Prejunctional modulation of non-adrenergic non-cholinergic (NANC) inhibitory responses in the isolated guinea-pig gastric fundus

The inhibitory neurotransmission of the stomach was investigated in isolated guinea-pig gastric fundus. In preparations treated with guanethidine (1 mu mol L-1 ) and p-fluoro-hexahydro-sila-difenidol (1 mu mol L-1 ), electrical stimulation evoked neurogenic inhibitory responses not modified by hexamethonium (100 mu mol L-1 ), suggesting that inhibitory postganglionic non-adrenergic non-cholinergic (NANC) nerve fibres are involved. The nitric oxide (NO)-synthase inhibitor N-omega -nitro-l-argininine-methyl-ester hydrochloride (1-100 mu mol L-1 ) and the soluble guanylyl cyclase inhibitor ODQ (0.1-3 mu mol L-1 ) also abolished such relaxant response, suggesting the involvement of NO/Cyclic Guanosine 3',5' monophosphate (cGMP) system as the final mechanism of muscle relaxation. The alpha (2) -adrenoceptor agonist, UK 14 304 (10 nmol L-1 -10 mu mol L-1 ) did not influence the electrical field stimulation (EFS)-evoked NANC responses. These latter responses were also refractory to a variety of receptor agonists and antagonists, acting at Gamma Aminobutyric Acid (GABA), serotonin 5HT(1a) , opioid mu , delta and kappa , muscarinic M-1 and M-2 , histamine H-2 and H-3 and cannabinoid receptors. The NANC response was insensitive to the P/Q-type Ca2+ -channel blocker omega -agatoxin TK (1 nmol L-1 -0.1 mu mol L-1 ), but partially inhibited by the N-type Ca2+ -channel blocker omega -conotoxin GVIA (0.1 nmol L-1 -0.1 mu mol L-1 ), and by the L-type Ca2+ -channel blockers nifedipine and calcicludine (0.1 nmol L-1 -0.1 mu mol L-1 ). These data suggest that the NANC relaxation of the isolated guinea-pig gastric fundus is mediated by NO as the final inhibitory (neuro)transmitter at the longitudinal smooth muscle cells. The mechanism(s) promoting NO production is/are Ca2+ -dependent, but apparently insensitive to presynaptic modulation. Both N- and L-type channels seem to occur in nitrergic nerve endings, where they contribute to trigger NO diffusion at the synaptic cleft.