Inhibition of endothelium-dependent relaxations by phorbol myristate acetate in canine coronary arteries: role of a pertussis toxin-sensitive G-protein.
Activation of protein kinase C by phorbol esters inhibits the endothelium-dependent relaxations evoked by certain stimuli. The release of endothelium-derived relaxing factor can be evoked by a number of distinct subcellular processes, including activation of a pertussis toxin-sensitive G-protein. The aim of the present study was to determine whether or not the inhibitory effect of phorbol esters on endothelial function was associated with inhibition of the pertussis toxin-sensitive pathway. Rings of canine coronary artery were suspended for isometric tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution, gassed with 95% O2-5% CO2 (37 degrees C). Treatment of arterial rings with pertussis toxin (100 ng/ml) or with phorbol myristate acetate (PMA, 10(-8) M) inhibited the endothelium-dependent relaxations produced by UK 14,304, an alpha-2 adrenergic agonist, leukotriene C4 or by NaF, a direct activator of G-proteins, but did not affect the endothelium-dependent relaxations produced by bradykinin or by A23187. If the arterial rings were first treated with pertussis toxin, PMA (10(-8) M) no longer inhibited the endothelium-dependent relaxations to NaF. Increasing the concentration of PMA (to 3 X 10(-8) and 10(-7) M) caused inhibition of responses to bradykinin. At higher concentrations, PMA (3 X 10(-7) and 10(-6)) also inhibited the relaxations evoked by A23187. The endothelium-independent relaxations evoked by nitroglycerin were not affected by PMA (10(-8) to 10(-6)).(ABSTRACT TRUNCATED AT 250 WORDS)
Flavahan
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NA
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Shimokawa
H
H
Vanhoutte
P M
PM
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000187:drug effects / Q000502:physiology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D037342:Pertussis Toxin; D010703:Phorbol Esters / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D010703:Phorbol Esters; D010566:Virulence Factors, Bordetella; D009569:Nitric Oxide; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate