Sunga P S, Rabkin S W
University of British Columbia, Vancouver, Canada.
Can J Physiol Pharmacol. 1994 Jun;72(6):602-12. doi: 10.1139/y94-086.
The objective of this study was to explore the action of angiotensin II (AII) on cardiac contractility and cyclic AMP (cAMP) generation by forskolin and isoproterenol in the hypertrophic myocardium of the salt-sensitive Dahl rat. Inbred Dahl S and Dahl R rats that had been on a diet supplemented with 6% NaCl were studied. The functional effects of the interaction of AII and forskolin on cardiac contractility were assessed in the isolated heart preparation. The effect on the cAMP signal transduction pathway was assessed in cardiomyocytes isolated from hearts of Dahl S and R rats. Dahl S rats developed cardiac hypertrophy on a high-salt diet, whereas Dahl R rats did not. Forskolin increased cardiac contractility, which was differently affected by AII, depending on whether the heart was from hypertrophied Dahl S rat or from the control Dahl R rat. AII accentuated forskolin-induced increases in cardiac contractility in hypertrophic hearts but diminished forskolin-induced increases in contractility in the nonhypertrophied hearts. This response was reflected in the cAMP response to forskolin, in that AII decreased forskolin-induced increases in cAMP in the nonhypertrophic heart. AII had the reverse effect in cardiomyocytes from hypertrophied hearts, as AII increased forskolin-induced cAMP production. This was shown to be due to an AII receptor mediated effect, as it was antagonized by the AII receptor antagonist saralasin. The same effects of AII were found on isoproterenol-induced increases in cAMP. Similar results occurred in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), suggesting that the effect was on cAMP production rather than cAMP degradation. This was attributed to an inhibitory G protein (Gi) mechanism, as the muscarinic agonist carbachol, which acts through Gi, produced the same effects as AII. Furthermore, the effects of AII were abolished by pertussis toxin, which inactivates Gi. These data indicate a reversal of control by AII in the hypertrophic Dahl S heart in response to forskolin, which activates adenylyl cyclase directly on the catalytic subunit, converting the substrate, ATP, to cAMP, independent of the guanine nucleotide activated protein, and in response to isoproterenol, which activates adenylyl cyclase through G protein mechanisms. All accentuated the forskolin-induced increase in cardiac contractility and cAMP generation in the hypertrophied ventricle but decreased both contractility and cAMP generation in nonhypertrophied hearts, suggesting that the process of cardiac hypertrophy in salt-sensitive Dahl rat may compensate for the reduction in intracellular cAMP by altering its regulatory control by AII.
本研究的目的是探讨血管紧张素II（AII）对盐敏感型Dahl大鼠肥厚心肌中由福斯高林和异丙肾上腺素引起的心肌收缩力及环磷酸腺苷（cAMP）生成的作用。研究了食用添加6%氯化钠饲料的近交系Dahl S和Dahl R大鼠。在离体心脏标本中评估AII与福斯高林相互作用对心肌收缩力的功能影响。在从Dahl S和R大鼠心脏分离的心肌细胞中评估对cAMP信号转导途径的影响。Dahl S大鼠在高盐饮食下出现心肌肥厚，而Dahl R大鼠未出现。福斯高林可增加心肌收缩力，AII对其影响因心脏来自肥厚的Dahl S大鼠还是对照的Dahl R大鼠而有所不同。AII增强了福斯高林诱导的肥厚心脏心肌收缩力增加，但减弱了福斯高林诱导的非肥厚心脏心肌收缩力增加。这种反应反映在对福斯高林的cAMP反应中，即AII降低了福斯高林诱导的非肥厚心脏中cAMP的增加。在肥厚心脏的心肌细胞中，AII产生相反的作用，因为AII增加了福斯高林诱导的cAMP产生。这表明是AII受体介导的效应，因为它被AII受体拮抗剂沙拉新所拮抗。在异丙肾上腺素诱导的cAMP增加方面也发现了AII的相同作用。在存在磷酸二酯酶抑制剂3 -异丁基-1 -甲基黄嘌呤（IBMX）的情况下出现了类似结果，表明该效应是对cAMP生成的影响而非对cAMP降解的影响。这归因于抑制性G蛋白（Gi）机制，因为通过Gi起作用的毒蕈碱激动剂卡巴胆碱产生了与AII相同的作用。此外，AII的作用被百日咳毒素消除，百日咳毒素可使Gi失活。这些数据表明，在肥厚的Dahl S心脏中，AII对福斯高林（其直接作用于催化亚基激活腺苷酸环化酶，将底物ATP转化为cAMP，不依赖鸟嘌呤核苷酸激活蛋白）和异丙肾上腺素（其通过G蛋白机制激活腺苷酸环化酶）的控制发生了逆转。AII增强了福斯高林诱导的肥厚心室心肌收缩力增加和cAMP生成，但降低了非肥厚心脏的心肌收缩力和cAMP生成，这表明盐敏感型Dahl大鼠的心肌肥厚过程可能通过改变AII对其的调节控制来补偿细胞内cAMP的减少。
