Halothane inhibits two components of calcium current in clonal (GH3) pituitary cells.

The effect of halothane on isolated calcium (Ca2+) current of clonal (GH3) pituitary cells was investigated using standard whole-cell clamp techniques at room temperature. Halothane (0.1-5.0 mM) reversibly reduced both the low-threshold, transient [low-voltage-activated (LVA)] component and the high-threshold [high-voltage-activated (HVA)] component of Ca2+ current. Halothane had little effect on the voltage dependence of activation or inactivation of either component of Ca2+ current. Inhibition of the peak high-threshold Ca2+ current was half-maximal at about 0.8 mM halothane, with maximal inhibition (100%) occurring with 5 mM halothane. When measured at the end of a 190-msec command step, half-maximal reduction of high-threshold current occurred at less than 0.5 mM halothane. The low-threshold transient current was less sensitive to halothane, with half-maximal inhibition of peak transient current activated at -30 mV occurring at approximately 1.3 mM. The effect of halothane on the HVA current was apparently not mediated by changes in intracellular Ca2+ concentration. The ability of halothane to inhibit Ca2+ current was unaffected by either the inclusion of the rapid Ca2+ buffer 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid (BAPTA) in the recording pipette or exposure of the cell to 10 mM caffeine. To assess the selectivity of the effect of halothane, the actions of halothane on two components of voltage-activated potassium (K+) current observed in the absence of extracellular Ca2+ and on voltage-dependent sodium (Na+) current were also examined. Halothane had no effect on the voltage-dependent, inactivating K+ current of GH3 cells at concentrations up to 1.2 mM. In contrast, the non-inactivating K+ current, though less sensitive to halothane than either Ca2+ current, was reduced by about 40% by 1.2 mM halothane at +20 mV. Peak Na+ current was also blocked by halothane, but 50% block required around 2.6 mM halothane with little effect at 1.6 mM. Reduction of Na+ current was associated with a substantial negative shift in the steady-state inactivation curve. Although the results indicate that a number of voltage-dependent ionic currents are sensitive to halothane, both components of Ca2+ current exhibit a greater sensitivity to halothane than any of three other voltage-dependent currents in GH3 cells. These results show that GH3 cell Ca2+ currents are selectively inhibited by clinically appropriate concentrations of halothane and that the reduction of Ca2+ current can account for the inhibition by halothane of TRH- or KCl-induced prolactin secretion in GH3 cells.     

Bone mass and body composition in normal women.

The interrelationships between measurements of bone mass and total-body bone mineral were examined in a cross-sectional study of normal healthy women aged 17-82 years. In addition we evaluated the relationship between measures of body composition, estimated by four independent techniques, and bone mass in the same population. Considering the group as a whole, bone mass at all sites correlated with each other and with total-body bone mineral (TBBM). Cancellous and cortical sites could predict TBBM equally well. As expected, all measurements of bone mass were significantly lower in postmenopausal women in comparison to premenopausal women. Declines in bone mass were only seen in premenopausal women in the femoral neck and Ward's triangle, not in lumbar spine, radius, or skeleton as a whole. In postmenopausal women bone mass correlated negatively with age and years from menopause equally at all sites. TBBM was significantly related to height and weight in both premenopausal and postmenopausal women. In premenopausal and postmenopausal women TBBM also correlated with fat mass, but TBBM was much better correlated with percentage body fat in premenopausal than postmenopausal women. TBBM was a constant proportion of lean body mass in premenopausal women, but the fraction of lean mass occupied by the skeleton declined with age in postmenopausal women. Correction of TBBM for lean mass did not change the relationship between TBBM and percentage fat in premenopausal women but eliminated the relationship in postmenopausal women. Regional measurements, which are at least partially corrected for body size by dividing mass by area, correlated less well with height and weight and with any index of obesity, especially in postmenopausal women.     

The combination oral and nutritional treatment of late-onset diabetes mellitus (CONTROL DM) trial results.

OBJECTIVE: To examine the effect of short-term improvements in glycaemic control on brachial artery endothelial function as a marker of cardiovascular health. METHODS: Persons with Type 2 diabetes who were poorly controlled on oral therapy were randomly assigned to monotherapy with repaglinide or combination therapy with repaglinide plus metformin. Brachial artery flow-mediated vasodilation was assessed by ultrasonography at randomization and following 16 weeks of therapy. The primary outcome was change in brachial artery endothelial function from baseline. Comparison of randomized groups was a secondary aim. RESULTS: Eighty-six participants were randomized, and 83 were followed to study completion. Post occlusion brachial artery vasodilation was 3.74% at baseline and 3.82% following 16 weeks of therapy (P = 0.77). The treatment effect was 0.08% (95% CI: -0.48%, 0.64%). No difference was seen between treatment groups (P = 0.69). Overall, A1C was reduced from 8.3% to 7.0%, with a greater reduction in the combination therapy group (from 8.4% to 6.7%) than in the monotherapy group (from 8.3% to 7.3%, p for difference between groups = 0.01). Statistically significant reductions were observed in fasting glucose, and plasminogen activator inhibitor-1. Statistically significant increases were observed for fasting insulin, uric acid, weight and BMI. CONCLUSIONS: Brachial artery endothelial function was not influenced by short-term improvements in glycaemic control. The CONTROL DM group was successful in lowering A1C. Future research should explore more intensive and longer-lasting improvements in glycaemic control on endothelial function. Some data previously published in abstract form (Diabetes 2001; 50 (Suppl. 2): A217).     

Hormone replacement therapy is associated with increased C-reactive protein in women with Type 2 diabetes in the Diabetes Heart Study.

AIMS: Increased levels of inflammatory biomarkers, especially C-reactive protein (CRP), are associated with increased risk for cardiovascular disease (CVD) events, such as myocardial infarction, stroke, peripheral vascular disease, and sudden cardiac death. Medical interventions that increase CRP levels, such as hormone replacement therapy (HRT) in post-menopausal women, are under increasing scrutiny. The effect of HRT on CRP levels in women with Type 2 diabetes (T2DM) is not well documented, and conflicting conclusions have been reported. The aim of this study was to determine the influence of HRT on women with diabetes in a large cross-sectional study. METHODS: Three hundred and twenty-seven post-menopausal women with T2DM from the Diabetes Heart Study participated. Current use of HRT was determined and serum CRP levels were measured using a high-sensitivity ELISA kit. Generalized estimating equation methods were used to assess the relationship of multiple clinical and lifestyle (e.g. smoking) measures on CRP levels including differences between women taking HRT (HRT+) and not taking HRT (HRT-). RESULTS: Overall serum CRP levels were strongly associated with body mass index (P < 0.0001) and age (P < 0.0001). Of the women, 243 were not using HRT and 84 were using HRT. HRT+ and HRT- women did not differ significantly in measures of clinical traits, with the exception of higher mean low-density lipoprotein cholesterol in HRT- women (P = 0.004). In all models tested, HRT+ women had significantly higher circulating CRP levels, with P-values ranging from 0.0045 to 0.010. CONCLUSIONS: In this study of serum CRP concentration as a function of HRT in women with Type 2 diabetes, there was consistent evidence for increased circulating CRP levels in women receiving oestrogen-containing HRT. Whether HRT-induced increases in CRP can account for the adverse cardiovascular effects of HRT remains to be established; however, based on these data, there is little reason to believe that diabetic women would be spared from such an effect.