Pulmonary vasodilator response to vagal stimulation is blocked by N omega-nitro-L-arginine methyl ester in the cat.

Abstract

The effect of Nc-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor production, on the vasodilator response to efferent vagal stimulation was investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was increased with U46619, efferent vagal stimulation decreased lobar arterial pressure in a stimulus-frequency-dependent manner. The decreases in lobar arterial pressure were enhanced by pretreatment with reserpine, were blocked by atropine, and were not altered by propranolol, indicating that the neurogenic vasodilator response was cholinergic in nature. The decreases in lobar arterial pressure in response to vagal stimulation and to exogenously administered acetylcholine were reduced after administration of L-NAME (100 mg/kg i.v.). Although L-NAME decreased pulmonary vasodilator responses to vagal stimulation and to acetylcholine, responses to adenosine, nicorandil, lemakalim, isoproterenol, prostaglandin E1, sodium nitroprusside, and 8-bromo-cGMP, agents that act by a variety of mechanisms, were not decreased. These results are consistent with the hypothesis that efferent vagal stimulation releases acetylcholine, which dilates the pulmonary vascular bed by stimulating the production of nitric oxide or a labile nitroso compound from L-arginine. (Circulation Research 1992;70: 364-369) E ndothelium-derived relaxing factor (EDRF), first described in 1980 by Furchgott and Zawadski,1 is now believed to be nitric oxide (NO) or a labile nitroso compound. NO is released from the amino acid precursor L-arginine in cultured endothelial cells, and N0-monomethyl-L-arginine (L-NMMA) in a stereospecific manner inhibits NO synthesis from L-arginine.2,3 L-NMMA has been shown to increase systemic vascular resistance and inhibit responses to endothelium-dependent vasodilator agents.4,5 In recent studies, N6-nitro-L-arginine (nitroarginine, L-NA) has been shown to be more potent than L-NMMA in inhibiting NO synthesis.6,7 L-NA and nitroarginine methyl ester (L-NAME) have been shown to increase vascular resistance and inhibit vasodilator responses to endothelium-dependent vasodilator agents such as acetylcholine and bradykinin in the pulmonary and systemic vascular beds.8,9 The results of studies in the peripheral and

Requirement for endothelium‐derived nitric oxide in vasodilatation produced by stimulation of cholinergic nerves in rat hindquarters

“…As L-arginine did not prevent or reverse the effects of L-NAME in those studies (Broten et al, 1992;McMahon et al, 1992) (Shirasaki & Su, 1985;Mugge et al, 1991). Since baseline perfusion pressure was not significantly altered after treatment with L-NOARG or CHAPS, the enhanced dilator response to SNP is likely to be due to the reported increased sensitivity of guanylate cyclase to exogenous NO when basal NO release is impaired (Moncada et al, 1991b).…”

“…These studies all concluded that NO mediates cholinergic neurogenic dilatation although the results of the two studies using L-NAME (McMahon et al, 1992;Broten et al, 1992) must be viewed with some caution due to the subsequent report that L-NAME possesses muscarinic receptor antagonist activity (Buxton et al, 1993). Furthermore, although the authors of two of those reports concluded that the endothelium was the source of the NO (Broten et al, 1992;Andriantsitohaina & Suprenant, 1992) no direct evidence was provided to support that conclusion.…”

Effect of inhibitors of nitric oxide release and action on vascular tone in isolated lungs of pig, sheep, dog and man.

“…Likewise, although significant differences in the structure of the muscular pulmonary arteries exist in these species (Kay, 1983) (Fineman, Crowley, Heymann & Soifer, 1991) or L-NAME and in anaesthetized but spontaneously breathing rabbits (Persson et al 1990) with L-NAME. Recent work has shown that neural stimulation of intact lungs may cause NO release either directly from non-adrenergic, non-cholinergic nerve stimulation (Liu, Crawley, Evans & Barnes, 1992) or as a secondary consequence of the release of acetylcholine (McMahon, Hood & Kadowitz, 1992); such alternate sources of NO could account for the changes observed in vivo. Use of isolated lungs avoids conflicting influences from neural mechanisms and precludes such a source of NO.…”

Cellular Mechanisms of Cardioprotection Afforded by Inhibitors of Angiotensin Converting Enzyme in Ischemic Hearts: Role of Bradykinin and Nitric Oxide.

“…NO is reported to have many cardioprotective effects on ischemia and reperfusion injury (21)(22)(23)(24)(25)(26). Thus, enhancement of NO production during ischemia and reperfusion by ACE inhibitors may reduce ischemia and reperfusion injury (27,28).…”