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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.  Relationship between steady-state pharmacokinetics and hemodynamic effects of inhaled isobutyl nitrite in conscious rats 
AAPS PharmSci  2000;2(2):8-15.
Our objective was to examine the pharmacokinetic/hemodynamic properties of inhaled isobutyl nitrite (ISBN) in rats. ISBN is one of the volatile organic nitrites that has been used primarily as a drug of abuse. Recent studies indicate, however, that these compounds may be superior to organic nitrates for cardiovascular use because they do not produce vascular tolerance. Rats inhaled ISBN over an exposure range of 20 to 1200 ppm for 1 hour. The effects of ISBN on blood pressure and heart rate were determined and blood concentrations of ISBN were analyzed with use of gas chromatography. Apparent steady-state blood levels of ISBN were achieved during inhalation and were linear with exposure concentration (blood concentration: 0.05 to 3.5 μM: exposure concentration: 23 to 1177 ppm; r2=0.92). Inhaled ISBN caused rapid, dose-dependent, and parallel reductions in systolic and diastolie pressure, while heart rate increased maximally to 22%. A sigmoid Emax model could describe the mean arterial pressure effect of inhaled ISBN (Emax=55%; EC50=0.51 μM). After inhalation, blood pressure and heart rate quickly returned to baseline, without any withdrawal rebound effect. Inhaled ISBN produced a rapid onset of action on heart rate and blood pressure, and these effects were sustained over 60 minutes of exposure. Abrupt drug withdrawal did not lead to hemodynamic rebound. The blood pressure effects were related to ISBN blood concentration by the sigmoid Emax model. These results provide new information on the pharmacokinetic pharmacodynamic relationship of a representative nitrite inhalant.
doi:10.1208/ps020211
PMCID: PMC2751025  PMID: 11741227
3.  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
4.  Comparison of methods for analyzing kinetic data from mechanism-based enzyme inactivation: Application to nitric oxide synthase 
AAPS PharmSci  2000;2(1):68-77.
The goals of this study were (1) to investigate the performance of 2 classical methods of kinetic analysis when applied to data from enzyme systems in which mechanism-based inactivation and enzyme degradation are present, and (2) to develop and validate a nonlinear method of kinetic data analysis that may perform better under these situations. A composite equation was derived to link various parameters that govern the kinetics of mechanism-based inactivation, viz., enzyme activity, inhibitor-binding affinity (K1), inactivation rate (Kinact), and enzyme degradation (kdeg). The relative accuracy and precision of parameter estimation by the Dixon and Kitz-Wilson methods and a new nonlinear method were evaluated by computer simulation. The behavior of these methods of analysis were validated experimentally, using the nitric oxide synthase enzyme, both in purified form and as expressed in murine macrophage cell cultures. We showed that the Dixon method, as expected, could not provide accurate estimates of K1 in the presence of either enzyme inactivation or instability. The Kitz-Wilson method could provide accurate estimates of these parameters; however, the precisions of these estimates were poorer than those obtained using the nonlinear method of analysis. We conclude that the nonlinear approach is superior to classical methods of data analysis for enzyme inhibitor kinetics, based on better efficiency, accuracy, and precision.
doi:10.1208/ps020108
PMCID: PMC2751003  PMID: 11741224

Results 1-4 (4)