J. S. Hood

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

The effect of N omega-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.

Influence of lemakalim on the pulmonary vascular bed of the cat

Pulmonary vascular responses to the K+ATP channel opener, lemakalim, were investigated in the intact-chest cat under constant flow conditions. When tone in the pulmonary vascular bed was elevated, intralobar injections of lemakalim caused dose-related decreases in lobar arterial pressure without changing left atrial pressure. Lemakalim was approximately 3-fold more potent than cromakalim in dilating the pulmonary vascular bed, and pulmonary vasodilator responses to these K+ATP channel openers were blocked by the K+ATP channel blocking agent, glybenclamide. Glybenclamide had no significant effect on pulmonary vasodilator responses to acetylcholine or vasoactive intestinal peptide (VIP) but decreased responses to calcitonin gene-related peptide (CGRP). These data show that lemakalim has potent pulmonary vasodilator activity and suggest that responses are due to activation of a glybenclamide-sensitive K+ATP channel.

Blockade of thromboxane/endoperoxide receptor-mediated responses in the pulmonary vascular bed of the cat by sulotroban

The effects of sulotroban (BM13.177; SK & F 95587), a thromboxane (TX) A2/endoperoxide (PGH2) receptor blocking agent on responses to the TXA2/PGH2 mimics, U46619 and U44069, were investigated in the pulmonary vascular bed of the intact-chest cat under constant flow conditions. Injections of U46619 and U44069 directly into the perfused lobar artery caused dose-related increases in lobar arterial pressure without altering left atrial pressure. Following administration of sulotroban in a dose of 5 mg/kg i.v., dose-response curves for U46619 and U44069 were shifted to the right in a parallel manner. The duration of the blocking effect of sulotroban was investigated, and responses to U46619 returned to approximately 50% of control in 120 min and were not significantly different from control 240 min after administration of the receptor antagonist. Sulotroban was without significant effect on responses to prostaglandin (PG) D2 or F2 alpha or serotonin, histamine, norepinephrine, angiotensin II or BAY K8644, an agent which enhances calcium entry. Sulotroban was without effect on responses to endothelin (ET)-1, sarafotoxin (S) 6a or S6c and platelet-activating factor (PAF). Sulotroban did not alter baseline vascular pressures in the cat and responses to the PG and TXA2/PGH2 precursor, arachidonic acid, were reduced. The present data show that sulotroban selectively blocks TXA2/PGH2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary vasodilator responses to RP 52891 are mediated by activation of a glibenclamide-sensitive KATP+ channel

Pulmonary vasodilator responses to the K+ATP channel opener, RP 52891, were investigated in the intact-chest cat under constant flow conditions. When pulmonary vascular tone was increased with U46619, intralobar injections of RP 52891 caused dose-related decreases in lobar arterial and systemic arterial pressures without altering left atrial pressure. RP 52891 was more potent than pinacidil but less potent than cromakalim in dilating the pulmonary vascular bed. Pulmonary vasodilator responses to RP 52891, cromakalim and pinacidil, but not to acetylcholine, nitroprusside or isoproterenol, were blocked by glibenclamide. These data demonstrate that RP 52891 has potent pulmonary vasodilator activity in the cat and suggest that responses are due to opening of a glibenclamide-sensitive K+ATP channel.

Pulmonary vascular and airway responses to endothelin-1 are mediated by different mechanisms in the cat.

The role of cyclooxygenase product formation and thromboxane A2 receptor activation in the response to endothelin-1 (ET-1) was investigated and compared in the airways and in the pulmonary vascular bed of the intact-chest cat. Intravenous injections of ET-1, 0.3 nmol/kg, increased lung resistance and decreased dynamic compliance. Bronchoconstrictor responses to ET-1 were decreased significantly by a cyclooxygenase inhibitor and by a thromboxane receptor blocking agent. In the pulmonary vascular bed of the cat under constant flow conditions, ET-1 increased lobar arterial pressure in a dose-related manner, and pulmonary vasconstrictor responses to the peptide were not altered by a cyclooxygenase inhibitor or thromboxane receptor blocking agent. The cyclooxygenase inhibitor blocked responses to the prostaglandin precursor, arachidonic acid; and the thromboxane receptor blocking agent reduced responses to the thromboxane mimic, U-46619. The present data suggest that bronchoconstrictor responses to ET-1 are dependent on the release of arachidonic acid, the formation of prostaglandins, and activation of thromboxane A2 receptors whereas pulmonary vasoconstrictor responses to the peptide are mediated by a different mechanism.