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°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) These results suggest that in canine coronary arteries, endothelial leukotriene and alpha-2 adrenergic receptors are linked to a pertussis toxin-sensitive G-protein that stimulates the release of endothelium-derived relaxing factor(s). At low concentrations, PMA inhibits selectively this pertussis toxin-sensitive pathway, possibly by inhibiting the function of the pertussis toxin-sensitive G-protein in the endothelial cells.
|ジャーナル||Journal of Pharmacology and Experimental Therapeutics|
|出版ステータス||Published - 1991|
ASJC Scopus subject areas
- Molecular Medicine