1 The contribution of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) to non-adrenergic non-cholinergic (NANC) relaxations in the pig gastric fundus was investigated. 2 Circular and longitudinal muscle strips were mounted for isotonic registration in the presence of atropine and guanethidine; tone was raised with 5-hydroxytryptamine. Electrical field stimulation with 10 s trains at 5 min intervals induced short-lasting, frequency-dependent relaxations while continuous stimulation with cumulative increase of the stimulation frequency induced sustained frequency-dependent relaxations in both types of strips; the electrically induced responses were abolished by tetrodotoxin. 3 The short-lasting as well as the sustained electrically induced NANC relaxations were significantly reduced by N-nitro-L-arginine methyl ester (L-NAME). Pretreatment with L-arginine but not Darginine, prevented the inhibitory effect of L-NAME except for sustained relaxations in the longitudinal muscle strips. 4 Sodium nitroprusside, forskolin, zaprinast and 3-isobutyl-1-methylxanthine induced concentrationdependent relaxations. Exogenous NO mimicked the short-lasting electrically induced relaxations, while endogenous VIP evoked sustained relaxations. The responses to exogenous NO and VIP were not influenced by tetrodotoxin and L-NAME. 5 a-Chymotrypsin abolished the responses to exogenous VIP but only moderately reduced NANC relaxations induced by continuous electrical stimulation. Zaprinast potentiated the relaxant responses to sodium nitroprusside and increased the duration of the NANC relaxations induced by electrical stimulation with 10 s trains in circular muscle strips but not in longitudinal muscle strips. 6 The cyclic GMP and cyclic AMP response to electrical stimulation, NO and VIP was measured in circular muscle strips. Short-lasting as well as sustained electrical field stimulation induced an approximately 1.5 fold increase in cyclic GMP content, while NO induced nearly a 40 fold increase. An increase in cyclic AMP content was obtained only with sustained electrical field stimulation. 7 Immunocytochemistry for NO synthase (NOS) revealed immunoreactive neuronal cell bodies in the submucous and myenteric plexuses and nerve fibres in both the circular and longitudinal muscle layer; double-labelling for NOS and VIP showed that VIP coexists in a major part of the intrinsic neurones. NADPH diaphorase-histochemistry showed the same pattern of nitrergic neurones and nerves as NOSimmunocytochemistry. 8 It is concluded that a cyclic GMP-and a cyclic AMP-dependent pathway for relaxation is present in both the circular and longitudinal muscle layer of the pig gastric fundus. NO appears to contribute to short-lasting as well as sustained NANC relaxations. A peptide, possibly VIP, may be involved during sustained stimulation at lower frequencies of stimulation.

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Experiments were performed on anesthetized rats to determine whether inhibition of endopeptidase 24.11 (EP) potentiates the biological activity of atrial natriuretic peptide, ANP-(99-126), and to examine the mechanisms that underlie this effect. Thiorphan (30 mg/kg iv), an inhibitor of EP, produced a modest increase in urinary sodium excretion when administered alone but did not affect urine flow, mean arterial pressure (MAP), or the endogenous level of plasma ANP. The infusion of ANP-(99-126) alone (67 ng.kg-1.min-1 iv) produced a modest natriuresis and decrease in MAP while increasing plasma ANP levels fivefold. When thiorphan (30 mg/kg iv) was administered during the ANP infusion, urine flow and urinary sodium excretion increased markedly but no further decrease in MAP or increase in plasma ANP levels was observed. This potentiation of the renal actions of ANP was not mediated by inhibition of angiotensin-converting enzyme, an increase in glomerular filtration rate, or an increase in renal blood flow but was completely abolished by a specific antagonist of the bradykinin receptor [( DArg0, Hyp3, Thi5, DPhe7, Thi8]bradykinin, 30 micrograms.kg-1.min-1 iv). These data suggest that inhibitors of EP can potentiate the renal activity of ANP by a mechanism which is independent of altered ANP catabolism and which may involve the accumulation of bradykinin, another substrate for EP, within the kidney.

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