Effects of acidosis on cardiotonic effect of forskolin

众所周知，呼吸/代谢性酸中毒会降低动物中儿茶酚胺和PDE III抑制剂的强心作用。本研究旨在确定降低pH值是否影响Forskolin的强心作用。18只大鼠连续输注2N盐酸约1小时，使pH值分别为7.4、7.2和7.0，然后以1、3和6μg/kg/min的速度静脉注射Forskolin 1小时。HR和Emax显著降低SVR，且呈剂量依赖性，但对血压无影响。然而，毛喉素增加CO和Emax的百分比不受pH值的影响。在体外研究中，将Hepes-Tyrode溶液的pH调节至pH=7.4、7.0和6.6，并累积给予Forskolin，其以浓度依赖性方式显著增加右心室和左心房的等长收缩力。然而，右心室和左心房的等长收缩力的增加（%）不受pH的影响。此外，在pH=7.4和6.6时，应用10 μ M毛喉素后，与载体（生理盐水）应用相比，右心室和左心房中细胞内cAMP的%变化相似<-3>。这些结果表明，毛喉素的强心作用不受pH降低的影响，这与儿茶酚胺和PDE III抑制剂形成鲜明对比。

Respiratory/metabolic acidosis is well known to reduce cardiotonic effect of catecholamines and PDE III inhibitors in animals. This investigation was designed to determine if cardiotonic effect of forskolin is influenced by lowered pH. Hydrochloric acid (2N) was continuously infused for approximately 1 hr to obtain pHa=7.4, 7.2 and 7.0 in 18 rats randomly assigned to three groups according to the pH. Then, forskolin was administered intravenously at 1, 3, and 6μg/kg/min for 1 hr. Forskolin increased CO, HR and Emax, and decreased SVR significantly and dose-dependently, but BP was not affected. Percent increase in CO and Emax by forskolin, however, was not influenced by pHa. In in vitro studies, pH of Hepes-Tyrode solution was adjusted at pH=7.4, 7.0, and 6.6 and forskolin was administered cumulatively, which increased isometric force of both right ventricle and left atrium significantly in a concentration-dependent manner. However, increases (%) in isometric force of both right ventricle and left atrium were not affected by pH. In addition, % changes in intracellular cAMP compared with vehicle (normal saline) application in both right ventricle and left atrium were similar at pH=7.4 and 6.6 after application of 10^<-3> M forskolin. These results indicate that the cardiotonic effect of forskolin is not affected by lowered pH, which is in clear contrast with catecholamines and PDE III inhibitors.