Zhenling Yao | PubMed Health

PubMed2006

Modeling circadian rhythms of glucocorticoid receptor and glutamine synthetase expression in rat skeletal muscle.

PURPOSE: The circadian rhythm of endogenous corticosterone (CS) may produce fluctuations of downstream gene expression in normal rats. This study examined changes in glucocorticoid receptor (GR) and glutamine synthetase (GS) expression in rat skeletal muscle in relation to plasma CS over a 24-h period. METHODS: Fifty-four normal male Wistar rats were sacrificed at 18 time points (n = 3) over 24 h. Plasma CS concentrations and gastrocnemius muscle GR and GS mRNA and GS activity were measured. RESULTS: The circadian rhythm of plasma CS was captured by a two-harmonic function. The expression of GR and GS mRNA and GS activity follow a circadian rhythm in normal rat skeletal muscle. GR mRNA reaches a trough at 4 h after the peak of plasma CS and it fluctuates between 0.55 and 0.9 fmol g tissue(-1). GS mRNA and activity reach peaks at 6 and 12 h after the endogenous CS peak. GS mRNA oscillates between 3 and 6 fmol g tissue(-1), whereas GS activity fluctuates between 17 and 23 micromol min(-1) g protein(-1). Mechanistic receptor/gene-mediated pharmacodynamic models were applied to describe the temporal patterns of GR mRNA, GS mRNA, and GS activity within the circadian cycle. CONCLUSIONS: The integrated models were able to capture the circadian expression patterns of plasma CS, and GR and GS in normal rat skeletal muscle showing a dependence of tissue gene expression on plasma CS.

Algorithms↗

PubMed2006

Assessment of basic indirect pharmacodynamic response models with physiological limits.

Many physiological factors are regulated by homeostatic mechanisms to maintain normal body function. Empirical lower Rl (Model I and IV) or upper Rh limits (Model II and III) were included in current basic indirect response (IDR) models to account for the additional role of physiological limits (IDRPL). Various characteristics of these models were evaluated with simulations and explicit equations. The simulations reveal that the expanded models exhibit most properties of basic indirect response models, such as slow response initiation, lag time between the kinetic and dynamic peaks, a large dose plateau, and shift in Tmax with dose. The proposed models always produce lesser net responses than predicted by basic IDR models. Simulations demonstrate that addition of a parameter limit which is close to the baseline has a great influence on the overall and maximum responses and fitted model parameters. Only stimulatory IDRPL Models III and IV allow resolution of all model parameters in the absence of clear indications or predetermined values of the lower or upper limits. However, all four models are able to resolve model parameters when subgroups with different baselines are simultaneously fitted. These models create new interpretations of the determinants of baseline conditions which can be important in assessing inter-subject variability in responses. The applicability of IDRPL models is demonstrated using several examples from the published literature. Indirect response models with physiological limits will be useful in characterizing drug responses for turnover systems which are maintained within a certain range.

5-alpha Reductase Inhibitors↗