Sermsappasuk P, Weiss M
Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Br J Pharmacol. 2009 Mar;156(5):764-73. doi: 10.1111/j.1476-5381.2008.00013.x. Epub 2009 Feb 13.
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.
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.
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.
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.
为利用拮抗剂（哌唑嗪）的瞬态反应来评估激动剂与α₁ - 肾上腺素能受体系统相互作用的特性，构建了哌唑嗪心脏摄取及其在受体部位与去氧肾上腺素竞争性相互作用的综合机制模型。基于激动作用的操作模型，目的是评估受体结合和信号转导过程作为去氧肾上腺素变力作用的决定因素。
在Langendorff灌注的大鼠心脏中，测量哌唑嗪流出浓度和左心室舒张末压，首先在1.27 nmol [(³)H]-哌唑嗪输注1分钟后，于12.3 μmol·L⁻¹去氧肾上腺素存在的情况下进行测量，其次，在灌注液中去氧肾上腺素浓度在30分钟后降至6.1 μmol·L⁻¹时，重复1.27 nmol [(³)H]-哌唑嗪的1分钟输注。
动力学模型解释了哌唑嗪的心脏摄取和受体结合动力学（解离常数，平均值±标准差：0.057±0.012 nmol·L⁻¹），假设去氧肾上腺素的竞争性置换（解离常数：101±13 μmol·L⁻¹）减少了激动剂对受体的占据，从而降低了收缩性。这种竞争性结合过程似乎是反应产生的速率决定步骤。受体占有率与变力反应之间的关系由一个效能参数（τ，受体密度与偶联效率之比）为4.9来描述。
哌唑嗪拮抗动力学的机制药效学建模允许在受体和受体后水平对α₁ - 肾上腺素能受体系统进行定量评估。
