Traebert M, Trebess I, Erlenkamp S, Hüser J, Kockskämper J, Glitsch H G, Hartung C, Welzel P
Arbeitsgruppe Muskelphysiologie, Ruhr-Universität, Bochum, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Nov;358(5):538-46. doi: 10.1007/pl00005290.
The effects of a new forskolin derivative, (13R)-spiroforskolin, on the ventricular cAMP-activated chloride current (I(Cl(cAMP))) and the atrial L-type calcium current (I(Ca,L)) were measured by means of whole-cell recording from isolated guinea-pig cardiac myocytes at 30 degrees C and 20-22 degrees C, respectively. In contrast to forskolin, the derivative contains a tetrahydrofuran rather than a tetrahydropyran moiety. (13R)-spiroforskolin activated I(Cl(CAMP)) in 58% of the ventricular myocytes studied. The concentration required for the half maximal effect (EC50 value) amounted to 9.6x10(-11) M and was lower than the EC50 value for forskolin (2.4x10(-8) M). (13R)-spiroforskolin evoked a smaller maximal I(Cl(cAMP)) amplitude than forskolin. The rundown of the (13R)-spiroforskolin-activated I(Cl(cAMP)) was faster than that of the forskolin-induced current. Neither forskolin nor (13R)-spiroforskolin in maximally effective concentrations increased I(Cl(cAMP)) in cells containing high concentrations of cAMP. Furthermore, as an activator of atrial I(Ca,L) (13R)-spiroforskolin displayed a smaller activation and a lower EC50 value (5.8x10(-10) M) than forskolin (EC50 value: 3.7x10(-7) M). The effect of (13R)-spiroforskolin was observed in only 30% of the atrial cells studied. None of the drugs exerted a stimulatory effect in atrial cells containing a high [cAMP]. The washout of the drug effect was significantly faster in (13R)-spiroforskolin- than in forskolin-treated atrial myocytes. We conclude that (13R)-spiroforskolin as a forskolin derivative displays unique characteristics. It is a more potent but less efficacious activator of cardiac ionic conductances than the parent compound. The results suggest that (13R)-spiroforskolin, like forskolin, most probably exerts its effects via stimulation of the adenylyl cyclase.
在30℃和20 - 22℃下，分别通过全细胞记录法，测量了一种新型福斯高林衍生物（13R）-螺环福斯高林对豚鼠离体心肌细胞心室环磷酸腺苷（cAMP）激活的氯离子电流（I(Cl(cAMP))）和心房L型钙电流（I(Ca,L)）的影响。与福斯高林不同，该衍生物含有一个四氢呋喃而非四氢吡喃部分。在研究的58%的心室肌细胞中，（13R）-螺环福斯高林激活了I(Cl(CAMP))。产生半数最大效应所需的浓度（EC50值）为9.6×10(-11) M，低于福斯高林的EC50值（2.4×10(-8) M）。（13R）-螺环福斯高林诱发的I(Cl(cAMP))最大幅度比福斯高林小。（13R）-螺环福斯高林激活的I(Cl(cAMP))的衰减比福斯高林诱导的电流更快。在含有高浓度cAMP的细胞中，最大有效浓度的福斯高林和（13R）-螺环福斯高林均未增加I(Cl(cAMP))。此外，作为心房I(Ca,L)的激活剂，（13R）-螺环福斯高林的激活作用比福斯高林小，且EC50值更低（5.8×10(-10) M），而福斯高林的EC50值为3.7×10(-7) M。在研究的仅30%的心房细胞中观察到了（13R）-螺环福斯高林的作用。在含有高[cAMP]的心房细胞中，这些药物均未产生刺激作用。（13R）-螺环福斯高林处理的心房肌细胞中药物效应的洗脱明显比福斯高林处理的更快。我们得出结论，（13R）-螺环福斯高林作为福斯高林衍生物具有独特的特性。与母体化合物相比，它是一种更有效的但效力较低的心脏离子电导激活剂。结果表明，（13R）-螺环福斯高林与福斯高林一样，很可能通过刺激腺苷酸环化酶发挥其作用。
