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 (+/-)-ethyl-7-(3-nitrophenyl)-5,8a-dimethyl-6-methoxycarbonyl-2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridin-8-carboxylate, is a novel compound that has been synthesized as a possible antihypertensive prodrug of the 1,4-dihydropyridine type. Its antihypertensive activity was described in a previous study by the authors (Morán, 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 participating in this antihypertensive action. Accordingly, we examined the effect of P5 on the pressor responses induced in pithed rats by noradrenaline (an alpha1-, alpha2- and beta-adrenoceptor agonist), xylazine (an alpha2-adrenoceptor agonist), methoxamine (an alpha1-adrenoceptor agonist), angiotensin I, angiotensin II, L-NAME (a nitric oxide synthase inhibitor) and BayK 8644 (a calcium channel agonist) and compared them with those 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 microg kg(-1)), xylazine (80 microg kg(-1)), angiotensin I (0.5 microg kg(-1)), angiotensin II (0.5 microg kg(-1)), BayK 8644 (30 microg kg(-1)) and L-NAME (10 mg kg(-1)). Nifedipine (10 microg kg(-1), i.v.) reduced the pressor responses to all these agonists and also to methoxamine (2 microg kg(-1)). 4. However, P5 was more effective than nifedipine in inhibiting these responses and its inhibitory effect lasted longer. Intravenous infusion of calcium gluconate (1 ml kg(-1) min(-1)) reversed the reduction in the pressor responses as a result of nifedipine. The effects of P5 were only reversed at 2-3 h after administration. 5 These results suggest that P5 has a strong capacity to inhibit the pressor responses to several agonists after its i.v. administration and that such effects are related to its potent antihypertensive activity.