Relaxation by nitroglycerin, sodium nitrite, and amyl nitrite of bovine coronary arterial smooth muscle was inhibited by the oxidant methylene blue. Methylene blue also inhibited activation of bovine coronary arterial soluble guanylate cyclase by nitroglycerin, which required addition of cysteine. At concentrations less than 10 mM, sodium nitrite required the addition of one of several thiols or ascorbate to activate guanylate cyclase from bovine coronary artery. Guanylate cyclase activation by large amounts (50 microL) of saturated amyl nitrite gas did not require, but was enhanced by, the addition of thiols or ascorbate. However, similar to sodium nitrite, guanylate cyclase activation by smaller amounts (5 microL) of saturated amyl nitrite gas did require the addition of one of various thiols or ascorbate. Methylene blue markedly inhibited guanylate cyclase activation by sodium nitrite in the presence of cysteine or ascorbate and similarly inhibited enzyme activation by amyl nitrite either in the absence or presence of cysteine or ascorbate. These data support the hypothesis that nitrates and nitrites relax vascular smooth muscle by stimulating cyclic GMP formation. The results further suggest that, similar to relaxation and guanylate cyclase activation by nitroso-containing compounds, relaxation and enzyme activation by nitrates and and nitrites may involve the formation of nitric oxide or complexes of nitric oxide as active intermediates.

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We hypothesized that substance P and capsaicin would cause the release of prostaglandin E2(PGE2) from intrapulmonary bronchi isolated from Sprague-Dawley rats. Substance P (1 μM) caused the release of PGE2, measured with enzyme immunoassay, from the isolated airway segments; PGE2 release was inhibited by the neurokinin (NK)1-receptor antagonist, RP-67580, by inhibition of cyclooxygenase with meclofenamate, and by removal of the epithelium. The release of PGE2 caused by capsaicin (1 μM) was similar in magnitude to that caused by substance P. The capsaicin-induced release of PGE2was inhibited by desensitization of sensory nerves with capsaicin and by RP-67580, meclofenamate, and epithelial denudation. We conclude that activation of NK1 receptors on epithelium causes release of PGE2, which most likely represents the ultimate mediator of airway smooth muscle relaxation, produced by exogenous neuropeptides and by activation of the sensory nerve inhibitory system. Epithelial damage, such as that seen in asthmatic airways, would disrupt this protective system in the lungs, which could contribute to the development of airway disease.

The contractile effects of serotonin (5-hydroxytryptamine, 5-HT) were compared in helical strips of intrapulmonary artery (IPA) and vein (IPV) isolated from lungs of dog, rabbit, cow, and man. 5-HT (10(-8) - 10(-4) M) increased force generation by IPA and IPV from the four species in a concentration-related manner. Sensitivities to 5-HT of IPA and IPV from the four species were similar, with median effective concentrations ranging from 3 X 10(-8) to 3 X 10(-7) M. However, maximal and contractile responses to 5-HT relative to those elicited by potassium were greater in canine and human IPA and bovine IPA and IPV than in rabbit IPA and IPV and canine and human IPV. Results obtained using specific pharmacology blocking agents suggest that 5-HT-induced contraction of canine and rabbit intrapulmonary vessels does not involve alpha-adrenergic mechanisms except, possibly, in rabbit IPV. The contractile effects of 5-HT observed in the present study suggest that 5-HT released from platelets could contribute to increased vascular resistance during pulmonary thromboembolism by actively constricting arterial and venous segments of the pulmonary vascular bed in a variety of species, including man.

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