Nonlinear mixed effects models applied to cumulative concentration–response curves

Thorin, Chantal; Mallem, Yassine; Noireaud, Jacques; Gogny, Marc; Desfontis, Jean‐Claude

doi:10.1211/jpp.62.03.0008

Cited by 16 publications

(6 citation statements)

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“…Linear Mixed effect (LME) model was used to analyze data from non-CCRCs (isolated heart) and CCRCs to insulin. Meanwhile, Non-linear Mixed Effect model (NLME) was used to assess data from CCRCs to Phe and Ach [ 45 ]. Contraction and relaxation were expressed as the percentage relaxation of the KCl- and Phe-induced precontraction, respectively.…”

Section: Methodsmentioning

confidence: 99%

Long-term high-fructose high-fat diet feeding elicits insulin resistance, exacerbates dyslipidemia and induces gut microbiota dysbiosis in WHHL rabbits

et al. 2022

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The metabolic syndrome (MetS) has become a global public health burden due to its link to cardiovascular disease and diabetes mellitus. The present study was designed to characterize the metabolic and cardiovascular disturbances, as well as changes in gut microbiota associated with high-fructose high-fat diet (HFFD)-induced MetS in Watanabe heritable hyperlipidemic (WHHL) rabbits. Twenty-one Watanabe rabbits were assigned to a control (n = 9) and HFFD (n = 12) groups, receiving a chow diet and a HFFD, respectively. During a 12-weeks protocol, morphological parameters were monitored; plasma fasting levels of lipids, glucose and insulin were measured and a glucose tolerance test (GTT) was performed. HOMA-IR was calculated. Cardiac function and vascular reactivity were evaluated using the Langendorff isolated heart and isolated carotid arteries methods, respectively. 16S rRNA sequencing of stool samples was used to determine gut microbial composition and abundance. HFFD-fed Watanabe rabbits exhibited increased fasting insulin (p < 0.03, 12th week vs. Baseline), HOMA-IR (p < 0.03 vs. Control), area under the curve of the GTT (p < 0.02 vs. Control), triglycerides (p < 0.05, 12th week vs. Baseline), TC (p < 0.01 vs. Control), LDL-C (p < 0.001 vs. Control). The HFFD group also displayed a significant decrease in intestinal microbial richness, evenness and diversity (FDR < 0.001, FDR < 0.0001, FDR < 0.01, respectively vs. Control group) and an increase in its Firmicutes/Bacteroidetes ratio (R = 3.39 in control vs. R = 28.24 in the HFFD group) indicating a shift in intestinal microbial composition and diversity. Our results suggest that HFFD induces insulin resistance and gut microbiota dysbiosis and accentuates dyslipidemia; and that, when subjected to HFFD, Watanabe rabbits might become a potential diet-induced MetS animal models with two main features, dyslipidemia and insulin resistance.

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Section: Methodsmentioning

confidence: 99%

Long-term high-fructose high-fat diet feeding elicits insulin resistance, exacerbates dyslipidemia and induces gut microbiota dysbiosis in WHHL rabbits

et al. 2022

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“…Results were expressed as a mean ± SE of n experiments, where n is the number of pig hearts (one PCA/pig heart). Different CCRCs were compared on R software (R Development Core Team 2007), using the linear mixed-effects model (Pinheiro and Bates 2000;Thorin et al 2010;Kabbesh et al 2012). The linear mixed-effects model must follow a normal distribution of residuals.…”

Section: Discussionmentioning

confidence: 99%

Celiprolol induces β₃-adrenoceptors-dependent relaxation in isolated porcine coronary arteries

Abdelkrim

Martignat

Gogny

et al. 2013

Can. J. Physiol. Pharmacol.

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In porcine coronary arteries (PCAs), celiprolol, a selective β(1)-adrenoceptors antagonist, induces vasodilatation by an endothelium- and nitric oxide (NO)-dependent pathway. However, the mechanisms of that vascular effect have not been precisely established. β(3)-Adrenoceptors have been shown to be involved in the relaxation per se of various vascular beds, including coronary vessels. Thus, we evaluated (i) the presence of β(3)-adrenoceptors in the PCA and (ii) their role in celiprolol-induced vasodilatation. PCA rings were placed in organ baths and preconstricted with KCl. All experiments were performed in the presence of nadolol (a β(1)/β(2)-adrenoceptor antagonist). Cumulative concentration-response curves to SR 58611A and ICI 215001 (2 β(3)-adrenoceptor agonists) and to celiprolol were constructed. We also used semiquantitative reverse transcription - polymerase chain reaction, which clearly showed the presence of β(3)-adrenoceptor transcripts. SR 58611A, ICI 215001, and celiprolol induced concentration-dependent relaxations in PCA rings. SR 58611A-induced relaxation was almost abolished after removal of endothelium or pretreatment with L-NAME (a NO synthase inhibitor). The vasorelaxations induced by SR 58611A and celiprolol were inhibited in the presence of SR 59230A and L-748337 (2 selective β(3)-adrenoceptor antagonists). We showed (i) that PCAs possess functional β(3)-adrenoceptors mediating endothelium- and NO-dependent relaxation, and (ii) that celiprolol exerts a β(3)-adrenoceptor agonistic activity in this vascular bed.

