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 μmol L−1) and p-fluoro-hexahydro-sila-difenidol (1 μmol L−1), electrical stimulation evoked neurogenic inhibitory responses not modified by hexamethonium (100 μmol L−1), suggesting that inhibitory postganglionic non-adrenergic non-cholinergic (NANC) nerve fibres are involved. The nitric oxide (NO)-synthase inhibitor Nω-nitro-l-argininine-methyl-ester hydrochloride (1–100 μmol L−1) and the soluble guanylyl cyclase inhibitor ODQ (0.1–3 μmol 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 α2-adrenoceptor agonist, UK 14 304 (10 nmol L−1–10 μmol 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 5HT1a, opioid μ, δ and κ, muscarinic M1 and M2, histamine H2 and H3 and cannabinoid receptors. The NANC response was insensitive to the P/Q-type Ca2+-channel blocker ω-agatoxin TK (1 nmol L−1–0.1 μ mol L−1), but partially inhibited by the N-type Ca2+-channel blocker ω-conotoxin GVIA (0.1 nmol L−1−0.1 μmol L−1), and by the L-type Ca2+-channel blockers nifedipine and calcicludine (0.1 nmol L−1−0.1 μmol 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.