Effect of pre-exposure to vasoconstrictors on isoprenaline-induced relaxation in rat aorta: Involvement of inducible nitric oxide synthase

1 The aim of this study was to determine whether a brief (30 min) episode o f contractile receptor stimulation could affect the degree of a subsequent vasorelaxation. Therefore, concentration-relaxation curves of the rat aorta to isoprenaline were compared before and after exposure of the tissue to n oradrenaline (100 mu M) or prostaglandin F-2 alpha (PGF(2 alpha), 100 mu M) . 2 Exposure to noradrenaline enhanced the second maximal relaxant effect of isoprenaline (from 20-95% relaxation). This effect was not due to significa nt differences in precontraction levels and was not modified by the presenc e of the endothelium. Treatment with PGF(2 alpha) mimicked the actions of n oradrenaline on subsequent vasorelaxation to isoprenaline. 3 Before exposure to noradrenaline (100 mu M), forskolin (10 mu M) did not produce any significant relaxation of the rat aorta. After exposure to nora drenaline, forskolin caused a concentration-dependent relaxation with a max imal effect of more than 90% in rings with and without endothelium suggesti ng that the change in vasorelaxation to isoprenaline occured downstream fro m the beta-adrenoceptor. 4 The increase in relaxation due to exposure to noradrenaline was markedly attenuated by treatment with a protein synthase inhibitor (cycloheximide), a nitric oxide (NO) synthase inhibitor (L-NC-nitroarginine methyl ester, L- NAME) and an inhibitor of the activation of soluble guanylyl cyclase (methy lene blue). 5 Western blot analysis showed an increase of inducible NO synthase (iNOS) in aortic rings exposed to noradrenaline or PGF(2 alpha). 6 Together, these findings suggest that pretreatment of rat aorta with nora drenaline or PGF(2 alpha) could induce vascular NOS which would in turn res ult in an increase in isoprenaline-induced vasorelaxation, this increase oc curing downstream from receptor activation. Such a mechanism might particip ate in cardioprotection during preconditioning induced by noradrenaline.