CHARACTERIZATION OF THE RELAXANT ACTION OF UROCORTIN, A NEW PEPTIDE RELATED TO CORTICOTROPIN-RELEASING FACTOR IN THE RAT ISOLATED BASILAR ARTERY

1 In addition to its well established neuroendocrine and neurotransmit ter effects, corticotropin releasing factor (CRF) exerts a potent vaso relaxant action. Recently, a CRF-related peptide, urocortin, has been identified in the mammalian brain. In the present study, the cerebral vasomotor action of this peptide and the mechanism underlying its rela xant effect are characterized. 2 Ring segments obtained from the rat b asilar artery were used for measurement of isometric force. The relaxa nt action of urocortin, CRF and sauvagine was studied in segments with a functionally intact endothelium. 3 In segments precontracted with p rostaglandin F-2 alpha, urocortin, CRF and sauvagine induced concentra tion-related relaxation. The order of potency was as follows (pD(2)+/- s.e.m. given in brackets): urocortin (9.32+/-0.07) > sauvagine (9.08+/ -0.08) > CRF (7.50+/-0.07). Complete relaxation was achieved with each agonist. Relaxation was not affected by removal of the endothelium bu t was markedly attenuated in segments precontracted with 50 mM K+ Kreb s solution. The relaxant effect of urocortin was inhibited by astressi n in an apparently competitive manner. A pA(2) value of 7.52 was estim ated for astressin. Inhibition of urocortin-induced relaxation was als o observed in the presence of the adenylate cyclase inhibitor SQ22536 (pD(2) in the presence of 300 mu M SQ22536, 9.36+/-0.05) and the Kf ch annel blockers tetraethylammonium (10 mM; pD2, 8.65+/-0.07), iberiotox in (100 nM; pD(2), 8.88+/-0.08) and apamin (10 nM; pD(2), 8.94 +/- 0.0 7). However, the inhibitory actions of SQ22536 and apamin or iberiotox in were not additive. 4 The results suggest that urocortin induces rel axation of cerebral arteries by activating CRF-R-2 receptors present i n the vascular wall. Relaxation appears to be mediated by adenylate cy clase stimulation and activation of Ca2+-dependent K+ channels.