A_1 receptors mediate adenosine inhibitory effects in mouse ileum via activation of potassium channels

摘要

Aims: We investigated the effects induced by exogenous adenosine on the spontaneous contractile activity of the longitudinal muscle of a mouse ileum, the receptor subtypes activated, the involvement of enteric nerves and whether opening of K~+ channels was a downstream event leading to the observed effects. Main methods: Mechanical responses of the mouse ileal longitudinal muscle to adenosine were examined in vitro as changes in isometric tension.Key findings: Adenosine caused a concentration-dependent reduction of the spontaneous contraction amplitude of the ileal longitudinal muscle up to its complete disappearance. This effect induced was markedly reduced by an A_1 receptor antagonist, but not by A_2 and A_3 receptor antagonists and mimicked only by the A_1, receptor agonist. Adenosine uptake inhibitors did not change adenosine potency. A_1 receptor expression was detected at the smooth muscle level. Adenosine responses were insensitive to tetrodotoxin, atropine or nitric oxide synthase inhibitor. Tetraethylammonium and iberiotoxin, BK_ca channel blockers, significantly reduced adenosine effects, whilst 4-aminopyridine, a K_v blocker, apamin, a small conductance Ca~(2+)-activated K~+ (SKca) channel blocker, charybdotoxin, an intermediate conductance Ca~(2+)-activated K~+ (IK_Ca) and BK_Ca channel blocker, or glibendamide, an ATP-sensitive K~+ channel blocker, had no effects. The combination of apamin plus iberiotoxin caused a reduction of the purinergic effects greater than iberiotoxin alone.Significance: Adenosine acts as an inhibitory modulator of the contractility of mouse ileal longitudinal muscle through postjunctional A_1 receptors, which in turn would induce opening of BK_Ca and SK_Ca potassium channels. This study would provide new insight in the pharmacology of purinergic receptors involved in the modulation of the gastrointestinal contractility.