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

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were 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 elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.

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Responses to pituitary adenylate cyclase-activating polypeptide (PACAP), a novel peptide derived from ovine hypothalamus with 68% sequence homology with vasoactive intestinal polypeptide (VIP), were investigated in the pulmonary and hindquarters vascular beds of the anesthetized cat under conditions of controlled blood flow. Injection of the peptide into the perfused lung lobe under elevated tone conditions produced dose-dependent decreases in lobar arterial pressure that were accompanied by biphasic changes in systemic arterial pressure characterized by an initial decrease followed by a secondary increase in pressure. When compared with other vasodilator agents in the pulmonary vascular bed, the relative order of potency was isoproterenol greater than PACAP greater than acetylcholine greater than calcitonin gene-related peptide greater than VIP. In the hindquarters vascular bed, intra-arterial injections of PACAP produced biphasic changes in hindquarters perfusion pressure characterized by initial decreases followed by secondary increases, which were accompanied by biphasic changes in systemic arterial pressure. In terms of relative vasodilator activity in the hindlimb, the order of relative potency was isoproterenol greater than acetylcholine greater than calcitonin gene-related peptide greater than VIP greater than PACAP. PACAP was the only agent that caused a secondary vasoconstrictor response in the hindlimb and produced biphasic changes in systemic arterial pressure. D-Phe2-VIP, a VIP receptor antagonist, blocked the hindquarters vasodilation in response to VIP but had no effect on responses to PACAP. The present investigation shows that PACAP produces pulmonary vasodilation, as well as dilation, and vasoconstriction in the systemic (hindlimb) vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary vascular responses to serotonin (5-hydroxytryptamine; 5-HT) were investigated in the intact-chest cat under constant-flow conditions. Injections of 5-HT into the perfused lobar artery in doses of 1-30 micrograms caused dose-related increases in lobar arterial pressure and, at doses of 3-30 micrograms, decreases in systemic arterial pressure. Left atrial pressure was not changed, and responses to 5-HT were not altered by a thromboxane receptor blocking agent. Responses to 5-HT were blocked by ketanserin in doses that did not alter responses to agonists that increase pulmonary vascular resistance by various mechanisms. The ketanserin-induced blockade was not surmountable and at a dose of 0.5 mg/kg iv persisted for > 4 h. Prazosin and yohimbine, selective alpha 1- and alpha 2-adrenoceptor antagonists, were without effect on the pressor response to 5-HT, and ketanserin did not reduce responses to norepinephrine or the alpha 1-agonists, phenylephrine and methoxamine. 5-HT and the thromboxane mimic, U-46619, produced large increases in pulmonary vascular resistance; however, U-46619 was 300 times more potent than 5-HT. 5-HT increased lobar arterial pressure when the lung was perfused with dextran, and increases in lobar arterial pressure in response to 5-HT were not diminished when lobar ventilation was interrupted but were enhanced by N omega-nitro-L-arginine methyl ester and to a small extent by meclofenamate. The present data suggest that increases in pulmonary vascular resistance in the cat in response to 5-HT are due to activation of an S2 receptor in undefined "resistance vessel elements." These data suggest that pulmonary vasoconstrictor responses to 5-HT may be modulated to a small extent by release of a vasodilator prostaglandin and endothelium-derived nitric oxide but are not dependent on activation of thromboxane receptors, changes in bronchomotor tone, and interaction with alpha 1-receptors or with formed elements in blood.