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 of 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 noradrenaline (100 microM) or prostaglandin F2alpha (PGF2alpha, 100 microM). 2. Exposure to noradrenaline enhanced the second maximal relaxant effect of isoprenaline (from 20 - 95% relaxation). This effect was not due to significant differences in precontraction levels and was not modified by the presence of the endothelium. Treatment with PGF2alpha mimicked the actions of noradrenaline on subsequent vasorelaxation to isoprenaline. 3. Before exposure to noradrenaline (100 microM), forskolin (10 microM) did not produce any significant relaxation of the rat aorta. After exposure to noradrenaline, forskolin caused a concentration-dependent relaxation with a maximal effect of more than 90% in rings with and without endothelium suggesting that the change in vasorelaxation to isoprenaline occurred downstream from 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-NG-nitroarginine methyl ester, L-NAME) and an inhibitor of the activation of soluble guanylyl cyclase (methylene blue). 5. Western blot analysis showed an increase of inducible NO synthase (iNOS) in aortic rings exposed to noradrenaline or PGF2alpha. 6. Together, these findings suggest that pretreatment of rat aorta with noradrenaline or PGF2alpha could induce vascular NOS which would in turn result in an increase in isoprenaline-induced vasorelaxation, this increase occurring downstream from receptor activation. Such a mechanism might participate in cardioprotection during preconditioning induced by noradrenaline.
Eckly-Michel
A
A
Université Louis Pasteur de Strasbourg, Laboratoire de Pharmacologie et de Physicochimie des Interactions Cellulaires et Moléculaires, UMR-CNRS, B.P. 24, 67401 Illkirch, France.
Keravis
T
T
Boudjemaa
N
N
Lugnier
C
C
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D002316:Cardiotonic Agents; D014662:Vasoconstrictor Agents; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007545:Isoproterenol; D009638:Norepinephrine