Nafazatrom (Bay g 6575) blunts canine hypoxic pulmonary vasoconstriction: evidence for a prostaglandin-mediated mechanism.
The eicosanoids are circulating vasoactive substances which may serve as modulators of pulmonary vasomotor tone. Nafazatrom (Bay g 6575) has been reported to raise circulating levels of prostaglandin I2 (PGI2) either by stimulating its synthesis or inhibiting its metabolism, and may also decrease leukotriene synthesis by inhibiting lipoxygenase. We evaluated the hemodynamic effects of nafazatrom administered intravenously in doses of 2,5, and 10 mg/kg in intact, anesthetized dogs ventilated with 21% and 10% oxygen. The hypoxia-induced increase in pulmonary vascular resistance was blunted by nafazatrom in an inverse dose-dependent fashion. Pretreatment with the cyclooxygenase inhibitor indomethacin (5 mg/kg subcutaneously twice daily for two days) abolished the response to low-dose nafazatrom. The pulmonary vasodilator response to the infusion of arachidonic acid (100 micrograms/kg/min) during hypoxic ventilation was blocked by the 10 mg/kg dose of nafazatrom. We conclude that nafazatrom blunts hypoxic pulmonary vasoconstriction in a manner consistent with a drug-induced increase in PGI2 activity, and that the inverse dose-dependent effects of the drug which we observed are due to an inhibition of cyclooxygenase at higher doses.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D004285:Dogs; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones; D014655:Vascular Resistance / Q000187:drug effects*
D001095:Arachidonic Acids; D011720:Pyrazoles; D047069:Pyrazolones; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases; C018845:nafazatrom