Mepacrine attenuates pulmonary vasoreactivity in rabbits

The organic peroxide tert-butyl hydroperoxide (t-bu-OOH) induces pulmonary vasoconstriction by stimulating production of thromboxane in the rabbit lung, possibly by activating phospholipase A₂. t-bu-OOH-induced vasoconstriction and thromboxane production is augmented by inhalational anesthetic agents, perhaps due to an effect of anesthetic agents on membrane lipids. To further investigate the mechanism of thromboxane generation, we studied the influence of the phospholipase A₂ inhibitor, mepacrine, in a dose known to inhibit the enzyme in other systems, on t-bu-OOH-induced pulmonary arterial vasoconstriction. We found that 10^-4 M mepacrine completely inhibited t-bu-OOH induced vasoconstriction. We also found that mepacrine inhibited arachidonic acid-induced pulmonary vasoconstriction but did not inhibit thromboxane productions. We also investigated the effect of mepacrine on two other pulmonary vasoconstrictors, angiotensin II (ANG II) and KCl, which do not act through arachidonic acid metabolites in the rabbit lung. Mepacrine inhibited both ANG-II and KCl-induced vasoconstriction. The inhibition by mepacrine of pulmonary vasoconstriction is reversible if the drug is washed out of the lung. This effect of mepacrine cannot be explained by phospholipase inhibition alone and is consistent with prevention of smooth muscle contraction.