[Beta 3-adrenoceptor-mediated relaxation of guinea-pig gastric funds smooth muscle: cAMP-independent characteristics and a primary role of 4-aminopyridine-sensitive voltage-dependent K+ (Kv) channels].
beta-Adrenoceptor subtypes which mediate relaxation of guinea-pig gastrointestinal smooth muscles in response to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline) and beta 3-adrenoceptor agonists (BRL37344 and (+/-)-CGP12177A) are predominantly beta 3-adrenoceptors. Although cAMP-PKA system is thought to play a substantial role in the smooth muscle relaxation mediated via beta 1- and beta 2-adrenoceptors, there is little information on the role of cAMP in beta 3-adrenoceptor-meidated relaxation. The present study was carried out to elucidate the role of cAMP in beta 3-adrenoceptor-meidated relaxation of guinea-pig gastric fundus smooth muscle. Furthermore, possible contribution of two types of K+ (voltage-dependent and Ca(2+)-activated K+, BKCa; voltage-dependent, Kv) channels was also examined pharmaco-mechanically. In gastric fundus smooth muscle, catecholamines and beta 3-adrenoceptor agonists elicited potent relaxations in the presence of beta 1- and beta 2-adrenoceptor antagonists. All of these relaxations were not diminished by an adenylate cyclase inhibitor, SQ-22,536 (100 microM), which indicates their characteristic of cAMP-independency. SQ-22,536-resistant, beta 3-adrenoceptor-mediated relaxations were strongly attenuated by a Kv channel blocker, 4-aminopyridine (3 mM), but not by iberiotoxin (100 nM), a selective blocker of BKCa channel. The present results indicate that 4-aminopyridine-sensitive Kv channels play a primary role in cAMP-independent relaxation of guinea-pig gastric fundus smooth muscle in response to the stimulations of beta 3-adrenoceptors.
Horinouchi
Takahiro
T
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, 2-2-1 Miyama, Funabashi-City, Chiba 274-8510, Japan.
Tanaka
Yoshio
Y
Koike
Katsuo
K
D015761:4-Aminopyridine / Q000378:metabolism* / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D005748:Gastric Fundus / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D024642:Potassium Channels, Voltage-Gated; D022702:Receptors, Adrenergic, beta-3; D015761:4-Aminopyridine; D000242:Cyclic AMP