van Amsterdam F T, van Amsterdam-Magnoni M S, Haas M, Punt N C, Zaagsma J
Department of Pharmacology and Therapeutics, University of Groningen, The Netherlands.
Naunyn Schmiedebergs Arch Pharmacol. 1990 Jan-Feb;341(1-2):137-42. doi: 10.1007/BF00195070.
We have studied the effects of 60 min global ischaemia and 30 min of subsequent reperfusion on the binding of [3H]-(+)-PN 200-110 and [3H]-(-)-devapamil (desmethoxyverapamil or D888) in rat heart membranes. The hearts were perfused in the Langendorff-mode and pretreated with 1 mumol/l verapamil, 30 nmol/l and 1 mumol/l nifedipine. After 60 min of global ischaemia in the absence of drugs, we found a reduction of [3H]-(+)-PN 200-110 binding sites, without changes in the equilibrium dissociation binding constant (Kd). After the subsequent reperfusion maximum specific binding (Bmax) was further reduced, whereas the Kd remained constant. [3H]-devapamil binding sites were influenced to a lower extend and showed only a decrease in Bmax at reperfusion. Pretreatment with 1 mumol/l verapamil completely prevented the changes which were observed for [3H]-(+)-PN 200-110. Pretreatment with a low, vasodilating concentration (30 nmol/l) of nifedipine displayed selective protection against the extra reduction in Bmax which was observed during reperfusion. It is concluded that calcium antagonists show protection against the ischaemia-induced loss of dihydropyridine binding sites in relation to their negative inotropic, energy-saving activity. Furthermore, nifedipine at low, vasodilating but not negative inotropic concentrations protects against further reperfusion-induced injury, which protection may be related to an improved flow during reperfusion.
我们研究了60分钟全心缺血及随后30分钟再灌注对大鼠心脏膜中[3H]-(+)-PN 200-110和[3H]-(-)-地尔硫䓬（去甲氧基维拉帕米或D888）结合的影响。心脏采用Langendorff模式灌注，并用1μmol/L维拉帕米、30 nmol/L和1μmol/L硝苯地平进行预处理。在无药物情况下进行60分钟全心缺血后，我们发现[3H]-(+)-PN 200-110结合位点减少，而平衡解离结合常数（Kd）无变化。随后再灌注后，最大特异性结合（Bmax）进一步降低，而Kd保持不变。[3H]-地尔硫䓬结合位点受影响程度较低，仅在再灌注时Bmax降低。1μmol/L维拉帕米预处理完全阻止了[3H]-(+)-PN 200-110所观察到的变化。低浓度（30 nmol/L）具有血管舒张作用的硝苯地平预处理对再灌注期间观察到的Bmax额外降低显示出选择性保护作用。结论是，钙拮抗剂相对于其负性肌力、节能活性，对缺血诱导的二氢吡啶结合位点丧失具有保护作用。此外，低浓度、具有血管舒张作用而非负性肌力作用的硝苯地平可防止再灌注诱导的进一步损伤，这种保护作用可能与再灌注期间血流改善有关。
