Characterization of the relaxant action of urocortin, a new peptide related to corticotropin-releasing factor in the rat isolated basilar artery.
In addition to its well established neuroendocrine and neurotransmitter effects, corticotropin releasing factor (CRF) exerts a potent vasorelaxant 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 relaxant effect are characterized. Ring segments obtained from the rat basilar artery were used for measurement of isometric force. The relaxant action of urocortin, CRF and sauvagine was studied in segments with a functionally intact endothelium. In segments precontracted with prostaglandin F2alpha, urocortin, CRF and sauvagine induced concentration-related relaxation. The order of potency was as follows (pD2+/-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 but was markedly attenuated in segments precontracted with 50 mM K+ Krebs solution. The relaxant effect of urocortin was inhibited by astressin in an apparently competitive manner. A pA2 value of 7.52 was estimated for astressin. Inhibition of urocortin-induced relaxation was also observed in the presence of the adenylate cyclase inhibitor SQ22536 (pD2 in the presence of 300 microM SQ22536, 9.36+/-0.05) and the K+ channel blockers tetraethylammonium (10 mM; pD2, 8.65+/-0.07), iberiotoxin (100 nM; pD2, 8.88+/-0.08) and apamin (10 nM; pD2, 8.94+/-0.07). However, the inhibitory actions of SQ22536 and apamin or iberiotoxin were not additive. The results suggest that urocortin induces relaxation of cerebral arteries by activating CRF-R2 receptors present in the vascular wall. Relaxation appears to be mediated by adenylate cyclase stimulation and activation of Ca2+-dependent K+ channels.
Schilling
L
L
Department of Neurosurgery, Faculty of Clinical Medicine Mannheim, University Heidelberg, Germany.
Kanzler
C
C
Schmiedek
P
P
Ehrenreich
H
H
D029845:Amphibian Proteins; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D015237:Dinoprost / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D036361:Peptide Hormones; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054832:Urocortins; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects
D029845:Amphibian Proteins; D036361:Peptide Hormones; D010455:Peptides; D054832:Urocortins; D014665:Vasodilator Agents; C025727:sauvagine; D003346:Corticotropin-Releasing Hormone; D015237:Dinoprost