Effects of P5, a novel oxazolo(3,2-a)pyridine derivative with a long-acting antihypertensive activity, on different agonist-mediated pressor responses in pithed rats

1 An oxazolo(3,2-a)pyridine derivative P5, described chemically as (+/-)-et hyl-7-(3-nitrophenyl)5, 8a-dimethyl-6-methoxycarbonyl-2,3,8,8a-tetrahydro-7 H-oxazolo[3,2-a]pyridin-8-carboxy- late, is a novel compound that has been synthesized as a possible antihypertensive prodrug of the 1,4-dihydropyridi ne type. Its antihypertensive activity was described in a previous study by the authors (Moron, Martin, Velasco, Martin, San Roman, Caballero, Puebla, Medarde & San Feliciano, 1997). 2 The aim of this work was to establish in vivo, the possible mechanisms pa rticipating in this antihypertensive action. Accordingly, we examined the e ffect of P5 on the pressor responses induced in pithed rats by noradrenalin e (an alpha (1)-, alpha (2)- and beta -adrenoceptor agonist), xylazine (an alpha (2)-adrenoceptor agonist), methoxamine (an alpha (1)-adrenoceptor ago nist), angiotensin I, angiotensin II, L-NAME (a nitric oxide synthase inhib itor) and BayK 8644 (a calcium channel agonist) and compared them with thos e of nifedipine, used as the reference drug. 3 Intravenous (i.v.) administration of P5 (2.5-10 mg; kg(-1)) inhibited the pressor responses to noradrenaline (1 mug kg(-1)), xylazine (80 mug kg(-1) ), angiotensin I (0.5 mug kg(-1)), angiotensin II (0.5 mug kg(-1)), BayK 86 44 (30 mug kg(-1)) and L-NAME (10 mg k(-1)). Nifedipine (10 mug kg(-1), i.v .) reduced the pressor responses to all these agonists and also to methoxam ine (2 Pg kg-1). 4 However, P5 was more effective than nifedipine in inhibiting these respon ses and its inhibitory effect lasted longer. Intravenous infusion of calciu m gluconate (1 ml kg(-1) min(-1)) reversed the reduction in the pressor res ponses as a result of nifedipine. The effects of PS were only reversed at 2 -3 h after administration. 5 These results suggest that P5 has a strong capacity to inhibit the presso r responses to several agonists after its i.v. administration and that such effects are related to its potent antihypertensive activity.