Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via β-adrenoceptors

We investigated the cAMP-dependent and -independent mechanisms of relaxation via β-adrenoceptor in rat detrusor muscle with and without pre-contraction. A microdialysis technique was used to measure detrusor tension and cAMP level on the same detrusor tissue. In non-contracted tissue, isoproterenol, clenbuterol (β2-adrenoceptor agonist) and FR165101, ((8S)-8-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)oxy]acetic acid hydrochloride (β3-adrenoceptor agonist) relaxed detrusor muscle and cAMP levels also increased in a concentration dependent manner. SQ22536 (adenylyl cyclase inhibitor) markedly suppressed relaxation, suggesting that β-adrenoceptor-mediated relaxation may be attributed mainly to cAMP-dependent mechanism. In high K+ pre-contracted tissue, although relaxation advanced in a concentration dependent manner, cAMP production reached a plateau at concentrations of more than 10− 7 M. SQ22536 had only a small inhibitory effect. However, large-conductance, Ca2+-activated K+ (BKCa) channel inhibitors, charybdotoxin and iberiotoxin markedly suppressed relaxation. These results suggest that in addition to cAMP-dependent pathway, BKCa channels are involved in the β-adrenoceptor agonists-induced relaxation in pre-contracted detrusor muscle.