Evidence for the primary role for 4-aminopyridine-sensitive K(v) channels in beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations of guinea-pig gastrointestinal smooth muscles.

Gastrointestinal smooth muscles exhibit relaxation in response to the stimulation of beta-adrenoceptors with catecholamines. Subtypes of beta-adrenoceptors which mediate catecholamine-elicited relaxations in gastrointestinal smooth muscles are predominantly atypical beta-adrenoceptors including beta(3)-adrenoceptors. Gastrointestinal smooth muscle relaxations mediated via beta(3)-adrenoceptors can occur independently of intracellular cyclic adenosine monophosphate (AMP) elevation. One of the mechanisms responsible for cyclic AMP-independent smooth muscle relaxation following activation of G(s) protein-coupled receptors could be activation of voltage-gated K(+) channels. In the present study, possible contribution of two types of K(+) (large-conductance, Ca(2+)-sensitive and voltage-gated K(+), BK(Ca); voltage-gated, K(v)) channels to beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations was compared in gastric fundus and duodenum smooth muscles isolated from the guinea-pig. In these gastrointestinal smooth muscles, three catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline) and two beta(3)-adrenoceptor agonists ((R(*), R(*))-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium (BRL37344) and (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy] -1,3-dihydro-2H-benzimidazol-2-one] hydrochloride ((+/-)-CGP12177A)) elicited a concentration-dependent relaxation in the presence of beta(1)- and beta(2)-adrenoceptor antagonists. The relaxations were unaffected by an adenylyl cyclase inhibitor, SQ-22536 (100 microM), which indicates their characteristic of cyclic AMP-independency. On the other hand, the SQ-22536-resistant, beta(3)-adrenoceptor-mediated relaxant components were potently attenuated when the tone was raised using high-KCl (80 mM) or in the presence of a K(v) channel blocker, 4-aminopyridine (4-AP, 1-3 mM). Iberiotoxin (100 nM), a selective blocker of BK(Ca) channels which significantly contribute to cyclic AMP-independent vascular smooth muscle relaxations induced through activation of G(s) protein-coupled receptors, did not apparently show any inhibitory effects on SQ-22536-resistant, beta(3)-adrenoceptor-mediated relaxations in these gastrointestinal smooth muscles. The present results indicate that 4-AP-sensitive K(v) channels play a primary role in beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations of guinea-pig gastrointestinal smooth muscles. In these smooth muscles, BK(Ca) channels seem to apparently contribute insignificantly to cyclic AMP-independent relaxations following stimulation of beta(3)-type of adrenoceptors.