Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2-butylamino)-4H- and 3-(3-methyl-2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers.

The preparation and the pharmacological evaluation of the R- and S-isomers of 3-(2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 42) and 3-(3-methyl-2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 44), two potassium channel openers, is described. Their optical purity was estimated by means of capillary electrophoresis (R- and S-BPDZ 42) and chiral HPLC (R- and S-BPDZ 44). The absolute configuration of each isomer of BPDZ 44 was deduced from crystallographic data. Pharmacological assays performed with the R- and S-isomers of BPDZ 44 revealed only slight differences in their activity on pancreatic B-cells but significant differences in their activity on vascular smooth muscle cells: the R-isomer being sixfold more potent than its corresponding S-isomer. The R-isomer of BPDZ 42 was shown to be more potent than its corresponding S-isomer on the endocrine pancreas. S-BPDZ 44 as well as R- and S-BPDZ 42 were found to exhibit tissue selectivity for the pancreatic versus the vascular smooth muscle tissue.

Blood levels of reduced/oxidized glutathione and plasma concentration of ascorbic acid during eccentric and concentric exercises of similar energy cost.

In an attempt to assess the possible oxidative stress associated with the transient exercise-induced activation of polymorphonuclear neutrophils (PMN), we compared the effects of eccentric and concentric exercises (downhill run: DR and uphill walk: UW, respectively) of equal duration (35 min) and similar energy cost (60% VO2max) on plasma levels of ascorbic acid ([AA]) and blood concentration of reduced ([GSH]) and oxidized ([GSSG]) glutathione. Eight healthy male subjects took part in this study. Plasma concentration of myeloperoxidase ([MPO]) was used as a specific marker of PMN activation. While there were no significant changes in [MPO] and [AA] in UW experiments, [MPO] increased (+80%) and [AA] decreased significantly during DR tests (P < 0.01 and P < 0.05, respectively). A significant negative relationship was observed between [AA] and [MPO] in DR experiments only (r = -0.49; P < 0.01). Mean (+/- SEM) basal GSH and GSSG concentrations, calculated by pooling the values measured before both tests, were 0.54 +/- 0.02 and 0.12 +/- 0.007 mM, respectively. The blood concentration of these compounds remained practically unchanged in both exercise tests. These results confirm the role played by the eccentric component of muscle contraction in transient exercise-induced PMN activation and suggest that this activation was partly involved in the decrease in [AA] observed in DR experiments. The oxidant stress associated with the exercise protocol used in this study was insufficient to alter blood levels of reduced and oxidized glutathione.