磷酸二酯酶 2、3 和 4 可降低 H-组氨酸受体激活在转基因小鼠离体心房中的心脏效应。
Phosphodiesterases 2, 3 and 4 can decrease cardiac effects of H-histamine-receptor activation in isolated atria of transgenic mice.
机构信息
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Str. 4, D-06112, Halle, Germany.
Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Liebigstraße 20, 04103, Leipzig, Germany.
出版信息
Naunyn Schmiedebergs Arch Pharmacol. 2021 Jun;394(6):1215-1229. doi: 10.1007/s00210-021-02052-y. Epub 2021 Feb 12.
Histamine exerts cAMP-dependent positive inotropic effects (PIE) and positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic mice which overexpress the human H-receptor in the heart (=H-TG). To determine whether these effects are antagonized by phosphodiesterases (PDEs), contractile studies were done in isolated left and right atrial preparations of H-TG. The contractile effects of histamine were tested in the additional presence of the PDE-inhibitorserythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA, 1 μM, PDE2-inhibitor) or cilostamide (1 μM, PDE3-inhibitor), rolipram (10 μM, a PDE4-inhibitor), and their combinations. Cilostamide (1 μM) and EHNA (1 μM), rolipram (1 μM), and EHNA (1 μM) and the combination of rolipram (0.1 μM) and cilostamide (1 μM) each increased the potency of histamine to elevate the force of contraction (FOC) in H-TG. Cilostamide (1 μM) and rolipram (10 μM) alone increased and EHNA (1 μM) decreased alone, and their combination increased the potency of histamine to increase the FOC in H-TG indicating that PDE3 and PDE4 regulate the inotropic effects of histamine in H-TG. The PDE inhibitors (EHNA, cilostamide, rolipram) alone did not alter the potency of histamine to increase the heart beat in H-TG whereas a combination of rolipram, cilostamide, and EHNA, or of rolipram and EHNA increased the potency of histamine to act on the beating rate. In summary, the data suggest that the PCE of histamine in H-TG atrium involves PDE 2 and 4 activities, whereas the PIE of histamine are diminished by activity of PDE 3 and 4.
组胺对转基因小鼠（即 H-TG）心脏中过表达人 H 受体的左、右心房分别产生 cAMP 依赖性正性变力效应（PIE）和正性变时效应（PCE）。为了确定这些效应是否被磷酸二酯酶（PDEs）拮抗，在 H-TG 的左、右心房分离标本中进行了收缩性研究。在存在 PDE 抑制剂的情况下测试了组胺的收缩作用：erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride（EHNA，1μM，PDE2 抑制剂）或 cilostamide（1μM，PDE3 抑制剂），rolipram（10μM，PDE4 抑制剂）及其组合。Cilostamide（1μM）和 EHNA（1μM）、rolipram（1μM）和 EHNA（1μM）以及 rolipram（0.1μM）和 cilostamide（1μM）的组合均增加了组胺的效力，从而提高了 H-TG 收缩力（FOC）。Cilostamide（1μM）和 rolipram（10μM）单独增加，EHNA（1μM）单独减少，它们的组合增加了组胺的效力，从而提高了 H-TG 的 FOC，表明 PDE3 和 PDE4 调节了 H-TG 中组胺的变力效应。PDE 抑制剂（EHNA、cilostamide、rolipram）单独使用不会改变组胺增加 H-TG 心跳的效力，而 rolipram、cilostamide 和 EHNA 的组合，或 rolipram 和 EHNA 的组合增加了组胺对心率的作用效力。总之，这些数据表明，H-TG 心房中组胺的 PCE 涉及 PDE2 和 4 活性，而组胺的 PIE 则被 PDE3 和 4 的活性所减弱。
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