Propofol inhibits phorbol 12, 13-dibutyrate-induced, protein kinase C-mediated contraction of rat aortic smooth muscle.
BACKGROUND
Propofol induces dose-dependent vasodilation and hypotension in the clinical situation, and protein kinase C (PKC)-mediated Ca2+ sensitization plays an important role in vascular smooth muscle contraction. This study is designed to examine the effects of propofol on the active phorbol ester (phorbol 12, 13-dibutyrate; PDBu)-induced, PKC-mediated contraction of rat aortic smooth muscle.


METHODS
The PDBu-induced contraction of endothelium-denuded rat aortic rings was measured in the presence or absence of PKC inhibitor, bisindolylmaleimide I, or propofol, using isometric force transducers. The PDBu-induced PKC phosphorylation of endothelium-denuded rat aortic strips was detected in the presence or absence of bisindolylmaleimide I or propofol, using Western blotting.


RESULTS
PDBu, but not the inactive phorbol ester, 4-alpha-phorbol 12-myristate-13-acetate, dose-dependently induced both a slowly developing sustained contraction and PKC phosphorylation of rat aortic smooth muscle, reaching the peak level at the concentration of 10(-6) M. The PDBu (10(-6) M)-induced contraction was dose-dependently inhibited by bisindolylmaleimide I with reductions of 6.8 +/- 1.8% (P > 0.05), 39.8 +/- 8.7% (P < 0.01) and 96.7 +/- 1.4% (P < 0.01) in response to concentrations of 5 x 10(-7) M, 10(-6)x M and 5 x 10(-6) M, respectively, and by propofol with decreases of 5.2 +/- 1. 6% (P > 0.05), 9.4 +/- 1.7% (P < 0.05), 65.3 +/- 9.2% (P < 0.01) and 96.2 +/- 1.6% (P < 0.01) in response to concentrations of 5 x 10(-7) M, 10(-6) M, 5 x 10(-6) M and 10(-5) M, respectively. Both bisindolylmaleimide I and propofol also inhibited the PDBu-induced increase in the density of the phosphorylated PKC bands in a dose-dependent manner, with decreases of 6.3 +/- 2.8% (P > 0.05), 42.9 +/- 3.2% (P < 0.01) and 96.6 +/- 3.4% (P < 0.01) in response to 5 x 10(-7) M, 10(-6) M or 5 x 10(-6) M bisindolylmaleimide I, respectively, and with decreases of 4.2 +/- 2.5% (P > 0.05), 13.5 +/- 1.7% (P < 0.05), 69.5 +/- 3.5% (P < 0.01) and 95.3 +/- 4.3% (P < 0.01) in response to 5 x 10(-7) M, 10(-6) M, 5 x 10(-6) M and 10(-5) M propofol, respectively.


CONCLUSIONS
Propofol dose-dependently inhibits PDBu-induced, PKC-mediated contraction of rat aortic smooth muscle.
Yu
J
J
Department of Anesthesiology, Wakayama Medical University, Wakayama City, Japan.
Kakutani
T
T
Mizumoto
K
K
Hasegawa
A
A
Hatano
Y
Y
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010766:Phosphorylation; D015742:Propofol / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D018686:Anesthetics, Intravenous; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; C088060:bisindolylmaleimide; D015742:Propofol