Effect of disease states on α1 -adrenoceptor binding and signal transduction parameters in isolated perfused heart: quantification by pharmacokinetic-pharmacodynamic modelling.
OBJECTIVE
To employ a pharmacokinetic-pharmacodynamic modelling approach for analysing the effect of experimental endotoxemia and mild hypoxia on α1 -adrenoceptor (α1 AR) binding and signal transduction.


METHODS
In Langendorff-perfused rat hearts, phenylephrine was continuously infused, and [(3) H]-prazosin was injected as single dose (infused over 1 min). Simultaneous analysis of the time courses of prazosin outflow concentration and inotropic response (left ventricular developed pressure) using an agonist-antagonist interaction model and nonlinear regression allowed to estimate receptor affinity, as well as the parameters of the operational model of agonism.


RESULTS
Both endotoxemia and hypoxia, significantly reduced the maximum response achievable in the system to 67% and 49% of the control group mean, respectively. In addition, endotoxemia decreased the efficiency of stimulus-response coupling and increased the steepness of the stimulus-response curve. In both disease models, no change in receptor affinity and density were found.


CONCLUSIONS
The results revealed the causes of reduced α1 AR-mediated inotropic responsiveness in endotoxemia and hypoxia. In contrast with traditional dose-response studies, it was possible to quantify separately the underlying changes in α1 AR binding and signal transduction.
Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Michael
M
Weiss
Petra
P
Arendt
Rana
R
Hassna
D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D019446:Endotoxemia / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology*; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D015398:Signal Transduction
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D011224:Prazosin
endotoxemia; hypoxia; inotropic response; perfused rat heart; α1-Adrenoceptor