Involvement of soluble guanylate cyclase α 1 and α 2, and SK Ca channels in NANC relaxation of mouse distal colon

Abstract

In distal colon, both nitric oxide (NO) and ATP are involved in non-adrenergic non-cholinergic (NANC) inhibitory neurotransmission. The role of the soluble guanylate cyclase (sGC) isoforms α 1β 1 and α 2β 1, and of the small conductance Ca 2+-dependent K + channels (SK Ca channels) in the relaxation of distal colon by exogenous NO and by NANC nerve stimulation was investigated, comparing wild type (WT) and sGCα 1 knockout (KO) mice. In WT strips, the relaxation induced by electrical field stimulation (EFS) at 1 Hz but not at 2–8 Hz was significantly reduced by the NO-synthase inhibitor l-NAME or the sGC inhibitor ODQ. In sGCα 1 KO strips, the EFS-induced relaxation at 1 Hz was significantly reduced and no longer influenced by l-NAME or ODQ. The SK Ca channel blocker apamin alone had no inhibitory effect on EFS-induced relaxation, but combined with ODQ or l-NAME, apamin inhibited the relaxation induced by EFS at 2–8 Hz in WT strips and at 8 Hz in sGCα 1 KO strips. Relaxation by exogenous NO was significantly attenuated in sGCα 1 KO strips, but could still be reduced further by ODQ. Basal cGMP levels were lower in sGCα 1 KO strips but NO still significantly increased cGMP levels versus basal. In conclusion, in the absence of sGCα 1β 1, exogenous NO is able to partially act through sGCα 2β 1. NO, acting via sGCα 1β 1, is the principal neurotransmitter in EFS-evoked responses at 1 Hz. At higher stimulation frequencies, NO, acting at sGCα 1β 1 and/or sGCα 2β 1, functions together with another transmitter, probably ATP acting via SK Ca channels, with some degree of redundancy.