Masanori Haba

Propofol Restores Brain Microvascular Function Impaired by High Glucose via the Decrease in Oxidative Stress

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 (10−6 to 10−4 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 × 10−7 or 10−6 m) in combination with d-glucose (20 mm). Superoxide production in the brain slice was determined by dihydroethidium (2 × 10−6 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 (10−5 m). Both propofol and the superoxide dismutase mimetic Tempol (10−4 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.

Beneficial effect of propofol on arterial adenosine triphosphate-sensitive K+ channel function impaired by thromboxane.

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 × 10−7 m) or a thromboxane A2 analogue U46619 (3 × 10−8 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 × 10−7 to 3 × 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.

Successful one-stage surgical removal of intravenous uterine leiomyomatosis with right heart extension

We report a 49-year-old woman with intravenous and intracardiac extension of uterine leiomyomatosis. After subtotal hysterectomy and salpingo-oophorectomy, an intravenous and intracardiac tumor was removed under normothermic cardiopulmonary bypass without cardiac arrest. Postoperatively, occlusion of the artery supplying the remaining uterine cervical stump was performed by the catheter coiling technique. More than 2 years after surgery, the patient is well without recurrence.

The Modulation of Vascular ATP-Sensitive K+ Channel Function via the Phosphatidylinositol 3-Kinase–Akt Pathway Activated by Phenylephrine

The present study examined the modulator role of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway activated by the α-1 adrenoceptor agonist phenylephrine in ATP-sensitive K+ channel function in intact vascular smooth muscle. We evaluated the ATP-sensitive K+ channel function and the activity of the PI3K–Akt pathway in the rat thoracic aorta without endothelium. The PI3K inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) (10−5 M) augmented relaxation in response to the ATP-sensitive K+ channel opener levcromakalim (10−8 to 3 × 10−6 M) in aortic rings contracted with phenylephrine (3 × 10−7 M) but not with 9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F2α (U46619; 3 × 10−8 M), although those agents induced similar contraction. ATP-sensitive K+ channel currents induced by levcromakalim (10−6 M) in the presence of phenylephrine (3 × 10−7 M) were enhanced by the nonselective α-adrenoceptor antagonist phentolamine (10−7 M) and LY294002 (10−5 M). Levels of the regulatory subunits of PI3K p85-α and p55-γ increased in the membrane fraction from aortas without endothelium treated with phenylephrine (3 × 10−7 M) but not with U46619 (3 × 10−8 M). Phenylephrine simultaneously augmented Akt phosphorylation at Ser473 and Thr308. Therefore, activation of the PI3K–Akt pathway seems to play a role in the impairment of ATP-sensitive K+ channel function in vascular smooth muscle exposed to α-1 adrenergic stimuli.

Cholinesterase inhibitor donepezil dilates cerebral parenchymal arterioles via the activation of neuronal nitric oxide synthase.

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 F2&agr; (5 × 10−7 m), donepezil (10−9–10−8 m) or acetylcholine (10−6–10−4 m) was added. In some experiments, brain slices were treated with a nonselective or a selective nitric oxide synthase inhibitor (NG-nitro-L-arginine methyl ester [10−4 m] and S-methyl-L-thiocitrulline [10−5 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 NG-nitro-L-arginine methyl ester completely abolished this response. Donepezil produced arteriolar dilation, which was inhibited by S-methyl-L-thiocitrulline or NG-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.