title: Modelling of alpha1-adrenoceptor-mediated temporal dynamics of inotropic response in rat heart to assess ligand binding and signal transduction parameters.
abstract: OBJECTIVE
  In order to use the transient response to an antagonist (prazosin) to evaluate properties of agonist interactions with the alpha(1)-adrenoceptor system, an integrative mechanistic model of cardiac uptake of prazosin and its competitive interaction with phenylephrine at the receptor site was developed. Based on the operational model of agonism, the aim was to evaluate both the receptor binding and signal transduction process as determinants of the inotropic effect of phenylephrine.
  
  
  METHODS
  In Langendorff-perfused rat hearts, prazosin outflow concentration and left ventricular developed pressure were measured, first in the presence of 12.3 micromol x L(-1) phenylephrine following a 1 min infusion of 1.27 nmol [(3)H]-prazosin, and second, when after 30 min the phenylephrine concentration in perfusate was reduced to 6.1 micromol x L(-1), the 1 min infusion of 1.27 nmol [(3)H]-prazosin was repeated.
  
  
  RESULTS
  The kinetic model accounted for cardiac uptake and receptor binding kinetics of prazosin (dissociation constant, mean +/- SD: 0.057 +/- 0.012 nmol.L(-1)), assuming that the competitive displacement of phenylephrine (dissociation constant: 101 +/- 13 nmol x L(-1)) reduced the receptor occupation by the agonist and, consequently, contractility. This competitive binding process appeared to be the rate-determining step in response generation. The relationship between receptor occupancy and inotropic response was described by an efficacy parameter (tau, ratio of receptor density and coupling efficiency) of 4.9.
  
  
  CONCLUSIONS
  Mechanistic pharmacodynamic modelling of the kinetics of antagonism by prazosin allows quantitative assessment of the alpha(1)-adrenoceptor system both at the receptor and post-receptor levels.
authors.affiliation: Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Sermsappasuk
authors.forename: M
authors.initials: M
authors.lastname: Weiss
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008297:Male; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010656:Phenylephrine / Q000493:pharmacokinetics / Q000494:pharmacology*; D011224:Prazosin / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D015398:Signal Transduction; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D011224:Prazosin