Kim D, Smith T W
Mol Pharmacol. 1986 Aug;30(2):164-70.
Dichlorobenzamil, an analog of amiloride, has been reported to inhibit Na-Ca exchange in sarcolemmal vesicles of guinea pig heart. To examine further the effect of the drug on Na-Ca exchange in intact cardiac cells and the pharmacological specificity of this action, we determined in cultured chick heart cells the effects of dichlorobenzamil on the following: contractile state, Nai-dependent Ca uptake, Ca uptake via slow Ca channels (defined as verapamil-inhibitable Ca uptake), Ca efflux via the sarcolemmal Ca pump, monovalent cation transport, and cellular Ca and Na content. Dichlorobenzamil produced a concentration-dependent decrease in the amplitude of cell motion (EC50 = 5 X 10(-7) M) and abolished the development of ouabain-induced rhythm disturbances and contracture. In normal or Na-loaded cells, dichlorobenzamil inhibited the Ca uptake rate, also in a concentration-dependent manner (EC50 = 6 X 10(-7) M). Dichlorobenzamil (6 X 10(-7) M) also caused a significant inhibition of the isoproterenol-induced elevation of Ca uptake. At 5 X 10(-5) M, dichlorobenzamil blocked completely Ca influx via slow Ca channels. Ca efflux rate was also reduced by dichlorobenzamil (EC50 = 10(-6) M). Replacement of Na with choline in the efflux medium to prevent Ca efflux via Na-Ca exchange did not alter the ED50 of the drug's inhibition of Ca efflux rate. Dichlorobenzamil caused concentration-dependent inhibition of sodium pump activity as judged by ouabain-sensitive 42K uptake (EC50 approximately 2 X 10(-6) M), and, at concentrations above 5 X 10(-7) M), produced an increase in steady state cellular Na content. These results indicate that dichlorobenzamil has several sites of action in intact heart cells and that the negative inotropic action of the drug is due, in part, to inhibition of Ca influx via both Na-Ca exchange and slow Ca channels.
据报道，二氯苯甲米（amiloride的类似物）可抑制豚鼠心脏肌膜囊泡中的钠钙交换。为了进一步研究该药物对完整心肌细胞钠钙交换的影响以及这种作用的药理学特异性，我们在培养的鸡心肌细胞中测定了二氯苯甲米对以下各项的影响：收缩状态、依赖细胞内钠（Nai）的钙摄取、通过慢钙通道的钙摄取（定义为维拉帕米可抑制的钙摄取）、通过肌膜钙泵的钙外流、单价阳离子转运以及细胞内钙和钠含量。二氯苯甲米使细胞运动幅度呈浓度依赖性降低（半数有效浓度[EC50] = 5×10⁻⁷ M），并消除了哇巴因诱导的节律紊乱和挛缩的发展。在正常或钠负荷的细胞中，二氯苯甲米也以浓度依赖性方式抑制钙摄取速率（EC50 = 6×10⁻⁷ M）。二氯苯甲米（6×10⁻⁷ M）还显著抑制异丙肾上腺素诱导的钙摄取升高。在5×10⁻⁵ M时，二氯苯甲米完全阻断通过慢钙通道的钙内流。二氯苯甲米也降低了钙外流速率（EC50 = 10⁻⁶ M）。在外流培养基中用胆碱替代钠以防止通过钠钙交换的钙外流，并未改变该药物抑制钙外流速率的半数有效剂量（ED50）。根据哇巴因敏感的⁴²K摄取判断，二氯苯甲米导致钠泵活性呈浓度依赖性抑制（EC50约为2×10⁻⁶ M），并且在浓度高于5×10⁻⁷ M时，使细胞内钠的稳态含量增加。这些结果表明，二氯苯甲米在完整心肌细胞中有多个作用位点，并且该药物的负性肌力作用部分归因于对通过钠钙交换和慢钙通道的钙内流的抑制。
