Tetsuya Kakutani

The Inhibitory Effects of Isoflurane on Protein Tyrosine Phosphorylation–modulated Contraction of Rat Aortic Smooth Muscle

Background:Tyrosine kinase–catalyzed protein tyrosine phosphorylation plays an important role in initiating and modulating vascular smooth muscle contraction. The aim of the current study was to examine the effects of isoflurane on sodium orthovanadate (Na3VO4), a potent protein tyrosine phosphatase inhibitor–induced, tyrosine phosphorylation–mediated contraction of rat aortic smooth muscle. Methods:The Na3VO4-induced contraction of rat aortic smooth muscle and tyrosine phosphorylation of proteins including phospholipase Cγ-1 (PLCγ-1) and p44/p42 mitogen-activated protein kinase (MAPK) were assessed in the presence of different concentrations of isoflurane, using isometric force measurement and Western blotting methods, respectively. Results:Na3VO4 (10−4 m) induced a gradually sustained contraction and significant increase in protein tyrosine phosphorylation of a set of substrates including PLCγ-1 and p42MAPK, all of which were markedly inhibited by genistein (5 × 10−5 m), a tyrosine kinase inhibitor. Isoflurane (1.2–3.5%) dose-dependently depressed the Na3VO4-induced contraction (P < 0.05–0.005; n = 8). Isoflurane also attenuated the total density of the Na3VO4-induced, tyrosine-phosphorylated substrate bands and the density of tyrosine-phosphorylated PLCγ-1 band and p42MAPK band (P < 0.05–0.005; n = 4) in a concentration-dependent manner. Conclusion:The findings of the current study, that isoflurane dose-dependently inhibits both the Na3VO4-stimulated contraction and tyrosine phosphorylation of a set of proteins including PLCγ-1 and p42MAPK in rat aortic smooth muscle, suggest that isoflurane depresses protein tyrosine phosphorylation–modulated contraction of vascular smooth muscle, especially that mediated by the tyrosine-phosphorylated PLCγ-1 and MAPK signaling pathways.

Effects of isoflurane and sevoflurane anesthesia on arteriovenous shunt flow in the lower limb of diabetic patients without autonomic neuropathy.

Background:Failure of sympathetic nerve control caused by diabetic neuropathy results in vasodilation of arteriovenous shunts. The aim of this study was to test the hypothesis that the function of arteriovenous anastomoses was disordered in mild diabetic patients without apparent neuropathy, and that volatile anesthetics opened arteriovenous shunts more greatly in nondiabetic patients than diabetic patients. Methods:Autonomic system function was assessed by cardiovascular reflex tests. Arterial–venous oxygen content difference (A-V&Dgr;O2) and partial oxygen pressure index (Pvo2/Pao2, the ratio of oxygen tension in femoral vein blood to that in femoral artery blood) were measured before and during isoflurane or sevoflurane anesthesia in 16 diabetic and 22 nondiabetic patients. Skin temperatures of the foot and leg were measured in 14 diabetic and 15 nondiabetic patients using thermography before and during anesthesia. Results:Pvo2/Pao2 before anesthesia was significantly higher in diabetic patients. In nondiabetics, venous oxygen content significantly increased and A-V&Dgr;O2 markedly decreased during anesthesia, but these parameters were unchanged in diabetics. Foot temperatures were higher in diabetics before anesthesia, and increased gradually and significantly in both groups during anesthesia, but with a greater increase in nondiabetic patients. Induction of anesthesia caused a larger decrease in leg temperature in diabetics than in nondiabetics. Conclusions:Diabetic patients have a higher Pvo2/Pao2 and a small core-to-peripheral temperature gradient before anesthesia, suggesting latent dysfunction of the autonomic nerve system, even in the absence of autonomic neuropathy. Volatile anesthesia opens the arteriovenous shunt in nondiabetics to a greater extent than in diabetic patients.

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.

Comparison of the effects of isoflurane and sevoflurane on protein tyrosine phosphorylation-mediated vascular contraction.

