Activation of protein kinase C inhibits extraction of serotonin by perfused rat lung in situ.
Pulmonary endothelial extraction (E) of serotonin (5-HT) is decreased after exposure to phorbol myristate acetate (PMA) in intact (D. Riggs, A. M. Havill, B. R. Pitt, and C. N. Gillis. J. Appl. Physiol. 64: 2508-2516, 1988.) or perfused (C. L. Myers and B. R. Pitt. J. Appl. Physiol. 65: 377-384, 1988.) lungs. Although the mechanism underlying this change is unclear, we hypothesized, based on studies in cultured pulmonary arterial endothelial cells [C. L. Myers, J. S. Lazo, and B. R. Pitt. Am. J. Physiol. 258 (Lung Cell. Mol. Physiol. 1): L253-L258, 1989] that activation of protein kinase C (PKC) by PMA inhibits this uptake process. Accordingly, we studied the ability of staurosporine, a potent inhibitor of PKC, to block the acute effect of PMA on E(5-HT) by rat lungs perfused at 10 ml/min with Krebs-bicarbonate with 3% albumin. Pulmonary E(5-HT) was measured by indicator-dilution techniques using 5-[3H]HT and [14C]dextran. Both PMA and mezerein (nonphorbol PKC activator) caused dose-dependent decreases in E(5-HT) and increases in perfusion pressure (Ppa). Staurosporine, alone, did not significantly affect either E(5-HT) or Ppa; however, staurosporine (100 nM) completely inhibited the effects of PMA (100 nM) on the above parameters. Papaverine, a nonspecific vasodilator, was able to partially inhibit the pressor response to PMA while not affecting the inhibition of E(5-HT) by PMA, suggesting that the effect on E(5-HT) was not secondary to vasoconstriction (and derecruitment). These data support the hypothesis that activation of PKC leads to prominent pulmonary vascular effects including vasoconstriction and inhibition of endothelial cell 5-HT uptake.
Weng
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Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Pitt
B R
BR
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D004224:Diterpenes; D004789:Enzyme Activation; D007700:Kinetics; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010208:Papaverine / Q000494:pharmacology; D010477:Perfusion; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000097:blood / Q000378:metabolism*; D019311:Staurosporine; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D002273:Carcinogens; D004224:Diterpenes; D010703:Phorbol Esters; D013729:Terpenes; C008876:phorbol-12,13-didecanoate; D012701:Serotonin; C011309:mezerein; D010208:Papaverine; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate