Search

With continued widespread acceptance of pedometers by both researchers and practitioners, evidence-based steps/day indices are needed to facilitate measurement and motivation applications of physical activity (PA) in public health. Therefore, the purpose of this article is to reprise, update, and extend the current understanding of dose-response relationships in terms of pedometer-determined PA. Any pedometer-based PA guideline presumes an accurate and standardized measure of steps; at this time, industry standards establishing quality control of instrumentation is limited to Japan where public health pedometer applications and the 10,000 steps.d slogan are traceable to the 1960s. Adult public health guidelines promote > or =30 min of at least moderate-intensity daily PA, and this translates to 3000-4000 steps if they are: 1) at least moderate intensity (i.e., > or =100 steps.min); 2) accumulated in at least 10-min bouts; and 3) taken over and above some minimal level of PA (i.e., number of daily steps) below which individuals might be classified as sedentary. A zone-based hierarchy is useful for both measurement and motivation purposes in adults: 1) <5000 steps.d (sedentary); 2) 5000-7499 steps.d (low active); 3) 7500-9999 steps.d (somewhat active); 4) > or =10,000-12,499 steps.d (active); and 5) > or =12,500 steps.d (highly active). Evidence to support youth-specific cutoff points is emerging. Criterion-referenced approaches based on selected health outcomes present the potential for advancing evidence-based steps/day standards in both adults and children from a measurement perspective. A tradeoff that needs to be acknowledged and considered is the impact on motivation when evidence-based cutoff points are interpreted by individuals as unattainable goals. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab., Methods: Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18 blood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients' sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between "baseline levels of 18 biomarkers" and "% change from baseline of EASI at 16 weeks of dupilumab treatment.", Discussion: This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.

Although ovarian serous carcinoma is a well-studied human gynecologic malignancy, this high-grade tumor remains fatal. The main purpose of this review is to summarize the accumulated evidence on serous malignant tumors and to clarify the unresolved issues. We discuss the 8 dichotomies of serous carcinoma: high grade versus low grade, ovarian versus extraovarian primary, extrauterine versus uterine primary, sporadic versus hereditary, orthodox versus alternative histology, p53 overexpression versus complete absence of immunophenotype, TP53-mutated versus intact precursor, and therapy responsive versus refractory. In addition, we summarize the molecular classification of high-grade serous carcinoma. This review would lead readers to rapid and parallel developments in understanding high-grade serous carcinoma.

Iatrogenic lymphoproliferative disorder (LPD) can develop in patients treated with immunosuppressive drugs for autoimmune or other inflammatory diseases. Here, we report a case of lymphomatoid granulomatosis of the skin that occurred as a methotrexate (MTX)-associated LPD. We also review the relevant literature. A 73-year-old woman presented to our department with an approximately 10-year history of MTX therapy for rheumatoid arthritis. Three months earlier, she noticed a small nodule in her right upper arm. It gradually enlarged, and the center began to decay. Grossly, the lesion was 40 × 40 mm in size with ulceration, and the surrounding skin presented dark red erythema. A biopsy specimen was taken for definitive diagnosis. Histologically, infiltrating growth of medium-to-large atypical lymphocytes was observed underneath the ulceration and was accompanied by small reactive lymphocytes. The atypical lymphocytes demonstrated a tendency to infiltrate the vessels, which showed an angiocentric pattern. Immunohistochemistry revealed that the atypical lymphoid cells were positive for CD79a, CD20, and CD30. In addition, in situ hybridization for Epstein-Barr virus (EBV) revealed expression of EBV-encoded small RNAs. The patient was diagnosed with MTX-associated LPD (lymphomatoid granulomatosis), owing to her history of MTX treatment, the expression of the atypical lymphocytes for B-cell markers and EBV-encoded small RNA, and the angiocentric infiltrating pattern. The lesion reportedly disappeared after withdrawal of MTX.

Aim: The aim of this study was to assess the acute and mid-term effects of drug-coated balloon (DCB) in terms of the healing process of non-flow-limiting dissections and changes in the neointimal area after DCB treatment using frequency domain optical coherence tomography (FD-OCT)., Patients and Methods: Thirty-six consecutive patients with in-stent restenosis pretreated with a scoring balloon were evaluated (19 and 17 patients with and without a DCB, respectively). FD-OCT was performed before and after each procedure during percutaneous coronary intervention and at 6 months of follow-up., Results: Clinical characteristics and baseline FD-OCT findings were comparable between the two groups. No patient required stent implantation because of low-pressure DCB-related dissections. In the acute phase, the DCB distributed paclitaxel to the vessel wall without increasing dissections. The DCB did not reduce the neointimal area by itself. At 6 months, more dissections healed in the DCB group (-4.5±2.3 vs. -2.7±1.3, P=0.02). The DCB group showed less change in the neointimal area (-0.04±0.92 vs. 1.06±1.57 mm, P=0.03)., Conclusion: The low-pressure DCB was not intended to expand the lumen, but instead to attach paclitaxel to the vessel wall by using FD-OCT examination. The DCB reduced the number of dissections and prevented neointimal proliferation during the mid-term follow-up.

Recent evidence has suggested that the hippocampal CA2 region plays an important role in the recognition process. We have reported that ischemic damage in the hippocampal CA2 region following transient ischemia is caused by apoptosis, but the underlying mechanisms are still not clear. Galectin-3 is a β-galactosidase-binding lectin that is important in cell proliferation and apoptotic regulation. We have also reported that galectin-3 was expressed in activated microglia in the CA1 region 96 h after transient ischemia. The aim of this study is to determine the localization and time course of galectin-3 expression in the CA2 region following transient forebrain ischemia. Galectin-3 immunostaining was observed in both interior side of CA1 region and CA2 region in hippocampus 60 h after ischemic insult. At 66 h, galectin-3 was observed in the whole CA1 region adjacent to the CA2 region in the hippocampus. Both galectin-3 expression and neuronal cell death in the CA2 region were significantly inhibited by hypothermia and by apoptosis-inhibiting reagents. These results suggest that galectin-3 in the CA2 region is expressed independent of that in the CA1 region. Protection of the expression of galectin-3 in the CA2 region might contribute toward the survival of CA2 pyramidal neurons.

Background: We sought to determine the effect of remifentanil on sinus node function and the atrial-His (AH) interval in pediatric patients undergoing radiofrequency catheter ablation., Methods: Sixty pediatric patients with Wolff-Parkinson-White syndrome were prospectively enrolled in this study. General anesthesia was induced and maintained with a continuous infusion of propofol. We recorded the calculated sinoatrial conduction time (CSACT), corrected sinus node recovery time (CSNRT), and AH interval when the patients were in a stable anesthetic state and compared the values before and during remifentanil administration at a moderate dose (0.2 μg · kg(-1) · min(-1)) or a high dose (0.4 μg · kg(-1) · min(-1)). Data are expressed as mean (95% confidence interval)., Results: At the moderate dose, remifentanil prolonged CSNRT (from 177 [117-237] milliseconds to 245 [167-322] milliseconds after administration; P=0.016), but had no effect on either CSACT (P=0.59) or AH interval (P=0.11). However, high-dose remifentanil prolonged both CSNRT (from 201 [144-260] milliseconds to 307 [232-382] milliseconds after administration; P=0.019) and CSACT (from 48 [31-65] milliseconds to 78 [59-96] milliseconds after administration; P=0.038), but had no effect on the AH interval (P=0.058). The interaction in CSNRT between remifentanil administration and its dose was not different (P=0.44)., Conclusion: Remifentanil may inhibit both intraatrial conduction and sinus node automaticity, but it has no effect on conduction through the atrioventricular node. Dose dependency was not observed within the range of 0.2 to 0.4 μg · kg(-1) · min(-1) of remifentanil., (© 2011 International Anesthesia Research Society)

Background: We conducted this study to examine, in cerebral parenchymal arterioles, whether 20-hydroxyeicosatetraenoic acid (20-HETE) induces constrictor responses via superoxide and whether propofol reduces this constriction., Methods: Electrical field stimulation or 20-HETE was applied to rat brain slices monitored by computer-assisted microscopy. In some experiments, a Na(+) channel antagonist tetrodotoxin, a 20-HETE synthesis inhibitor HET0016, a superoxide scavenger, Tiron, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium (DPI) and gp91ds-tat, or propofol was added. The superoxide level in the brain slice and the production rate in the absence of slices were evaluated by dihydroethidium fluorescence or cytochrome c reduction with a superoxide-generating system, respectively., Results: Electrical stimulation induced constriction of the cerebral parenchymal arteriole, whereas this response was abolished by tetrodotoxin, HET0016, Tiron, or DPI. 20-HETE (10(-8)-10(-6) mol/L) produced arteriolar constriction, which was inhibited by Tiron or DPI. Propofol reduced the constriction induced by electrical stimulation or 20-HETE. 20-HETE induced superoxide production in the brain slice, which was reduced by Tiron, gp91ds-tat, or propofol. However, propofol did not alter the superoxide production rate in the absence of brain slices., Conclusions: Either neuronal transmission-dependent or exogenous 20-HETE seems to induce cerebral parenchymal arteriolar constriction via superoxide production resulting from NADPH oxidase activation. Propofol is likely to prevent this constriction via inhibition of NADPH oxidase, but not by its scavenging effect on superoxide.

Background: It is not known whether thromboxane A2 impairs adenosine triphosphate (ATP)-sensitive K channel function via increased production of superoxide in blood vessels and whether propofol as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor restores this modification., Methods: Rat aortas without endothelium were used for isometric force recording, measurements of membrane potential, and superoxide production and Western immunoblotting. Vasorelaxation to an ATP-sensitive K channel opener levcromakalim was obtained during contraction to phenylephrine (3 x 10(-7) M) or a thromboxane A2 analogue U46619 (3 x 10(-7) M). In some experiments, aortas were incubated with an ATP-sensitive K channel antagonist glibenclamide, a superoxide inhibitor Tiron, a nonselective NADPH oxidase inhibitor apocynin, a hydrogen peroxide scavenger catalase, a xanthine oxidase inhibitor allopurinol, a thromboxane receptor antagonist SQ29548 or propofol (3 x 10(-7) to 3 x 10(-6) M)., Results: Levcromakalim-induced vasorelaxation was abolished by glibenclamide in rings contracted with either vasoconstrictor agent. Tiron, apocynin, and propofol, but not catalase, augmented the vasodilator response as well as the hyperpolarization by levcromakalim in aortas contracted with U46619. Tiron, apocynin, SQ29548, and propofol, but not allopurinol, similarly reduced in situ levels of superoxide within aortic vascular smooth muscle exposed to U46619. Protein expression of a NADPH oxidase subunit p47phox increased in these arteries, and this augmentation was abolished by propofol., Conclusions: Thromboxane receptor activation induces vascular oxidative stress via NADPH oxidase, resulting in the impairment of ATP-sensitive K channel function. Propofol reduces this stress via inhibition of a NADPH oxidase subunit p47phox and, therefore, restores ATP-sensitive K channel function.

Background: Vascular contraction is regulated by myosin light chain (MLC) phosphorylation. Inhibition of MLC phosphatase (MLCP) increases MLC phosphorylation for a given Ca(2+) concentration, and results in promoting myofilament Ca(2+) sensitivity. MLCP activity is mainly determined by protein kinase C (PKC) and Rho kinase through the phosphorylation of both PKC-potentiated inhibitory protein (CPI-17) and myosin phosphatase target subunit (MYPT1). We have previously demonstrated that sevoflurane inhibits PKC phosphorylation and membrane translocation of Rho kinase. This study was designed to investigate the effects of sevoflurane and isoflurane on CPI-17, MYPT1, and MLC phosphorylation in response to angiotensin II (Ang II) in rat aortic smooth muscle., Methods: The effects of sevoflurane or isoflurane (1-3 minimum alveolar concentration) on the vasoconstriction and phosphorylation of MLC, CPI-17, MYPT1 at Thr853 and MYPT1 at Thr696 in response to Ang II were investigated using isometric force transducer and Western blotting, respectively., Results: Ang II (10(-7) M) elicited a transient contraction of rat aortic smooth muscle that was inhibited by both sevoflurane and isoflurane in a concentration-dependent manner. Ang II also induced an increase in the phosphorylation of MLC, CPI-17, MYPT1/Thr853 and MYPT1/Thr696. Sevoflurane inhibited the phosphorylation of MLC, CPI-17, and MYPT1/Thr853 in response to Ang II in a concentration-dependent manner. Isoflurane also inhibited MLC phosphorylation in response to Ang II, which was associated with decreases in MYPT1/Thr853, but not in CPI-17. Neither sevoflurane nor isoflurane affected the Ang II-induced phosphorylation of MYPT1/Thr696., Conclusion: Although both volatile anesthetics inhibited Ang II-induced vasoconstriction and MLC phosphorylation to similar extent, the mechanisms behind the inhibitory effects of each anesthetic on MLCP activity appear to differ.

Background: In some types of pediatric supraventricular tachycardia, reentrant mechanisms are sensitive to enhanced vagal tone. Propofol is a feasible anesthetic for pediatric electrophysiological study and radiofrequency catheter ablation. Although fentanyl and propofol infusions both enhance cardiac vagal tone, it is unclear whether the combination of propofol and fentanyl has a potential to enhance it. In this study, we evaluated the hypothesis that fentanyl combined with propofol could alter cardiac electrophysiological activities in pediatric patients undergoing electrophysiological study and radiofrequency catheter ablation., Methods: Twenty-seven pediatric patients (9 Wolff-Parkinson-White syndrome, 7 concealed accessory pathway and 11 atrioventricular nodal reentry tachycardia) were enrolled in this study. Anesthesia was induced with propofol 2.0 mg/kg and was maintained with a continuous infusion of propofol at a rate of 100-167 microg x kg(-1) x min(-1). During a stable anesthetic state, the calculated sinoatrial conduction time and corrected sinus node recovery time (CSNRT) were measured before and after fentanyl administration. The fentanyl dose consisted of an initial 2.0 microg/kg IV bolus and subsequent continuous infusion of 0.075 microg x kg(-1) x min(-1)., Results: Bispectral Index scores and systemic blood pressure remained unchanged throughout the examinations. Fentanyl administration significantly prolonged CSNRT (P = 0.005) but not calculated sinoatrial conduction time (P = 0.35)., Conclusion: Since an enhanced cardiac vagal tone is one of the causative factors for prolonged CSNRT, our findings greatly support the hypothesis that fentanyl combined with propofol has a potential to enhance cardiac vagal tone.

Nitric oxide (NO) plays pivotal roles in controlling physiological functions, participates in pathophysiological intervention, and is involved in mechanisms underlying beneficial or untoward actions of therapeutic agents. Endogenous nitric oxide is formed by three isoforms of nitric oxide synthase: endothelial, neurogenic and inducible. The former two are constitutively present mainly in the endothelium and nervous system, respectively, and the latter one is induced by lipopolysaccharides or cytokines mainly in mitochondria and glial cells. Constitutively formed nitric oxide modulates the actions of morphine and related analgesics by either enhancing or reducing antinociception. Tolerance to and dependence on morphine or its withdrawal syndrome are likely prevented by nitric oxide synthase inhibition. Information concerning modulation of morphine actions by nitric oxide is undoubtedly useful in establishing new strategies for efficient antinociceptive treatment and for minimizing noxious and unintended reactions.

Background: An acetylcholinesterase inhibitor donepezil currently is used to treat patients with Alzheimer disease. However, its direct effect on cerebral blood vessels has not been evaluated. The present study was designed to examine whether donepezil induces acute cerebral arteriolar dilation and whether neuronal nitric oxide synthase contributes to this vasodilator response., Methods: Brain slices were obtained from neuronal nitric oxide synthase knock-out or C57BL/6J strain (control) mice as well as Wistar rats. Parenchymal arterioles were monitored using videomicroscopy. During constriction to prostaglandin F2alpha (5 x 10 m), donepezil (10-10 m) or acetylcholine (10-10 m) was added. In some experiments, brain slices were treated with a nonselective or a selective nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [10 m] and S-methyl-L-thiocitrulline [10 m], respectively). An immunohistochemical analysis was performed using antibodies for neuronal nitric oxide synthase and acetylcholinesterase., Results: Acetylcholine concentration-dependently dilated rat parenchymal arterioles, while S-methyl-L-thiocitrulline as well as N-nitro-L-arginine methyl ester completely abolished this response. Donepezil produced arteriolar dilation, which was inhibited by S-methyl-L-thiocitrulline or N-nitro-L-arginine methyl ester. Donepezil failed to induce arteriolar dilation in the brain slice from the neuronal nitric oxide synthase knock-out mice. Immunohistochemical analysis revealed spatial relationship between neuronal nitric oxide synthase and acetylcholinesterase in the arteriolar wall., Conclusions: Donepezil produces acute vasodilation induced by a selective activation of neuronal nitric oxide synthase in the cerebral parenchymal arterioles. This agent may be capable of enhancing this enzymatic activity directly or via acetylcholinesterase existing on the arteriolar wall.

Background: Vascular dysfunction induced by hyperglycemia has not been studied in cerebral parenchymal circulation. The current study was designed to examine whether high glucose impairs dilation of cerebral parenchymal arterioles via nitric oxide synthase, and whether propofol recovers this vasodilation by reducing superoxide levels in the brain., Methods: Cerebral parenchymal arterioles in the rat brain slices were monitored using computer-assisted videomicroscopy. Vasodilation induced by acetylcholine (10 to 10 m) was obtained after the incubation of brain slices for 60 min with any addition of l-glucose (20 mm), d-glucose (20 mm), or propofol (3 x 10 or 10 m) in combination with d-glucose (20 mm). Superoxide production in the brain slice was determined by dihydroethidium (2 x 10 m) fluorescence., Results: Addition of d-glucose, but not l-glucose, reduced arteriolar dilation by acetylcholine, whereas the dilation was abolished by the neuronal nitric oxide synthase inhibitor S-methyl-l-thiocitrulline (10 m). Both propofol and the superoxide dismutase mimetic Tempol (10 m) restored the arteriolar dilation in response to acetylcholine in the brain slice treated with d-glucose. Addition of d-glucose increased superoxide production in the brain slice, whereas propofol, Tempol, and the nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase inhibitor apocynin (1 mm) similarly inhibited it., Conclusions: Clinically relevant concentrations of propofol ameliorate neuronal nitric oxide synthase-dependent dilation impaired by high glucose in the cerebral parenchymal arterioles via the effect on superoxide levels. Propofol may be protective against cerebral microvascular malfunction resulting from oxidative stress by acute hyperglycemia.

There has been an explosive increase in the amount of interesting information about the physiologic and pathophysiologic roles of nitric oxide in cardiovascular, nervous, and immune systems. The possible involvement of the nitric oxide-cyclic guanosine monophosphate pathway in the effects of anesthetic agents has been the focus of many investigators. Relaxations of cerebral and peripheral arterial smooth muscle as well as increases in cerebral and other regional blood flows induced by anesthetic agents are mediated mainly via nitric oxide released from the endothelium and/or the nitrergic nerve and also via prostaglandin I2 or endothelium-derived hyperpolarizing factor. Preconditioning with volatile anesthetics protects against ischemia-reperfusion-induced myocardial dysfunction and cell death or neurotoxicity, possibly through nitric oxide release. Inhibition of nitric oxide synthase decreases the anesthetic requirement. Involvement of nitric oxide in the effects of volatile, intravenous, and local anesthetics differs. This review article includes a summary of information about the sites and mechanisms by which various anesthetic agents interact with the nitric oxide-cyclic guanosine monophosphate system.

Background: Sphingosylphosphorylcholine may induce coronary vasospasm by the activation of Rho kinase. We designed the current study to examine the differential effects of anesthetics on Rho kinase activation induced by sphingosylphosphorylcholine in porcine coronary arteries., Methods: Rings of porcine coronary artery without endothelium were prepared in tissue bath containing modified Krebs-Ringer bicarbonate solution. Using isometric force recording, concentration-response curves in response to sphingosylphosphorylcholine were obtained in the absence or in the presence of sevoflurane, propofol, or a selective Rho kinase inhibitor Y27632, which was added 15 min before the application of sphingosylphosphorylcholine. Intracellular translocation of Rho A toward the plasma membrane and phosphorylation of the myosin-targeting subunit of myosin light chain phosphatase were also evaluated by Western blotting., Results: Sphingosylphosphorylcholine (10(-7) to 10(-5) M) produced contraction of the porcine coronary artery, which was abolished by a selective Rho kinase inhibitor Y27632 (2 x 10(-6) M). Sevoflurane (1.7%) reduced sphingosylphosphorylcholine-induced coronary artery constriction, and the higher concentration (3.4%) abolished it (P < 0.05). In contrast, propofol (3 x 10(-6) M and 10(-5) M) had no effect on coronary artery constriction due to sphingosylphosphorylcholine. Sevoflurane, but not propofol, reduced intracellular translocation of Rho A toward the plasma membrane. Sevoflurane and Y27632, but not propofol, similarly decreased (64.4% or 70.8% reduction, respectively, P < 0.05) phosphorylation of the myosin-targeting subunit of myosin light chain phosphatase., Conclusions: Sphingosylphosphorylcholine induces coronary vasocontriction via activation of Rho kinase. Sevoflurane, but not propofol, inhibits this pathway, resulting in prevention of vasoconstriction.

Background: Angiotensin II (Ang II)-induced vascular contraction is mediated both by a Ca(2+)-mediated signaling pathway and a Ca(2+) sensitization mechanism. We recently demonstrated that sevoflurane inhibits the contractile response to Ang II, mainly by inhibiting protein kinase C (PKC) phosphorylation that regulates myofilament Ca(2+) sensitivity, without significant alteration of intracellular Ca(2+) concentration ([Ca(2+)](i)) in rat aortic smooth muscle. The current study was designed to determine the mechanisms by which isoflurane inhibits Ang II-induced contraction of rat aortic smooth muscle., Methods: The effects of isoflurane on vasoconstriction, increase in [Ca(2+)](i), and phosphorylation of PKC in response to Ang II (10(-7) M) were investigated, using an isometric force transducer, a fluorometer, and Western blotting, respectively., Results: Ang II elicited a transient contraction of rat aortic smooth muscle that was associated with an increase in [Ca(2+)](i) and PKC phosphorylation. Isoflurane (1.2%-3.5%) inhibited Ang II-induced contraction of rat aortic smooth muscle in a concentration-dependent manner (P < 0.05 at 1.2%, P < 0.01 at 2.3% and 3.5% isoflurane, n = 6). Isoflurane also inhibited elevation of [Ca(2+)](i) in response to Ang II (P < 0.01 at 2.3% and 3.5% isoflurane, n = 6), but failed to affect Ang II-induced phosphorylation of PKC at concentrations up to 3.5% (n = 7)., Conclusion: These results suggest that, unlike sevoflurane, the inhibitory effect of isoflurane on Ang II-induced contraction is mainly mediated by attenuation of the Ca(2+)-mediated signaling pathway.

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-VDeltaO2) 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-VDeltaO2 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.

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 alpha-adrenergic receptor antagonist phentolamine (3 x 10(-9) M) caused a similar vasodilator effect (approximately 20% of vasorelaxation compared with maximal vasorelaxation induced by papaverine [3 x 10(-4) M]), whereas glibenclamide did not alter vasorelaxation induced by droperidol. Droperidol (3 x 10(-8) M to 10(-7) M) augmented vasorelaxation and hyperpolarization produced by levcromakalim, whereas phentolamine (3 x 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 alpha-adrenergic receptors in vascular smooth muscles.

Although inward rectifier K+ channels contribute to the regulation of cerebral circulation, dilation of cerebral microvasculature mediated by these channels has not been demonstrated in chronic hypertension. We designed the present study to examine the roles of inward rectifier K+ channels in the vasodilation produced by increased levels of extracellular K+ in cerebral parenchymal arterioles from hypertensive and normotensive rats. During constriction to prostaglandin F2alpha (5 x 10(-7) M), the arterioles within brain slices were evaluated using computer-assisted microscopy. Potassium chloride (KCl) induced vasodilation in cerebral arterioles from normotensive (5-10 mM) and hypertensive (5-15 mM) rats, whereas an inward rectifier K+ channel antagonist barium chloride (BaCl2; 10(-5) M) completely abolished the vasodilation in both strains. In arterioles of hypertensive rats, vasodilator responses to KCl were augmented compared with those in normotensive rats. In contrast, the vasodilator responses induced by sodium nitroprusside (3 x 10(-8) to 3 x 10(-6) M) in these two strains were similar. These results suggest that in cerebral cortex parenchymal microvessels, inward rectifier K+ channels play a crucial role in vasodilation produced by extracellular K+ and that the dilation of cerebral arterioles via these channels is augmented in chronic hypertension.

Unlabelled: 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., Implications: The effects of sevoflurane and isoflurane on the development of nitroglycerin (TNG) tolerance were investigated in isolated rat aorta. TNG tolerance was induced by incubation of the vascular tissue in the bathing media containing TNG (10-5 M) for 30 min. Sevoflurane, but not isoflurane, enhances TNG tolerance, possibly by additive generation of oxygen-derived free radicals.

Unlabelled: Sevoflurane dilates blood vessels and reduces arterial blood pressure in a dose-dependent manner. Angiotensin II (Ang II) is one of the primary regulators of vascular tension and arterial blood pressure, and the p44/42 mitogen-activated protein kinases (p44/42 MAPK) are involved in Ang II-mediated vascular smooth muscle contraction. We designed this study to examine the effects of sevoflurane on Ang II-induced, p44/42 MAPK-mediated contraction of rat aortic smooth muscle. The effects of the p44/42 MAPK kinase (MEK1/2) inhibitor, PD 098059 (10(-5) molar [M], 5 x 10(-5) M and 10(-4) M), and sevoflurane (1.7%, 3.4%, and 5.1%) on Ang II-induced contraction and p44/42 MAPK phosphorylation were tested in rat aortic smooth muscle, using isometric force measurement and Western blot analysis, respectively. Ang II induced both a transient contractile response and phosphorylation of p44/42 MAPK, which were significantly attenuated by PD 098059 (P < 0.05-0.01). Sevoflurane inhibited Ang II-induced contractile response in a dose-dependent manner (P < 0.05 and 0.01 in response to 3.4% and 5.1% sevoflurane, respectively). Sevoflurane also dose-dependently depressed Ang II-elicited p44/42 MAPK phosphorylation (P < 0.01 in response to 3.4% and 5.1% sevoflurane). These results suggest that the inhibitory effect of sevoflurane on Ang II-induced vasoconstriction is, at least in part, caused by the inhibition of the p44/42 MAPK-mediated signaling pathway., Implications: The present study demonstrates that sevoflurane can dose-dependently inhibit both angiotensin II (Ang II)-induced contraction and p44/42 MAPK phosphorylation of rat aortic smooth muscle. These data suggest that sevoflurane-produced inhibition of Ang II-induced vasoconstriction is, at least in part, caused by depression of the p44/42 MAPK-mediated signaling pathway.

Objective: The present study was designed to examine in the human omental artery whether high concentrations of D-glucose inhibit the activity of ATP-sensitive K+ channels in the vascular smooth muscle and whether this inhibitory effect is mediated by the production of superoxide., Methods and Results: Human omental arteries without endothelium were suspended for isometric force recording. Changes in membrane potentials were recorded and production of superoxide was evaluated. Glibenclamide abolished vasorelaxation and hyperpolarization in response to levcromakalim. D-glucose (10 to 20 mmol/L) but not l-glucose (20 mmol/L) reduced these vasorelaxation and hyperpolarization. Tiron and diphenyleneiodonium, but not catalase, restored vasorelaxation and hyperpolarization in response to levcromakalim in arteries treated with D-glucose. Calphostin C and Gö6976 simultaneously recovered these vasorelaxation and hyperpolarization in arteries treated with D-glucose. Phorbol 12-myristate 13 acetate (PMA) inhibited the vasorelaxation and hyperpolarization, which are recovered by calphostin C as well as Gö6976. D-glucose and PMA, but not l-glucose, significantly increased superoxide production from the arteries, whereas such increased production was reversed by Tiron., Conclusions: These results suggest that in the human visceral artery, acute hyperglycemia modulates vasodilation mediated by ATP-sensitive K+ channels via the production of superoxide possibly mediated by the activation of protein kinase C.

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 Cgamma-1 (PLCgamma-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 PLCgamma-1 and p42MAPK, all of which were markedly inhibited by genistein (5 x 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 PLCgamma-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 PLCgamma-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 PLCgamma-1 and MAPK signaling pathways.

Vasodilator effects of adenosine triphosphate (ATP)-sensitive, as well as inward rectifier, K+ channel openers have not been well demonstrated in cerebral microvessels. Although lidocaine impairs vasorelaxation via ATP-sensitive K+ channels in the rat aorta, the effects of this compound on K+ channels in the cerebral circulation have not been shown. We designed the present study to examine whether ATP-sensitive and inward rectifier K+ channels contribute to vasodilator responses in cerebral microvessels and whether the vasodilation mediated by these channels is inhibited by lidocaine. Rat brain slices were monitored using a computer-assisted videomicroscopy. Cerebral parenchymal arterioles (diameter, 5-10 microm) were contracted with prostaglandin F(2alpha), and thereafter potassium chloride (KCl), levcromakalim, or sodium nitroprusside was added to the perfusion chamber. Levcromakalim and KCl produced vasodilation of the cerebral parenchymal arterioles, which was abolished by an ATP-sensitive K+ channel antagonist, glibenclamide, or an inward rectifier K+ channel antagonist, barium chloride, respectively. Lidocaine (10(-5) to 3 x 10(-5) M) inhibited the dilation produced by levcromakalim but not by KCl or sodium nitroprusside. In parenchymal arterioles of the cerebral cortex, lidocaine seems to reduce vasodilation mediated by ATP-sensitive K+ channels but not by inward rectifier K+ channels.

Background: Whether volatile anesthetics attenuate angiotensin II-mediated vascular tone has not been determined. The current study was designed to investigate the effects of sevoflurane on the angiotensin II-stimulated, Ca2+- and protein kinase C (PKC)-mediated contraction of rat aortic smooth muscle., Methods: The dose-dependent effects of sevoflurane on angiotensin II (10 m)-induced contraction, the increase in intracellular Ca2+ concentration, and PKC phosphorylation of rat aortic smooth muscle were measured using an isometric force transducer, a fluorometer, and Western blotting, respectively., Results: Angiotensin II induced a transient increase in intracellular Ca2+ concentration, phosphorylation of Ca2+-dependent PKC (cPKC)-alpha, and consequently, a transient contraction of rat aortic smooth muscle. Phosphorylation of the Ca2+-independent PKC-epsilon was not detected. The angiotensin II-induced contraction was almost completely abolished by removing extracellular Ca2+ and was significantly inhibited by the selective cPKC inhibitor Gö 6976 (10 M) but was not inhibited by the nonselective PKC inhibitor Ro 31-8425 (10 M). Sevoflurane dose-dependently inhibited the angiotensin II-induced contraction, with reductions of 14.2 +/- 5.2% (P > 0.05), 26.7 +/- 8.9% (P < 0.05), and 38.5 +/- 12.8% (P < 0.01) (n = 10) in response to 1.7, 3.4, and 5.1% sevoflurane, respectively. The angiotensin II-elicited increase in intracellular Ca2+ concentration was not significantly influenced by 3.4, 5.1, or 8.5% sevoflurane. However, cPKC-alpha phosphorylation induced by angiotensin II was inhibited dose dependently by 1.7, 3.4, and 5.1% sevoflurane, with depressions of 20.5 +/- 14.2% (P > 0.05), 37.0 +/- 17.8% (P < 0.05), and 62.5 +/- 12.2% (P < 0.01) (n = 4), respectively., Conclusion: The current study indicates that Ca2+ and cPKC-alpha are involved in angiotensin II-induced vascular contraction. Sevoflurane dose-dependently inhibited the angiotensin II-stimulated, cPKC-mediated but not Ca2+-elicited contraction of rat aortic smooth muscle.

Background: Carbon dioxide is an important vasodilator of cerebral blood vessels. Cerebral vasodilation mediated by adenosine triphosphate (ATP)-sensitive K+ channels has not been demonstrated in precapillary microvessel levels. Therefore, the current study was designed to examine whether ATP-sensitive K+ channels play a role in vasodilation induced by mild hypercapnia in precapillary arterioles of the rat cerebral cortex., Methods: Brain slices from rat cerebral cortex were prepared and superfused with artificial cerebrospinal fluid, including normal (Pco2 = 40 mmHg; pH = 7.4), hypercapnic (Pco2 = 50 mmHg; pH = 7.3), and hypercapnic normal pH (Pco2 = 50 mmHg; pH = 7.4) solutions. The ID of a cerebral parenchymal arteriole (5-9.5 microm) was monitored using computerized videomicroscopy., Results: During contraction to prostaglandin F2alpha (5 x 10(-7) m), hypercapnia, but not hypercapnia under normal pH, induced marked vasodilation, which was completely abolished by the selective ATP-sensitive K+ channel antagonist glibenclamide (5 x 10(-6) m). However, the selective Ca2+-dependent K+ channel antagonist iberiotoxin (10(-7) m) as well as the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10(-4) m) did not alter vasodilation. A selective ATP-sensitive K+ channel opener, levcromakalim (3 x 10(-8) to 3 x 10(-7) m), induced vasodilation, whereas this vasodilation was abolished by glibenclamide., Conclusion: These results suggest that in parenchymal microvessels of the rat cerebral cortex, decreased pH corresponding with hypercapnia, but not hypercapnia itself, contributes to cerebral vasodilation produced by carbon dioxide and that ATP-sensitive K+ channels play a major role in vasodilator responses produced by mild hypercapnia.

Unlabelled: Cerebral microemboli can occur during arthroplasty with the use of bone cement. Astroglial S-100B protein is a sensitive marker of cerebral damage. Therefore, we designed this study to determine the effect of bone cement on the brain by investigating serum levels of S-100B protein in patients undergoing bone surgery with or without bone cement. Fourteen patients undergoing knee arthroplasty (n = 7) or reamed intramedullary nailing for tibial fracture (n = 7) requiring a pneumatic tourniquet were enrolled in this study. Bone cement containing polymethyl methacrylate and methyl methacrylate was used for every patient undergoing knee arthroplasty. Serum samples were obtained from venous blood before the induction of general anesthesia, 15 min after deflation of a pneumatic tourniquet, and 3 days after the operation. The serum level of S-100B protein was significantly increased 15 min after a pneumatic tourniquet deflation in the knee arthroplasty group compared with the tibial fracture group (0.41 and 0.08 ng/mL, respectively; P < 0.05). In all patients studied, no neurological abnormalities were noted in the postoperative period. These results suggest that, in patients undergoing knee arthroplasty, bone cement may transiently induce astroglial injury, although it does not alter neurological outcome., Implications: Serum S-100B protein was significantly increased 15 min after a pneumatic tourniquet deflation in patients undergoing knee arthroplasty with bone cement, but not in those undergoing reamed intramedullary nailing for tibial fracture without bone cement. These results suggest that bone cement may transiently induce astroglial injury.

Background: The Rho/Rho-kinase signaling pathway plays an important role in mediating Ca2+ sensitization of vascular smooth muscle. The effect of anesthetics on Rho/Rho-kinase-mediated vasoconstriction has not been determined to date. This study is designed to examine the possible inhibitory effects of sevoflurane on the Rho/Rho-kinase pathway by measuring guanosine 5'-[gamma-thio]triphosphate (GTP gamma S)-stimulated contraction and translocation of RhoA (one of the three Rho subtypes) and Rock-2 (one of the two Rho-kinase subtypes) from the cytosol to the membrane in rat aortic smooth muscle., Methods: GTP gamma S-induced contraction of rat aortic endothelium-denuded rings was measured using an isometric force transducer, and GTP gamma S-stimulated membrane translocation of RhoA and Rock-2 in smooth muscle cells was detected with Western blotting in the presence and absence of sevoflurane., Results: GTP gamma S (10(-4) m) induced a sustained contraction, which was significantly inhibited by the Rho-kinase inhibitor, Y27632 (3 x 10(-6) m). Before treatment with GTP gamma S, RhoA and Rock-2 were detected primarily in the cytosolic fraction. GTP gamma S (10(-4) m) stimulated the translocation of RhoA and Rock-2 from the cytosol to the membrane, which was sustained for more than 60 min. Sevoflurane (1.7, 3.4, and 5.1%) concentration dependently inhibited the GTP gamma S-induced constriction of rat aortic smooth muscle with a reduction of constriction of 52-75% (P < 0.01, n = 8), and attenuated the translocation of RhoA and Rock-2 by 31-66% and 34-78%, respectively (P < 0.05-0.01, respectively; n = 4)., Conclusion: The current findings show that sevoflurane depresses the GTP gamma S-stimulated contraction and translocation of both Rho and Rho-kinase from the cytosol in a concentration-dependent manner, indicating that sevoflurane is able to inhibit vasoconstriction mediated by the Rho/Rho-kinase pathway in rat aortic smooth muscle.

Unlabelled: Hypoxia induces vasodilation, partly via the activation of K(+) channels. Lidocaine impairs vasorelaxation mediated by a K(+) channel opener, suggesting that this antiarrhythmic drug may inhibit hypoxia-induced vasodilation mediated by K(+) channels. We designed the current study to determine whether, in the carotid artery, K(+) channels contribute to vasorelaxation in response to hypoxia and whether lidocaine modulates vasorelaxation induced by K(+) channels via pathophysiological and pharmacological stimuli. Rings of rat common carotid artery without endothelium were suspended for isometric force recording. During contraction to phenylephrine, hypoxia-induced vasorelaxation or concentration-response to an adenosine triphosphate-sensitive K(+) channel opener was obtained changing control gas to hypoxic gas and the cumulative addition of levcromakalim, respectively. Hypoxia-induced vasorelaxation was significantly reduced by glibenclamide (5 micro M) but not by iberiotoxin (0.1 micro M), apamin (0.1 micro M), BaCl(2) (10 micro M), or 4-aminopyridine (1 mM). Levcromakalim-induced vasorelaxation was completely abolished by glibenclamide. Lidocaine (10-100 micro M) concentration-dependently inhibited this vasodilation, whereas it did not affect hypoxia-induced vasodilation. These results suggest that adenosine triphosphate-sensitive K(+) channels play a role in hypoxia-induced vasodilation in the rat carotid artery and that lidocaine differentially modulates vasodilation via these channels activated by pathophysiological and pharmacological stimuli., Implications: In rat carotid artery, levcromakalim produced vasorelaxation mediated by adenosine triphosphate (ATP)-sensitive K(+) channels, whereas hypoxia induced it partly via these channels. Lidocaine inhibited vasorelaxation induced by an ATP-sensitive K(+) channel opener but not by hypoxia, indicating the differential mechanisms of modulatory effects of this antiarrhythmic drug on vasodilation via ATP-sensitive K(+) channels activated by pathophysiological and pharmacological stimuli.

Unlabelled: The modification of vasodilation through adenosine triphosphate (ATP)-sensitive K(+) channels induced by antiarrhythmic drugs has not been studied in chronic hypertension. We designed the present study to examine whether mexiletine modulates vasorelaxation via these channels in hypertensive rat aortas. Normotensive and hypertensive rat aortas without endothelium were suspended for isometric force recording. Mexiletine (3 x 10(-5) M) increased vasorelaxation induced by levcromakalim (10(-8)-10(-5) M) in normotensive, but not hypertensive, rat aortas. Mexiletine (10(-5) to 3 x 10(-5) M) also augmented vasorelaxation to sodium nitroprusside (10(-10)-10(-5) M) only in normotensive rat aortas, whereas mexiletine (3 x 10(-5) M) did not affect this vasodilation in aortas treated with an ATP-sensitive K(+) channel antagonist glibenclamide (10(-5) M). A nitric oxide scavenger (carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide; 10(-3) M) abolished augmented vasorelaxation to sodium nitroprusside induced by mexiletine (3 x 10(-5) M) in normotensive rat aortas, whereas a soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one; 10(-5) M) failed to alter this augmentation of vasorelaxation. These results suggest that mexiletine induces augmentation of vasodilation via ATP-sensitive K(+) channels activated by the opener as well as a nitric oxide donor only in normotensive rat aortas. The vasodilator effects of mexiletine are partly caused by the soluble guanylate cyclase-independent action of nitric oxide on these channels., Implications: Mexiletine induces augmentation of vasodilation mediated by adenosine triphosphate (ATP)-sensitive K(+) channels activated by the opener as well as a nitric oxide donor in normotensive, but not hypertensive, rat aortas, partly by the soluble guanylate cyclase-independent action of nitric oxide on ATP-sensitive K(+) channels of vascular smooth muscle cells.

Background: The effect of ketamine on vasodilation mediated by adenosine triphosphate (ATP)-sensitive K(+) channels has not been studied. The present study was designed to determine whether ketamine might stereoselectively affect vasorelaxation induced by an ATP-sensitive K(+) channel opener in the isolated rat aorta., Methods: Rings of the rat aorta with or without endothelium were suspended for isometric force recording. During contraction to phenylephrine (3 x 10(-7) M), vasorelaxation in response to an ATP-sensitive K(+) channel opener levcromakalim (10(-8) to 10(-5) M) or a nitric oxide donor sodium nitroprusside (10(-10) to 10(-5) M) was obtained. Glibenclamide (10(-5) M), S(+) ketamine (10(-4) M), or ketamine racemate (10(-5) to 10(-4) M) was applied 15 min before addition of phenylephrine., Results: Vasorelaxation induced by levcromakalim was completely abolished by an ATP-sensitive K(+) channel antagonist glibenclamide (10(-5) M) in the aorta with or without endothelium. Ketamine racemate (3 x 10(-5) to 10(-4) M) significantly inhibited this vasorelaxation in a concentration-dependent fashion, whereas S(+) ketamine did not affect the relaxation. However, the highest concentration of ketamine racemate and S(+) ketamine used in the present study did not alter vasorelaxation in response to sodium nitroprusside in the aorta without endothelium., Conclusion: In the isolated rat aorta, clinically relevant concentrations of ketamine racemate can inhibit relaxation induced by an ATP-sensitive K(+) channel opener, whereas S(+) ketamine did not produce any inhibitory effect on this vasorelaxation. These results suggest that ketamine stereoselectively alters vasodilation ATP-sensitive K(+) channels in the conduit artery.