Effects of lead on the secretion and disappearance of renin in rabbits

The disappearance rate of renin from plasma was evaluated in both acutely and chronically leadexposed rabbits. In addition, the effects of lead (Pb) on in vitro renin secretion were determined with rabbit renal cortical slices. Rabbits acutely exposed to Pb (0.3 to 2.0 mg/kg, iv) demonstrated no increase in plasma renin activity (PRA), but a markedly prolonged disappearance of renin following nephrectomy. Together, these observations suggest that renin secretion must have been inhibited; consistent with this hypothesis was the finding that rabbit renal cortical slices exposed to Pb (10-5 or 10-6) in vitro secreted significantly less renin than did controls. Thus, the effects of large acute doses of Pb in the rabbit are simultaneous inhibition of both renin secretion and clearance. Chronically Pb-exposed rabbits (500 or 1000 ppm in drinking water) had renin halflives that were not different from controls (6 to 8 min). PRA was also not significantly different in the three groups. Renal slices from both groups of Pb-exposed rabbits secreted significantly more renin in vitro compared to controls, despite the fact that renal renin concentrations were similar in the three groups. However, the responsiveness to a beta adrenergic stimulus was significantly lower in the slices from rabbits treated with 1000 ppm Pb. Taken together these data suggest that PRA in the chronically Pb-exposed rabbit reflects a tendency for increased basal renin secretion, but a counteracting suppression of renin release secondary to adrenergically mediated stimuli; thus, PRA might be reduced, unchanged, or elevated depending upon experimental conditions. Clearance of renin does not seem to be altered in the chronically Pb-exposed rabbit.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25185/1/0000624.pd

Effect of ADRB2 polymorphisms on response to longacting beta(2)-agonist therapy:a pharmacogenetic analysis of two randomised studies

Background New evidence has suggested that people with asthma who are homozygous for arginine at aminoacid 16 of the beta(2)-adrenergic receptor (ADRB2) might not benefit from longacting beta(2)-agonist therapy. We, therefore, investigated whether ADRB2 polymorphisms affect response to longacting beta(2)-agonists in combination with inhaled corticosteroids. Methods Asthmatics were stratified by ADRB2 genotype in two studies to assess the effects of inhaled corticosteroids plus longacting beta(2)-agonists on asthma exacerbations. In study 1 (double-blind), 2250 asthmatics were randomly assigned to budesonide plus formoterol maintenance and reliever therapy, fixed-dose budesonide plus formoterol, or fixed-dose fluticasone plus salmeterol for 6 months. Study 2 (open-label) consisted of 405 asthmatics and compared an adjustable regimen of budesonide plus formoterol with fixed-dose budesonide plus formoterol and fixed-dose fluticasone plus salmeterol for 7 months. The relation between ADRB2 polymorphism, severe asthma exacerbations, and other asthma outcomes was analysed. Primary endpoints for studies 1 and 2 were severe asthma exacerbation and asthma control as assessed by measures of exacerbations, respectively. Findings In study 1, Gly16Arg genotype had no effect on the percentage of participants with severe exacerbations across all treatment groups (99 [12%] of 833 Gly/Gly, 110 [11%] of 1028 Gly/Arg, and 32 [9%] of 361 Arg/Arg participants). Secondary endpoints, including forced expiratory volume in 1 s, peak expiratory flow, use of as-needed medication, and number of nights with awakenings were similar between genotype groups. No relation was recorded between ADRB2 haplotype and primary and secondary endpoints. In study 2, the frequency of asthma exacerbations (15 [9%] of 168 Gly/Gly, 13 [8%] of 169 Gly/Arg, and 6 [9%] of 67 Arg/Arg participants) and other study endpoints were closely similar for all ADRB2 genotypes. Interpretation Since we showed no pharmacogenetic effect of ADRB2 variation on therapeutic response in asthma, patients, irrespective of their genotype, can continue to receive inhaled corticosteroids plus longacting beta(2)-agonists

Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species.

International audienceMetformin, one of the most commonly used drugs for the treatment of type II diabetes, was recently found to exert its therapeutic effects, at least in part, by activating the AMP-activated protein kinase (AMPK). However, the site of its action, as well as the mechanism to activate AMPK, remains elusive. Here we report how metformin activates AMPK. In cultured bovine aortic endothelial cells, metformin dose-dependently activated AMPK in parallel with increased detection of reactive nitrogen species (RNS). Further, either depletion of mitochondria or adenoviral overexpression of superoxide dismutases, as well as inhibition of nitric-oxide synthase, abolished the metformin-enhanced phosphorylations and activities of AMPK, implicating that activation of AMPK by metformin might be mediated by the mitochondria-derived RNS. Furthermore, administration of metformin, which increased 3-nitrotyrosine staining in hearts of C57BL6, resulted in parallel activation of AMPK in the aorta and hearts of C57BL6 mice but not in those of endothelial nitric-oxide synthase (eNOS) knockout mice in which metformin had no effect on 3-nitrotyrosine staining. Because the eNOS knockout mice expressed normal levels of AMPK-alpha that was activated by 5-aminoimidazole-4-carboxamide riboside, an AMPK agonist, these data indicate that RNS generated by metformin is required for AMPK activation in vivo. In addition, metformin significantly increased the co-immunoprecipitation of AMPK and its upstream kinase, LKB1, in C57BL6 mice administered to metformin in vivo. Using pharmacological and genetic inhibitors, we found that inhibition of either c-Src or PI3K abolished AMPK that was enhanced by metformin. We conclude that activation of AMPK by metformin might be mediated by mitochondria-derived RNS, and activation of the c-Src/PI3K pathway might generate a metabolite or other molecule inside the cell to promote AMPK activation by the LKB1 complex