Protein kinase C influences rat pulmonary vascular reactivity.
To test the role of protein kinase C in the control of pulmonary vascular tone and reactivity, we examined the effects of the activators, phorbol 12-myristate-13-acetate (PMA), mezerein, and 1,2-dioctanyl-rac-glycerol (1,2-DOG), in rat isolated large pulmonary arteries and salt solution-perfused lungs. PMA (500 nM) and mezerein (100 nM) induced slow, sustained contractions of isolated pulmonary arteries. These contractions were not inhibited by nifedipine (1 microM), the intracellular Ca2+ blocker TMB-8 (50 microM), a 0 Ca2+ and EGTA (2 mM) bath, or endothelial denudation. They were reduced by amiloride (500 microM), an inhibitor of Na+/H+ exchange, and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7); (50 microM), an inhibitor of protein kinase C. PMA caused concentration-dependent (5 to 500 nM) potentiation of KCl, serotonin, and A23187 contractions of isolated pulmonary arteries. The effect of PMA on norepinephrine contraction was dependent on both concentration and time. Whereas PMA potentiated norepinephrine contraction after 5 min, it inhibited the response after 60 min. PMA and mezerein also caused concentration-dependent (0.5 to 500 nM) vasoconstriction in isolated lungs. The PMA vasoconstriction was unaltered by meclofenamate (1.6 microM) but was attenuated by nifedipine (1 microM). Low concentrations of PMA (5 nM) and 1,2-DOG (50 microM) potentiated both hypoxic and KCl vasoconstriction in isolated lungs. In contrast, the hypoxic and KCl responses were blunted by H-7 (30 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
Orton
E C
EC
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver.
Raffestin
B
B
McMurtry
I F
IF
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D004224:Diterpenes; D004730:Endothelium, Vascular / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D006859:Hydrogen / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D004075:Diglycerides; D004224:Diterpenes; D013729:Terpenes; C044295:1,2-dioctanoylglycerol; C011309:mezerein; D006859:Hydrogen; D012964:Sodium; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium