P2Y<inf>1</inf> receptors mediate inhibitory neuromuscular transmission and enteric neuronal activation in small intestine

There is increasing evidence that adenosine 5′-triphosphate or a related purine plays a crucial role in smooth muscle relaxation and enteric synaptic neurotransmission. Accordingly, the aim of the present work is to investigate the role P2Y1 receptors in purinergic inhibitory neurotransmission (pig ileum) and enteric neuronal activation in the small intestine (guinea-pig ileum). Using contractility measurements, micro-electrode recordings and Ca2+ imaging we found that (i) adenosine 5′-Ο-2-thiodiphosphate (ADPβS) (10 μmol L-1) caused smooth muscle relaxation and hyperpolarization that was antagonized by MRS2179 (10 μmol L-1) a P2Y1 receptor antagonist and apamin (1 μmol L-1); (ii) electrical field stimulation (EFS) caused a non-nitrergic inhibitory junction potential (IJP) and relaxation that was antagonized by MRS2179 (10 μmol L-1); (iii) P2Y1 receptors were immunolocalized in smooth muscle cells and enteric neurons; (iv) superfusion of ADPβS (1 μmol L-1) induced Ca2+ transients in myenteric neurons that were inhibited by MRS2179 (1 μmol L -1), but not by tetrodotoxin (1 μmol L-1); and (v) EFS induced calcium transients were partially inhibited by MRS2179 (1 μmol L -1). We conclude that in the small intestine purinergic neuromuscular transmission responsible for the IJP and non-nitrergic relaxation is mediated by P2Y1 receptors located in smooth muscle cells. Functional P2Y 1 receptors are also present in guinea-pig myenteric neurons. Therefore, P2Y1 receptors might be an important pharmacological target to modulate gastrointestinal functions. © 2007 The Authors.