Protein kinase C-mediated pulmonary vasoconstriction in rabbit: role of Ca2+, AA metabolites, and vasodilators.
We studied the effects of three chemically distinct protein kinase C activators on pulmonary vascular tone in the buffer-perfused isolated rabbit lung. The three activators, 12-deoxyphorbol 13-isobutyrate (12,13-phorbol), mezerein, and 1-oleoyl-2-acetyl-sn-glycerol, produce concentration-dependent increases in pulmonary arterial pressure, whereas the inactive compound 4 alpha-phorbol 12,13-dibutyrate does not affect pulmonary arterial pressure. Reducing calcium availability with verapamil, a calcium-free buffer, or a chelator of intracellular calcium significantly decreases the response to 12,13-phorbol or mezerein. Pretreatment with phloretin, an inhibitor of protein kinase C, has no affect on the vasoconstriction caused by infusion of a KCl bolus, but it does inhibit in a dose-dependent manner the response to 12,13-phorbol and mezerein. 12,13-Phorbol at a concentration of 2.5 microM, but not of 1 microM, stimulates prostacyclin and thromboxane synthesis by the isolated lung. Because inhibitors of thromboxane synthesis significantly decrease the response, thromboxane likely contributes to the vasoconstriction produced by higher concentrations of 12,13-phorbol and mezerein. Pretreatment with isoproterenol or nitroprusside reduces the increase in pulmonary arterial pressure caused by the protein kinase C activators but does not reverse vasoconstriction, even though subsequent treatment with verapamil does. In summary, activating protein kinase C in the isolated rabbit lung causes long-lasting pulmonary vasoconstriction, reducing calcium availability decreases the response, part of the increase in pulmonary arterial pressure appears secondary to thromboxane generation, and pretreatment with isoproterenol or nitroprusside prevents the vasoconstriction, but posttreatment with these vasodilators is ineffective.
Michael
J R
JR
Medical Service, Veterans Affairs Medical Center, Salt Lake City, Utah.
Yang
J
J
Farrukh
I S
IS
Gurtner
G H
GH
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000502:physiology*; D002273:Carcinogens / Q000494:pharmacology; D004224:Diterpenes; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010693:Phloretin / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D013729:Terpenes / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001095:Arachidonic Acids; D002273:Carcinogens; D004224:Diterpenes; D013729:Terpenes; D014665:Vasodilator Agents; D009599:Nitroprusside; C011309:mezerein; D015240:Phorbol 12,13-Dibutyrate; D011189:Potassium Chloride; D011493:Protein Kinase C; D007545:Isoproterenol; D010693:Phloretin; D002118:Calcium