Sevoflurane does not alter norepinephrine-induced intracellular Ca2+ changes in the diabetic rat aorta

Abstract

Purpose The effect of volatile anesthetics on the mechanism(s) of vascular contraction in diabetes mellitus (DM) has not been fully understood. The current study was designed to determine the effects of sevoflurane on the norepinephrine (NE)-induced changes in contractile state and intracellular Ca 2? concentrations ([Ca 2? ] i ) in the spontaneously developing type 2 DM rat. Methods The effects of sevoflurane on NE (10 -6 M)-induced vasoconstriction and increase in [Ca 2? ] i in the aortas from Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 DM model, and from age-matched control Long-Evans Tokushima Otsuka (LETO) rats were investigated using an isometric force transducer and fluorometer with fura-2 as an indicator of [Ca 2? ] i . Results Norepinephrine-induced increases in tension and [Ca 2? ] i in OLETF rats were 54.8%, 95% confidence interval (CI) 36.9-72.6% and 58.8%, 95% CI 51.5-66.1%, respectively, and in LETO rats they were 46.4%, 95% CI 39.0-53.7% and 53.8%, 95% CI 46.9-60.7%, respectively, when expressed as the percentage relative to that induced by KCl 30 mM. In LETO rats, sevoflurane at a concentration of 3.4% inhibited the vascular contraction (9.4%, 95% CI 6.3-12.6%; P \ 0.001) and the increase in [Ca 2? ] i (33.3%, 95% CI 27.4-39.2%; P = 0.002).In OLETF rats, however, sevoflurane failed to affect either the NE-induced contraction (43.6%, 95% CI 28.3-58.9%; P = 0.68) or the elevation in [Ca 2? ] i (60.5%, 95% CI 56.3-64.8%; P = 0.93). Conclusion Sevoflurane at clinically relevant concentrations inhibited the NE-induced increase in [Ca 2? ] i in the aortic smooth muscle from normal rats but not in that from type 2 DM rats. Thus, a Ca 2? -signalling pathway resistant to sevoflurane appears to exist in the type 2 DM rat aorta. ResuméObjectif L'effet des anesthe´siques volatils sur les me´canismes de contraction vasculaire en pre´sence de diabe`te sucre´n'est pas encore tout a`fait compris. L'e´tude en cours a e´te´conçue afin de de´terminer les effets du se´voflurane sur les changements de contractilite´et de concentration intracellulaire de Ca 2? ([Ca 2? ] i ) induits par la nore´pinephrine (NE) en cas de de´veloppement spontaned u diabe`te sucre´de type 2 chez le rat.

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

“…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. Recent studies have shown that arterial reactivity to acetylcholine (ACh) and Ang II in diabetic mice is signi cantly changed, which is related to an increase in Rho kinase activity [27] .…”

“…Studies have shown that SEVO at clinical concentrations can signi cantly inhibit the response of nondiabetic rats to norepinephrine (NE), but it has no effect on diabetic rats [23] . Clinical studies have also demonstrated that the foot skin temperature of nondiabetic patients is higher than that of diabetic patients induced by ISO or SEVO anesthesia, suggesting that thermoregulation controlled by the sympathetic nervous system is impaired in diabetic patients [24] .…”

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

“…Fujii et al showed that SEVO did not alter the changes in Ca 2+ in aortic cells of diabetic rats induced by NE [ 25 ], and SEVO at clinical concentrations could significantly inhibit the response of nondiabetic rats to NE but had no such effect on diabetic rats. Recent studies have shown that arterial reactivity to acetylcholine (ACh) and Ang II in diabetic mice is significantly changed, which is related to an increase in Rho kinase activity [ 30 ].…”

“…Studies have shown that SEVO at clinical concentrations can significantly inhibit the response of nondiabetic rats to norepinephrine (NE), but it has no effect on diabetic rats [ 25 ]. Clinical studies have also demonstrated that the foot skin temperature of nondiabetic patients is higher than that of diabetic patients induced by ISO or SEVO anesthesia, suggesting that thermoregulation controlled by the sympathetic nervous system is impaired in diabetic patients [ 26 ].…”

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

“…Several reports also showed that SEVO decreased myofilament Ca 2+ sensitivity by regulating Rho kinase and PKC activity [ 1 , 17 , 18 ]. We recently showed that SEVO does not alter norepinephrine-induced intracellular Ca 2+ changes in the diabetic rat aorta [ 28 ]. These data further demonstrate that myofilament Ca 2+ sensitization, not Ca 2+ -dependent mechanisms, is involved in modulating vascular tension by SEV.…”