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1.  Effects of obesity on the pharmacodynamics of nitroglycerin in conscious rats 
AAPS PharmSci  2002;4(4):80-88.
Literature reports have suggested that hemodynamic response toward organic nitrates may be reduced in obese patients, but this effect has not been studied. We compared the mean arterial pressure (MAP) responses toward single doses of nitroglycerin (NTG), 0.5–50μg) in conscious Zucker obese (ZOB), Zucker lean (ZL), and Sprague-Dawley (SD) rats. NTG tolerance development in these animal groups was separately examined. Rats received 1 and 10μg/min of NTG or vehicle infusion, and the maximal MAP response to an hourly 30μg NTG IVchallenge dose (CD) was measured. Steady-state NTG plasma concentrations were measured during 10μg/min NTG infusion. The Emax and ED50 values obtained were 33.9± 3.6 and 3.5±1.7μg for SD rats, 33.2±4.1 and 3.0±1.4μg for ZL rats, and 34.8±3.9 and 5.3±2.8μg for ZOB rats, respectively. No difference was found in the dose-response curves among these 3 groups (p>.05, 2-way ANOVA). Neither the dynamics of NTG tolerance development, nor the steady-state NTG plasma concentrations, were found to differ among these 3 animal groups. These results showed that ZOB rats are not more resistant to the hemodynamic effects of organic nitrates compared with their lean controls. Thus, the acute and chronic hemodynamic effects by the presence of obesity in a conscious animal model of genetic obesity.
doi:10.1208/ps040428
PMCID: PMC2751317  PMID: 12646000
nitrate tolerance; Zucker; noninsulin dependent diabetes; mellitus; nitric oxide; obesity
2.  cDNA Microarray analysis of vascular gene expression after nitric oxide donor infusion in rats: Implications for nitrate tolerance mechanisms 
AAPS PharmSci  2002;4(2):45-55.
Vascular nitrate tolerance is often accompanied by changes in the activity and/or expression of a number of proteins. However, it is not known whether these changes are associated with the vasodilatory properties of nitrates, or with their tolerance mechanisms. We examined the hemodynamic effects and vascular gene expressions of 2 nitric oxide (NO) donors: nitroglycerin (NTG) and S-nitroso-N-acetylpenicillamine (SNAP). Rats received 10 μg/min NTG, SNAP, or vehicle infusion for 8 hours. Hemodynamic tolerance was monitored by the maximal mean arterial pressure (MAP) response to a 30-μg NTG or SNAP bolus challenge dose (CD) at various times during infusion. Gene expression in rat aorta after NTG or SNAP treatment was determined using cDNA microarrays, and the relative differences in expression after drug treatment were evaluated using several statistical techniques. MAP response of the NTG CD was attenuated from the first hour of NTG infusion (P<.001, analysis of variance [ANOVA]), but not after SNAP (P>.05, ANOVA) or control infusion (P> .05, ANOVA). Student t-statistics revealed that 447 rat genes in the aorta were significantly altered by NTG treatment (P <.05). An adjusted t-statistic approach using resampling techniques identified a subset of 290 genes that remained significantly different between NTG treatment vs control. In contrast, SNAP treatment resulted in the up-regulation of only 7 genes and the downregulation of 34 genes. These results indicate that continuous NTG infusion induced widespread changes in vascular gene expression, many of which are consistent with the multifactorial and complex mechanisms reported for nitrate tolerance.
doi:10.1208/ps040208
PMCID: PMC2751295  PMID: 12102617
DNA microarray; gene regulation; nitrate tolerance; nitric oxide donor; nitroglycerin

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