53857 nor ketanserin lowered DBP in pithed rats. It is concluded that ketanserin in high doses lowers DBP in anesthetized SHR partly by alpha-1 adrenoceptor blockade, but that ketanserin and LY 53857 in high doses have additional blood pressure lowering properties, unrelated to peripheral 5-HT2 receptor blockade.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Anesthesia; Animals; Blood Pressure; Ergolines; Heart Rate; Hypertension; Ketanserin; Male; Prazosin; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha; Receptors, Serotonin; Serotonin Antagonists; Tetrahydronaphthalenes; Xylazine

LY53857 was a potent antagonist of vascular contraction to serotonin, which is mediated by serotonergic (5-HT2) receptors, with a dissociation constant in vitro of 5.4 X 10(-11) M. Unlike several other serotonin antagonists, LY53857 showed minimal affinity for vascular alpha adrenergic receptors (dissociation constant of 1.4 X 10(-5) M). Thus, LY53857 was a highly potent and selective antagonist at 5-HT2 receptors. In vivo activity paralleled the in vitro observations. In pithed spontaneously hypertensive rats (SHR), LY53857 at 0.1 and 3.0 mg/kg i.p. produced a 22-and 480-fold shift, respectively, in the pressor response to serotonin whereas LY53857 at 10 mg/kg did not alter the pressor response to the alpha receptor agonist, methoxamine. Furthermore, LY53857 administered peripherally also inhibited central serotonin receptors, as evidenced by blockade of the serum corticosterone increase produced by the central actions of the serotonin agonist, quipazine, and by antagonism of tryptamine-induced convulsions in rats. LY53857 in doses that blocked the pressor response to serotonin and that blocked central serotonin receptors did not lower mean arterial blood pressure in the SHR. Thus, the lack of effectiveness of LY53857 to lower blood pressure in the SHR indicates that blockade of both central and vascular serotonin receptors is not a sufficient mechanism to lower blood pressure in this model of hypertension.

Topics: Animals; Blood Pressure; Ergolines; Heart Rate; Hypertension; Male; Muscle, Smooth, Vascular; Pressoreceptors; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Serotonin; Serotonin Antagonists