Sevoflurane and isoflurane inhibit KCl-induced Class II phosphoinositide 3-kinase α subunit mediated vasoconstriction in rat aorta

Abstract

BackgroundClass II phosphoinositide 3-kinase α-isoform (PI3K-C2α) is involved in regulating KCl-induced vascular smooth muscle contraction. The current study was to investigate the effects of sevoflurane (SEVO) and isoflurane (ISO) on KCl-elicited PI3KC2α mediated vasoconstriction in rat aortic smooth muscle.MethodsIsometric force, in the absence or presence of SEVO or ISO (1 ~ 3 minimum alveolar concentration, MAC), PI3K inhibitor LY294002, Rho kinase inhibitor Y27632, and membrane translocation of PI3K-p85, PI3K-C2α, Rho kinase (Rock II), or phosphorylation of MYPT1/Thr853, MYPT1/Thr696, CPI-17/Thr38 and MLC in response to KCl (60 mM) was measured by using isometric force transducer and western blotting analysis, respectively.ResultsKCl elicited a rapid and sustained contraction of rat aortic smooth muscle that was inhibited by both SEVO and ISO in a concentration-dependent manner, and also suppressed by LY294002 (1 mM) and Y27632 (1 uM). LY294002 (1 mM) and Y27632 (1 uM) also inhibited KCl-induced MLC phosphorylation. LY294002 (1 mM) inhibited KCl-induced PI3K-p85, PI3K-C2α membrane translocation in response to KCl (p <0.05, p < 0.01, respectively). Not only Y27632 (1 uM), but also LY294002 (1 mM), inhibited KCl-induced Rock-II membrane translocation (p < 0.01). SEVO and ISO inhibited KCl-stimulated MLC phosphorylation, PI3K-C2α and Rock-II,not PI3K p85 membrane translocation in a concentration-dependent manner in rat aorta. Both SEVO and ISO suppressed the MYPT1/Thr853, not MYPT1/Thr696 and CPI-17/Thr38, MLC phosphorylation in response to KCl.ConclusionPI3K-C2α mediates part of SEVO and ISO-mediated vasodilation in rat aorta. The cellular mechanisms underlying the inhibitory effect of volatile anesthetics might be mediated by KCl/PI3K-C2α/Rho kinase/MYPT1/MLC pathway.

Sevoflurane and isoflurane inhibit KCl-induced, Rho kinase-mediated, and PI3K-participated vasoconstriction in aged diabetic rat aortas

“…ISO also inhibited MLC phosphorylation in response to Ang II, which was associated with a decrease in MYPT1/Thr853 but not CPI-17 phosphorylation [20] . Moreover, we demonstrated that SEVO and ISO can mediate rat aortic vasodilation through the KCl/PI3K-C2α/Rho kinase/MYPT1/MLC pathway [21] . In addition, recent studies have con rmed that SEVO can inhibit the activity of Rho kinase in vascular smooth muscle cells and enhance vasodilation under PI3K inhibition [22] .…”

“…We also demonstrated that SEVO and ISO attenuated KCl (60 mM)-induced arterial contraction in a concentrationdependent manner and that LY294002 (10 mM) and Y27632 (1 µM) also inhibited contraction. The KCl/PI3K-C2α/Rho kinase/MLCP/MLC pathway may mediate the intracellular mechanism of VSM contraction induced by volatile anesthetics [21] . Fujii et al showed that SEVO did not alter the changes in Ca 2+ in aortic cells of diabetic rats induced by NE [23] , and SEVO at clinical concentrations could signi cantly inhibit the response of nondiabetic rats to NE but had no such effect on diabetic rats.…”

“…Consistent with our previous method [21] , KCl (60 mM) was used as an agonist for VSM contraction of the rat aorta in the two groups. Endothelium-denuded aortic rings were equilibrated under a resting tension of 3 g in Krebs bicarbonate solution (KBS) (in mmol/L NaCl, 118.2; KCl, 4.6; CaCl 2 , 2.5; KH 2 PO 4 , 1.2; MgSO 4 , 1.2; NaHCO 3 , 24.8; and dextrose 10) at 37°C and gassed with a mixture of 95 % (v/v) O2 and 5 % (v/v) CO 2 with a fresh gas ow of 2 L/min.…”

RhoA/rho-kinase, nitric oxide and inflammatory response in LIMA during OPCABG with isoflurane preconditioning

“…However, whether miRs regulate expression of RhoA/ROK in arterial grafts induced by isoflurane exposure remain unknown. Yang et al [33] demonstrated that Iso inhibit KCl-induced PI3K-C2α-participation, Rho kinase-mediated MLC phosphorylation, and vasoconstriction in rat aortic smooth muscle. Here, our data indicated that isoflurane preconditioning supressed the expression of RhoA/ROK and activated endothelial eNOS, resulting in vasodilation of LIMA, so we demonstrated that isoflurane preconditioning may be very useful for reperfusion of ischemic myocardium after revascularization for left anterior descending coronary artery.…”

PI3K inhibitors in thrombosis and cardiovascular disease

“…PI3Kγ's role in both hypertension and (the often associated) inflammation means inhibitors of this isoform might be attractive therapeutic candidates via both anti‐hypertensive and anti‐inflammatory properties [173,176]. Other Class I PI3K isoforms may also hold roles in hypertension, with p110δ expression being upregulated in aortas of hypertensive rats [177], while Class II PI3KC2α appears to regulate vascular smooth muscle contraction and play a role in spontaneous hypertension in rats via a Ca 2+ ‐PI3KC2α‐RHO axis [178–180].…”