The Mechanisms Of Propofol-induced Relaxation On Isolated Thoracic Aorta Rings In Rats

Objective: To investigate the mechanisms of propofol-induced relaxation on isolated thoracic aorta rings in rats.Methods: 1.Vascular rings were randomly divided into endothelium-intact group and endothelium-denuded group, and each group was then divided into 5 subgroups:①1×10^-6mol/L norepinephrine (NA)group (n=6);②1×10^-6mol/L NA + propofol group(n=6);③1×10^-6mol/L NA+0.18% intralipid group(n=6) and 1×10^-6mol/L NA+1×10^-4mol/L propofol group(n=6);④1×10^-4mol/L L-NAME + 1×10^-6mol/L NA+ propofol group (n=6) (this subgroup was not included in the denuded group);⑤1×10^-5mol/L glibenclamide+1×10^-6mol/L NA+ propofol group (n=6). On the basis of maximal vasoconstriction evoked by NA(1×10^-6mol/L), propofol was added in progressively increasing cumulative concentrations (1×10^-6mol/L , 5×10^-6mol/L , 1×10^-5mol/L ,5×10^-5mol/L,10^-4mol/L) at a 15 minute interval ,and the effects of propofol-induced relaxation were observed in both endothelium-intact and endothelium-denuded rat aortic rings. 2. Vascular rings of SD rats were randomly divided into endothelial-intact group and denuded group, and each group was divided into 6 subgroups:①10nmol/L Go6976+1×10^-6mol/LNA+ propofol group (n=6);②10μmol/L Rottlerin+1×10^-6mol/L NA+ propofol group (n=6);③2μmol/L PKCε-Pseudo+1×10^-6mol/L NA+ propofol group (n=6);④2μmol/L PKCθ-Pseudo+1×10^-6mol/L NA+ propofol group (n=6);⑤2μmol/L PKCζ-Pseudo+1×10^-6mol/L NA+ propofol group (n=6);⑥control group:1×10^-6mol/L NA+ propofol group (n=6) . PKCαinhibitor Go6976, PKCδinhibitor Rottlerin, PKCζ, PKCθand PKCεpseudosubstrates were used to pretreat isolated thoracic aorta rings for 30min. Then do the same method 1, and the changes of vascular tone were observed.Results: 1. Propofol relaxed precontracted rat aortic rings in both concentration-dependent and endothelium-dependent manners. The presence of intact endothelium, propofol-induced vasodilation were (11.28±1.51)%, (25.23±4.03)%, (44.08±4.49)%, (66.28±4.83)% and (74.59±4.78)% at the concentrations of 1×10^-6mol/L, 5×10^-6mol/L, 1×10^-5mol/L, 5×10^-5mol/L, 1×10^-4mol/L, respectively, which were significantly greater than that in endothelium-denuded group (p<0.01) . Propofol-induced vasodilation was inhibited by L-NAME (10^-4 mol/L), a nitric oxide synthase inhibitor (p<0.01), and was also suppressed by glibenclamide, a specific inhibitor of KATP channels in endothelium-intact aorta. In addition, the vasodilation induced by 1×10^-6 mol/L and 5×10^-6mol/L of propofol was reversed by glibenclamide. 2. In endothelium-intact group, Go6976, PKCεand PKCθpseudosubstrates inhibited propofol-induced vasodilation, respectively (p<0.05 vs. in endothelial-intact control group). Rottlerin also inhibited propofol-induced vasodilation, and even reversed the effect of 1×10^-6 to 5×10^-5mol/L propofol (p<0.05 vs the baseline). In contrast, in endothelial-denuded group, preincubation with all of these inhibitors of PKC isoforms enhanced propofol-induced vasodilation (p<0.05 vs in endothelium-denuded control gruop).Conclusion: 1. Propofol causes vasodilation of isolated thoracic aorta rings in both endothelium-dependent and concentration dependent manners. Nitric oxide and KATP channels at least in part mediate the drug-induced vasodilation. 2. PKC isoforms such as PKCα, PKCδ, PKCεand PKCθhave distinct regulatory roles in mediating propofol-induced vasodilation depenging upon the presence or absence of endothelium.