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“…To examine the general null hypotheses that there were no group differences for firing frequency and burst activity, current–response curves for chronic alcohol drinking and alcohol naïve P rats were initially compared using nonlinear mixed effects models (Vonesh and Carter, ). These models allow accurate estimation of population parameters from limited sample sizes and correct for variance heterogeneity often accompanying cumulative dose–response data (Thorin et al., ). Current response curves from 0 to −14 nA were constructed for each group of rats and group‐by‐curve interactions were fitted using the Linear and Nonlinear Mixed Effects Models package for R (Pinheiro and Bates, ), treating individual neurons as a random effect to account for within‐group variability in neuronal responses.…”

Section: Methodsmentioning

confidence: 99%

“…For determining EC 50 values, the data were normalized. For this, baseline values were subtracted from the responses after each ejection current; current–responses were converted to percent maximum response and curves were constructed based on a nonlinear mixed effects model (Thorin et al., ). Group EC 50 and E max estimates were compared by examining 95% confidence intervals.…”

Section: Methodsmentioning

confidence: 99%

Decreased Sensitivity ofNMDAReceptors on Dopaminergic Neurons from the Posterior Ventral Tegmental Area Following Chronic Nondependent Alcohol Consumption

Fitzgerald

Liu

Morzorati

2012

Alcoholism Clin & Exp Res

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Background The mesocorticolimbic dopamine system mediates the reinforcing effects of salient stimuli, including drugs of abuse. Nondependent chronic alcohol consumption modifies this system, resulting in an increased number of spontaneously active dopamine neurons in the posterior ventral tegmental area (VTA) of alcohol-preferring (P) rats. Enhanced responses of postsynaptic glutamate receptors may contribute to the increase in active dopamine neurons. Thus, excitations of putative dopamine neurons to locally-applied NMDA (glutamate receptor subtype agonist) were evaluated. Methods P rats were assigned to alcohol naïve (water only) or alcohol drinking (continuous access to 15% alcohol and water for 8 consecutive weeks) groups. Responses of 23 putative dopamine neurons from naïve rats and 19 putative dopamine neurons from drinking rats were assessed in vivo using microiontophoretically-applied NMDA. Current-response curves for firing frequency and burst activity were constructed using nonlinear mixed effects models. Between-group comparisons were made for EC50 (effective current producing a half maximal excitatory response), Emax (maximal excitatory effect) and the CDB (the current at which depolarization block - marked decrease in neuronal activity - occurred). Results Drinking P rats steadily consumed alcohol over the eight-week protocol and did not exhibit signs of dependence or withdrawal. Putative dopamine neurons from drinking rats exhibited resistance to depolarization block (higher CDB values) and required larger doses of NMDA to elicit moderate excitatory responses (higher EC50 values), consistent with decreased receptor affinity. Maximal excitatory responses (Emax) did not differ between the groups, consistent with no change in receptor number. Blood alcohol was at undetectable levels at the time of experimentation. Conclusions NMDA receptor sensitivity is decreased on posterior VTA putative dopamine neurons in P rats on a nondependent schedule of alcohol consumption. Mechanisms underlying increased spontaneous dopamine neuron activity may be independent of changes in NMDA receptor function. Decreased NMDA receptor sensitivity may precede the development of dependence.

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Nonlinear mixed effects models applied to cumulative concentration–response curves

Abstract: Using the method presently described, it is now possible to detect significant differences for each pharmacological parameter estimated in different situations, even for designs with small samples size (i.e. at least six complete curves).

Cited by 16 publications

References 9 publications

Long-term high-fructose high-fat diet feeding elicits insulin resistance, exacerbates dyslipidemia and induces gut microbiota dysbiosis in WHHL rabbits

Long-term high-fructose high-fat diet feeding elicits insulin resistance, exacerbates dyslipidemia and induces gut microbiota dysbiosis in WHHL rabbits

Celiprolol induces β₃-adrenoceptors-dependent relaxation in isolated porcine coronary arteries

Decreased Sensitivity ofNMDAReceptors on Dopaminergic Neurons from the Posterior Ventral Tegmental Area Following Chronic Nondependent Alcohol Consumption

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Nonlinear mixed effects models applied to cumulative concentration–response curves

Abstract: Using the method presently described, it is now possible to detect significant differences for each pharmacological parameter estimated in different situations, even for designs with small samples size (i.e. at least six complete curves).

Cited by 16 publications

References 9 publications

Long-term high-fructose high-fat diet feeding elicits insulin resistance, exacerbates dyslipidemia and induces gut microbiota dysbiosis in WHHL rabbits

Long-term high-fructose high-fat diet feeding elicits insulin resistance, exacerbates dyslipidemia and induces gut microbiota dysbiosis in WHHL rabbits

Celiprolol induces β3-adrenoceptors-dependent relaxation in isolated porcine coronary arteries

Decreased Sensitivity ofNMDAReceptors on Dopaminergic Neurons from the Posterior Ventral Tegmental Area Following Chronic Nondependent Alcohol Consumption

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Celiprolol induces β₃-adrenoceptors-dependent relaxation in isolated porcine coronary arteries