Effects of the polyphenol resveratrol on contractility of human term pregnant myometrium

The ideal agent for prevention and treatment of uterine abnormal contractility has not been found. The polyphenol resveratrol possesses a wide spectrum of pharmacologic properties, but its influence on the contractility of human myometrium is not defined. The present study evaluated the effect of resveratrol on the oxytocin-induced contractions of human term pregnant myometrium in vitro and the contribution of different K+ channels to resveratrol action. Resveratrol induced a concentration-dependent relaxation of myometrium contractions (pD(2) value and maximal responses were 4.52 and 82.25%, respectively). Glibenclamide, a selective blocker of ATP-sensitive (K-ATP), iberiotoxin, a selective blockers of big-calcium sensitive (BKCa) and 4-aminopiridine, a non-selective blocker of voltage-sensitive (Kv) channels induced a significant shift to the right of the concentration-response curves of resveratrol. Inhibition achieved by 0.1 mM resveratrol was insensitive to all K+ channel blockers. A K+ channel opener, pinacidil, inhibited oxytocin-induced contractions of pregnant myometrium with comparable potency and efficacy to resveratrol (pD(2) values and maximal relaxation were 4.52 and 83.67%, respectively). Based on K+ channel opener/blocker affinities, it appears that the inhibitory response of resveratrol involves different myometrial K+ channels. When applied in high concentrations, resveratrol has an additional K+-channel-independent mechanism(s) of action. Furthermore, immunohistochemistry staining and western blot analyses detected the presence and distribution of K-ATP, BKCa and Kv channel proteins in pregnant myometrium

The Effects of Potassium Channel Opener P1075 on the Human Saphenous Vein and Human Internal Mammary Artery

Because adrenergic contractions can contribute to the development of life-threatening spasm of coronary artery bypass graft, this study was performed to investigate the effect of adenosine 3-phosphate (ATP)-sensitive K(+) channel (K(ATP)) opener P1075 on contractions of isolated human saphenous vein (HSV) and human internal mammary artery (HIMA). Phasic contractions were evoked by electric field stimulation (20 Hz) and noradrenaline. The sustained contractions were evoked by phenylephrine. The presence of pore-forming Kir6.1 and Kir6.2 subunits of the K(ATP) channels in the HIMA and only Kir6.2 in the HSV was confirmed immunomorphologically. P1075 inhibited in the HSV only, the electrical field stimulation contractions more strongly than noradrenaline contractions. In addition, the phenylephrine contractions of HSV were more sensitive to P1075 in comparison to those of HIMA. Glibenclamide, a K(ATP) channel blocker antagonized the vasodilatation produced by P1075 in both grafts differently, because its effect was more prominent on the P1075-induced inhibition of contractions of HSV than of HIMA. We conclude that P1075 has a vasorelaxant effect and inhibited adrenergic contractions of the tested grafts. This effect is graft and vasoconstrictor selective and seems to be mediated by Kir6.1-and/or Kir6.2-containing K(ATP) channels. Thus, P1075 can be considered as a potential drug in the prevention of graft spasm

Glucocorticoid Receptor and Molecular Chaperones in the Pathogenesis of Adrenal Incidentalomas: Potential Role of Reduced Sensitivity to Glucocorticoids

Glucocorticoid (GC) sensitivity depends on glucocorticoid receptor (GR) and heat shock proteins (Hsps). We investigated whether common GR genes (ER22/23EK N363S, BclI, and 9 beta) and adrenocorticotropin receptor promoter polymorphisms influence susceptibility for unilateral adrenal incidentaloma (AI), plus GR and Hsp expression in tumorous (n = 19), peritumorous (n = 13) and normal adrenocortical (n = 11) tissues. Patients (n = 112), population-matched controls (n = 100) and tumor tissues (n = 32) were genotyped for these polymorphisms. Postdexamethasone serum cortisol was higher in patients (p<0.001). GR gene variants, larger allele of BclI (odds ratio (OR) 2.9; 95% confidence interval (CI) 1.7-5.1; p < 0.001) and minor allele of 9 beta (OR 3.0; 95% CI 1.6-5.7; p < 0.001) were independent predictors of Al. In patients, the first allele is linked with larger tumors (p = 0.002) and the latter with higher postdexamethasone cortisol levels (p = 0.025). Both allele carriers had lesser waist circumference (p = 0.02), similar adrenocorticotropin and higher basal (p = 0.024) and postdexamethasone cortisol concentrations (p < 0.001). Tumorous and constitutional genotypes were similar. GR-D is the major receptor isoform in normal adrenal cortex by Western blotting. Loss of other receptor isoforms, decrease in immunostaining for GR (p < 0.0001), underexpression of chaperones (p <= 0.01) and the presence of inducible Hsp70 were found in adenomas. In conclusion, GR gene variants, C allele of BclI and minor allele of 9 beta, are associated with Als. Their concurrent presence in patients reduces GC sensitivity Normal adrenal cortex preferentially expresses GR-D. In adenomas, the lack of other GR isoforms and underexpression of heat shock proteins perhaps permanently impair GC signaling, which could promote dysregulated cortisol production and tumor growth. The innate GC sensitivity probably modifies these effects. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00261Ministry of Science and Technological Development of Serbia [III41009