Role of nitric oxide and guanosine 3′,5′‐cyclic monophosphate in mediating nonadrenergic, noncholinergic relaxation in guinea‐pig pulmonary arteries

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Abstract
Nonadrenergic, noncholinergic (NANC) nerves mediate vasodilatation in guinea‐pig pulmonary artery (PA) by both endothelium‐dependent and endothelium‐independent mechanisms. The transmitter(s) involved in the endothelium‐independent pathway have not yet been identified. We have therefore investigated the possibility that nitric oxide (NO) and guanosine 3′,5′‐cyclic monophosphate (cyclic GMP) may mediate this neural vasodilator response in guinea‐pig branch PA rings denuded of endothelium. Electric field stimulation (EFS, 50 V, 0.2 ms) induced a frequency‐dependent (1–24 Hz), tetrodotoxin‐sensitive relaxation of the U44069‐precontracted PA rings in the presence of adrenergic and cholinergic blockade. The NO synthase inhibitors NG‐monomethyl l‐arginine (l‐NMMA, 100 μm) and NG‐nitro l‐arginine methyl ester (l‐NAME, 30 μm), and the guanylyl cyclase inhibitor methylene blue (5 μm) inhibited the EFS (16 Hz)‐induced relaxation by 53 ± 5, 74 ± 9 and 82 ± 9% respectively (n = 5–7, P < 0.01, compared with control rings). Excess concentrations of l‐, but not d‐arginine (300 μm) completely reversed the inhibitory effect of l‐NMMA. The EFS‐elicited relaxation (4 Hz) was potentiated by 1 μm zaprinast, a type V phosphodiesterase inhibitor which inhibits guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) degradation, but was unaffected by 0.1 μm zardaverine, a type III/IV phosphodiesterase inhibitor which inhibits cyclic AMP degradation. EFS (50 V, 0.2 ms, 16 Hz) induced a 3 fold increase in tissue cyclic GMP content, an action which was inhibited by l‐NMMA (100 μm). Pyrogallol (100 μm), a superoxide anion generator, also inhibited the EFS‐induced relaxation by 53 ± 9%, and this effect was prevented by superoxide dismutase. Chemical sympathetic denervation with 6‐hydroxydopamine had no effect on the relaxant response to EFS in the endothelium‐denuded PA rings. In endothelium‐denuded branch PA rings at resting tone, l‐NMMA (100 μm) significantly augmented the adrenergic contractile response, an effect which was completely reversed by l‐arginine, but not by d‐arginine. In the same groups of vessel rings, l‐NMMA had no significant effect on the matched contractile response to exogenous noradrenaline. These results suggest that NO may be released from intramural nerve endings other than adrenergic nerves (probably NANC nerves), and this leads to vasodilatation via activation of guanylyl cyclase.

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