Michiro Ishikawa

Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways.

*Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo-/-ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo-/-ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFα and resistin in adipose tissues of ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle.

Endothelin-1- and endothelin-3-induced vasorelaxation via common generation of endothelium-derived nitric oxide

The vasorelaxant effects by endothelin-1 (ET-1) and endothelin-3 (ET-3), and their mechanisms of action were studied in isolated porcine pulmonary arterial strips. ET-1 and ET-3 dose-dependently (10(-9) - 10(-8) M) relaxed vascular strips precontracted with norepinephrine only in the presence of endothelium. The maximal vasorelaxant effect by ET-1 was about 70% of that by ET-3. The ET-1- and ET-3- induced vasorelaxation was blocked by NG-nitro-L-arginine, an inhibitor of nitric oxide synthesis, and methylene blue, an inhibitor of soluble guanylate cyclase. The present data suggest that vascular smooth muscle relaxation induced by ET-1 and ET-3 is mainly ascribed to synthesis and release of nitric oxide from L-arginine in endothelium.

A rare case of laryngeal myxoma

We report a rare case of laryngeal myxoma in a 57-year-old Japanese man. Except for a five-year history of gradually progressive hoarseness, he had been in good health. Video-stroboscopic examination revealed a solid mass in the anterior third of the right vocal fold. Phonosurgery performed with a microscope showed that the mass was encapsulated and located between the epithelium and vocal fold ligaments of the right vocal fold. This hard, elastic mass which measured 7 mm in diameter, was diagnosed as a myxoma. Only three cases of myxoma of the larynx have been reported in the English literature, with only one other case involving the vocal fold.

The contractile mechanism of beraprost sodium, a stable prostacyclin analog, in the isolated canine femoral vein.

SummaryThe vascular contractile mechanism of prostacyclin (PGI2) was investigated using beraprost sodium (BPS), a stable PGI2 analog. Ring strips without endothelium isolated from canine femoral veins and arteries were used. BPS induced a dose-dependent contraction without precontraction and after precontraction with norepinephrine (NE) or 60 mM K+ in the veins. In contrast, BPS induced a dose-dependent relaxation after precontraction with U46619, a thromboxane A2 (TXA2) analog, or prostaglandin F2α (PGF2α) in the veins. In the arteries, BPS induced contraction at higher concentrations after precontraction with NE. However, BPS relaxed arteries dose-dependently after precontraction with PGF2α. By pretreatment with 13-azaprostanoic acid (13-APA), a TXA2/endoperoxide receptor antagonist, the dose-response curve of BPS in the veins was shifted to the right. Schild plot analysis resulted in a linear regression with a slope of 0.86 ± 0.13, which was not significantly different from unity, and the pA2 value for 13-APA against BPS was 7.10 ± 0.06. By pretreatment with BPS, the dose-response curve of U46619 in the veins was shifted to the right. Kaumann plot analysis resulted in a linear regression with a slope of 0.89 ± 0.09, which was not significantly different from unity, and the pA2 value for BPS against U46619 was 5.68 ± 0.04. These findings indicate that BPS is a partial agonist for the TXA2/endoperoxide receptors.

Effect of hyperhomocysteinemia on endothelial activation and dysfunction in patients with end-stage renal disease.

metabolism, and atherosclerosis. Metabolism 1987;36(suppl 1):1–8. 14. Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, Imaizumi T. Endogenous nitric oxide synthase inhibitor. A novel marker of atherosclerosis. Circulation 1999;99:1141–1146. 15. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction-dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 1999;99:3092–3095. 16. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37: 1595–1607. 17. Reaven GM, Chen Y-DI, Hollenbeck CB, Sheu WHH, Ostrega D, Polonsky KS. Plasma insulin C-peptide, and proinsulin concentrations in obese and nonobese individuals with varying degrees of glucose tolerance. J Clin Endocrinol Metab 1993;76:44–48. 18. Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Aterioscler Thromb 1994;14:753– 759. 19. Huang PL. Disruption of the endothelial nitric oxide synthase gene: effect on vascular response to injury. Am J Cardiol 1998;82(10A):57S–59S.

Effect of captopril on acetylcholine-induced relaxation in the presence of nitroglycerin tolerance in isolated rabbit aorta.

We investigated the effects of angiotensin converting enzyme inhibitors on acetylcholine-induced endothelium-dependent vasodilation in the presence of nitroglycerin tolerance in rings of rabbit thoracic aorta mounted in tissue baths and precontracted with 10(-6) M norepinephrine. The vasorelaxant effects of acetylcholine were measured before and after 1 h treatment with 5 x 10(-4) M nitroglycerin. The acetylcholine dose-response curve shifted to the right after the induction of nitroglycerin tolerance. Pretreatment with captopril (a sulfhydryl angiotensin converting enzyme inhibitor), but not with M-1 (a metabolite of delapril and a nonsulfhydryl angiotensin converting enzyme inhibitor) restored acetylcholine-induced relaxation. Pretreatment with N-acetylcysteine also restored reduced acetylcholine-induced relaxation. These results suggest that the sulfhydryl group plays a major role in restoration of reduced acetylcholine-induced vasodilation in the presence of nitroglycerin tolerance.