Terzic A, Vogel S M
Department of Pharmacology, University of Illinois College of Medicine, Chicago.
J Pharmacol Exp Ther. 1991 Apr;257(1):520-9.
Alpha adrenoceptor agonists have been reported to increase contractile force and to stimulate Na+/H+ exchange in the heart. We studied the influence of hexamethylamiloride (HMA), a selective inhibitor of Na+/H+ exchange, on the positive inotropic action of phenylephrine in isolated, paced rat left atria (3 microM propranolol). HMA (10 microM) blocked the ouabain-induced contracture, an event dependent on Na+ uptake via the Na+/H+ exchanger. The same concentration of HMA prevented 50% of the positive inotropic effect of phenylephrine (10 microM), but had no effect on base-line developed force. HMA reduced the maximal effect (234 +/- 19 vs. 117 +/- 20% increase of base-line), but not the EC50 (4.4 +/- 1.0 vs. 3.6 +/- 2 microM) of phenylephrine. Phenylephrine (100 microM) caused both a leftward and upward shift of the Ca++ concentration-effect curve, but only a leftward shift, in the additional presence of HMA (3 microM). It is known that lithium, but not choline, will exchange for H+ via the Na+/H+ exchanger: phenylephrine's (100 microM) positive inotropic effect in choline-substituted solutions averaged 37% of that in lithium-substituted solutions. The positive inotropic effect of phenylephrine was amplified by ouabain (200 microM). These results are consistent with the hypothesis that alpha adrenoceptor agonists produce their positive inotropic effects, in part, via stimulation of Na+/H+ exchange. Such stimulation could cause an intracellular alkalinization and (in the presence of ouabain), elevated intracellular Na+.
据报道，α肾上腺素能受体激动剂可增强心肌收缩力并刺激心脏中的Na⁺/H⁺交换。我们研究了Na⁺/H⁺交换的选择性抑制剂六甲铵（HMA）对苯肾上腺素在离体、起搏大鼠左心房（含3μM普萘洛尔）中产生的正性肌力作用的影响。HMA（10μM）可阻断哇巴因诱导的挛缩，该事件依赖于通过Na⁺/H⁺交换体摄取Na⁺。相同浓度的HMA可抑制苯肾上腺素（10μM）50%的正性肌力作用，但对基线收缩力无影响。HMA降低了苯肾上腺素的最大效应（基线增加234±19%对117±20%），但未改变其半数有效浓度（EC50）（4.4±1.0对3.6±2μM）。在额外存在HMA（3μM）的情况下，苯肾上腺素（100μM）使Ca²⁺浓度-效应曲线向左上方移位，但仅向左移位。已知锂可通过Na⁺/H⁺交换体与H⁺进行交换，而胆碱则不能：在胆碱替代溶液中，苯肾上腺素（100μM）的正性肌力作用平均为锂替代溶液中的37%。哇巴因（200μM）可增强苯肾上腺素的正性肌力作用。这些结果与以下假设一致，即α肾上腺素能受体激动剂部分通过刺激Na⁺/H⁺交换产生其正性肌力作用。这种刺激可导致细胞内碱化，并（在存在哇巴因的情况下）使细胞内Na⁺升高。