Background:  Isoflurane induces greater effects on vasodilation and decreasing blood pressure than sevoflurane. Tyrosine kinase‐catalyzed protein tyrosine phosphorylation plays an important role in regulating vascular smooth muscle contraction. The aim of the present study was to compare the effects of isoflurane and sevoflurane on tyrosine phosphorylation‐mediated vascular constriction, by assessing the degree of sodium orthovanadate (Na3VO4, tyrosine phosphatase inhibitor)‐induced contraction and protein tyrosine phosphorylation of rat aortic smooth muscle.

Transient phlebitis induced by a bolus injection of propofol

redness of his veins disappeared (Fig. 1b). After that, the course of the patient during and after anesthesia was uneventful, even though we repeatedly administered the same concentration of vecuronium in a bolus manner (1–2 mg i.v.) during the surgery. The delayed redness at these veins did not recur. The incidence of such transient phlebitis after injection of propofol has not been well known. To understand the Transient phlebitis induced by a bolus injection of propofol

Augmented Activity of Adenosine Triphosphate-Sensitive K Channels Induced by Droperidol in the Rat Aorta

Droperidol produces the inhibition of K+ channels in cardiac myocytes. However, the effects of droperidol on K+ channels have not been studied in blood vessels. Therefore, we designed the present study to determine whether droperidol modulates the activity of adenosine triphosphate (ATP)-sensitive K+ channels in vascular smooth muscle cells. Rat aortic rings without endothelium were suspended or used for isometric force and membrane potential recordings, respectively. Vasorelaxation and hyperpolarization induced by levcromakalim (10−8 to 10−5 M or 10−5 M, respectively) were completely abolished by the ATP-sensitive K+ channel antagonist glibenclamide (10−5 M). Droperidol (10−7 M) and an α-adrenergic receptor antagonist phentolamine (3 × 10−9 M) caused a similar vasodilator effect (approximately 20% of vasorelaxation compared with maximal vasorelaxation induced by papaverine [3 × 10−4 M]), whereas glibenclamide did not alter vasorelaxation induced by droperidol. Droperidol (3 × 10−8 M to 10−7 M) augmented vasorelaxation and hyperpolarization produced by levcromakalim, whereas phentolamine (3 × 10−9 M) did not alter this vasorelaxation. Glibenclamide (10−5 M) abolished the vasodilating and hyperpolarizing effects of levcromakalim in the aorta treated with droperidol (10−7 M). These results suggest that droperidol augments vasodilator activity via ATP-sensitive K+ channels. However, it is unlikely that this augmentation is mediated by the inhibition of α-adrenergic receptors in vascular smooth muscles.

Sevoflurane enhances nitroglycerin tolerance in rat aorta: implications for the desensitization of soluble guanylate cyclase possibly through the additive generation of superoxide anions and/or hydroxyl radicals within vascular smooth muscle.

Nitroglycerin (TNG) tolerance, defined as an impaired vasodilation response to TNG, has been recently demonstrated to be associated with increased production of reactive species. We designed this study to investigate the mechanisms that mediate TNG tolerance and to compare the effects of sevoflurane and isoflurane on the development of TNG tolerance. Tension changes in rat aortic rings without endothelium were recorded. The cumulative relaxant responses to TNG (10−8–10−5 M) were assessed in phenylephrine-contracted rings. To induce TNG tolerance, the rings were then incubated in the bathing solution containing TNG (10−5 M) for 30 min in the presence or absence of each anesthetic (1 to 3 MAC). After washout of TNG and anesthetic, the second response to TNG was obtained. Some rings were pretreated with oxygen radical scavengers or sulfhydryl supplements. The first and the second responses to TNG were compared. Sevoflurane at 3 MAC, but not sevoflurane at smaller concentrations or isoflurane, enhanced TNG tolerance when administered in combination with TNG. Sevoflurane alone had no effect on TNG tolerance. The enhancement of TNG tolerance in the case of a combined sevoflurane and TNG treatment was inhibited in the presence of oxygen radical scavengers or at a smaller oxygen concentration (25%). Sevoflurane at a concentration of 3 MAC in hyperoxic condition enhances the development of TNG tolerance, possibly by additive generation of superoxide anions or hydroxyl radicals within vascular smooth muscle.