Reinhardt D, Roggenbach W, Schmidt U, Schümann H J
Eur J Pharmacol. 1977 Jan 21;41(2):123-32. doi: 10.1016/0014-2999(77)90201-1.
Contractile responses of guinea-pig atria to papaverine were analyzed under different stimulation frequencies. Atria, driven at 2 Hz, showed positive inotropic responses to papaverine which were maximal within 10-15 min. These responses were maintained for 60 min in the presence of low concentrations of papaverine (up to 10(-5) M), but reversed into marked negative inotropic effects under the influence of higher concentrations. The well-known frequency-force relationship was reversed by papaverine. At low stimulation rates papaverine elicited positive inotropic responses, which gradually decreased with increasing frequencies until strong cardiodepression occurred. A frequency-force curve obtained in the presence of both the Ca2+-antagonistic drug D 600 and the inhibitor of the phosphodiesterase theophylline was similar to that obtained under the influence of papaverine. Theophylline alone evoked positive inotropic effects at all frequencies studied and left the character of the ascending staircase unchanged. In contrast, D 600 was ineffective at low, but cardiodepressive at high stimulation frequencies. In the presence of D 600 or papaverine high external Ca2+ could not restore a normal frequency-force relationship. The reversal of the frequency-force relationship as produced by D 600 and papaverine could not be obtained by lowering of the external Ca2+. The present results show that papaverine is able to evoke marked positive inotropic effects at low stimulation frequencies by inhibition of phosphodiesterase. At high frequencies, however, these effects are masked by negative inotropic responses due to the inhibitory action of papaverine on Ca2+-exchange of the cardiac muscle cell.
在不同刺激频率下分析了豚鼠心房对罂粟碱的收缩反应。以2Hz驱动的心房对罂粟碱表现出正性肌力反应，在10 - 15分钟内达到最大。在低浓度罂粟碱（高达10(-5)M）存在下，这些反应持续60分钟，但在高浓度影响下转变为明显的负性肌力作用。罂粟碱使众所周知的频率-张力关系发生了逆转。在低刺激频率下，罂粟碱引起正性肌力反应，随着频率增加逐渐降低，直到出现强烈的心功能抑制。在同时存在钙拮抗剂D 600和磷酸二酯酶抑制剂茶碱的情况下获得的频率-张力曲线与在罂粟碱影响下获得的曲线相似。单独使用茶碱在所有研究频率下均引起正性肌力作用，且不改变升阶梯的特征。相比之下，D 600在低刺激频率下无效，但在高刺激频率下具有心功能抑制作用。在存在D 600或罂粟碱的情况下，高细胞外钙不能恢复正常的频率-张力关系。降低细胞外钙不能获得D 600和罂粟碱所产生的频率-张力关系的逆转。目前的结果表明，罂粟碱在低刺激频率下能够通过抑制磷酸二酯酶引起明显的正性肌力作用。然而，在高频率下，由于罂粟碱对心肌细胞钙交换的抑制作用，这些作用被负性肌力反应所掩盖。
