No abstract

SUMMARY1. The inhibitory innervation of the taenia of the guinea-pig caecum has been studied, after blocking the responses to stimulation of excitatory cholinergic nerves with atropine.2. Stimulation of the perivascular nerves supplying the taenia caused relaxations. These nerves had properties which were typical of sympathetic post-ganglionic adrenergic nerves. The relaxations caused by stimulation were maximal at frequencies of stimulation above 30 pulses/sec and they were abolished by bretylium, guanethidine and l,l-dimethyl-4-phenylpiperazinium iodide (DMPP).3. The taenia is also innervated by intramural inhibitory nerves with their cell bodies in Auerbach's plexus. These nerves can be excited by electrical stimulation ofthe taenia or by the application ofganglion-stimulating drugs.4. The intramural inhibitory nerves have different properties from sympathetic adrenergic nerves. Relaxations in response to stimulation were maximal with frequencies of stimulation of about 5 pulses/sec and they were not blocked by bretylium, guanethidine or DMPP.5. Preganglionic cholinergic fibres in the caecal wall make synaptic connexions with the intramural inhibitory neurones.6. The role of the intramural inhibitory neurones in intestinal activity and their possible connexions with the central nervous system have been discussed.

1 The nitric oxide (NO) synthesis inhibitors NG-monomethyl L-arginine (L-NMMA) and L-nitroarginine methyl ester (L-NAME) reduced relaxations of guinea-pig tracheal smooth muscle elicited by stimulation of intramural non-adrenergic, non-cholinergic (NANC) nerves, but D-NMMA had no effect. L-NAME was 10-30 times more potent than L-NMMA. Relaxations produced by sodium nitroprusside and vasoactive intestinal polypeptide (VIP) were not affected by L-NMMA or L-NAME. 2 The inhibitory effect of L-NMMA on NANC-mediated relaxations was partially reversed by L-arginine but was not affected by D-arginine. 3 VIP antibody and a-chymotrypsin abolished or greatly reduced the relaxant action of VIP and reduced relaxations elicited by stimulation of NANC nerves; the residual NANC relaxation was further reduced by L-NAME. 4 The results suggest that NO and VIP are mediators of NANC-induced relaxations of guinea-pig tracheal smooth muscle. We propose the term 'nitrergic' to describe transmission processes which are mediated by NO.

1. The possibility that transmission at some non-adrenergic, non-cholinergic (NANC) neuro-effector junctions is mediated by nitric oxide (NO) arose from the discoveries that NO mediated the effects of nitrovasodilator drugs and that endothelium-derived relaxing factor (EDRF) was NO or a NO-yielding substance. 2. NO donated by nitrovasodilator drugs or formed by endothelial cells activates soluble guanylate cyclase in smooth muscle and the consequent increase in cyclic guanosine monophosphate (cGMP) results in relaxation. The relaxations produced by stimulation of some NANC nerves are also due to a rise in cGMP. 3. The biosynthesis of NO by oxidation of a terminal guanidino nitrogen of L-arginine is inhibited by some NG-substituted analogues of L-arginine. These substances block EDRF formation by NO synthase and endothelium-dependent vasodilatation, and the blockade is overcome by L-arginine 4. NANC relaxations in some tissues are blocked by NG-substituted analogues of L-arginine and restored by L-arginine. Other agents that affect endothelium-dependent vasodilator responses produce corresponding changes in responses to stimulation of these NANC nerves. Such observations indicate that transmission is mediated by NO: we have termed this mode of transmission nitrergic. 5. There is evidence for nitrergic innervation of smooth muscle in the gastrointestinal tract, genito-urinary system, trachea and some blood vessels (penile and cerebral arteries). 6. The recognition of a mediator role for NO in neurotransmission calls for reconsideration of previously accepted generalizations about mechanisms of transmission. 7. Studies on nitrergic transmission will provide new insights into physiological control mechanisms and pathophysiological processes and may lead to new therapeutic developments.

1. The nitric oxide (NO) synthesis inhibitor NG-monomethyl-L-arginine (L-NMMA), but not D-NMMA, inhibited the NANC-mediated relaxations of the rat anococcygeus muscle, but did not affect the relaxation produced by sodium nitroprusside. 2. The inhibitory effect of L-NMMA was reversed by L-arginine but not by D-arginine, and prior exposure to L-arginine blocked the effect of L-NMMA. 3. The noradrenergically mediated contractions of the anococcygeus elicited by field stimulation were slightly enhanced by L-NMMA, but the response to noradrenaline was not affected. 4. The results suggest that NANC transmission in the rat anococcygeus muscle involves the generation of NO from arginine.