Touyz R M, Fareh J, Thibault G, Schiffrin E L
Medical Research Council (MRC) Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.
Hypertension. 1996 Nov;28(5):797-805. doi: 10.1161/01.hyp.28.5.797.
The vasoactive peptides angiotensin II (Ang II) and endothelin-1 (ET-1) have been implicated in cardiac hypertrophy. This study investigates Ang II and ET-1 effects on intracellular free calcium concentration and the receptor subtype through which agonist-induced calcium responses are mediated in isolated cardiomyocytes and fibroblasts from hypertrophied hearts of spontaneously hypertensive rats (SHR). We measured intracellular free calcium concentration by fura 2 methodology and determined receptor status by radioligand binding assays. Ang II (10(-12) to 10(-7) mol/L) had no effect on cardiomyocyte calcium levels in control Wistar-Kyoto rats but significantly increased (P < .01) intracellular free calcium concentration in a dose-dependent manner in cardiomyocytes from SHR. Ang II total and specific binding were increased (P < .05) in SHR cardiomyocytes. Calcium responses elicited by 10(-7) to 10(-5) mol/L Ang II were significantly reduced (P < .01) in SHR fibroblasts despite no significant change in Ang II receptor density. The angiotensin type 1 receptor blocker losartan (1 mumol/L) blocked Ang II-stimulated calcium transients, whereas the angiotensin type 2 receptor blocker PD 123319 had no effect. ET-1- and sarafotoxin S6c-induced calcium responses in cardiomyocytes and fibroblasts were not different between hypertensive and control groups. In conclusion, Ang II and ET-1 elicit distinct and differential responses in a cell-specific manner in cardiomyocytes and fibroblasts from hypertrophied hearts of SHR. Whereas Ang II-mediated effects, which are elicited via angiotensin type 1 receptors, are detectable in cardiomyocytes from SHR, responses to Ang II are blunted in fibroblasts from SHR, and ET-1-related actions are similar in cells from both rat groups. Stimulation of cardiomyocytes by Ang II in hypertrophied hearts associated with pressure overload in genetic hypertension suggests that Ang II could modulate the function of cardiomyocytes of SHR but not those of Wistar-Kyoto rats, whereas cardiac actions of ET-1 do not change with the development of hypertension.
血管活性肽血管紧张素II（Ang II）和内皮素-1（ET-1）与心脏肥大有关。本研究调查了Ang II和ET-1对细胞内游离钙浓度的影响，以及在自发性高血压大鼠（SHR）肥厚心脏的分离心肌细胞和成纤维细胞中，激动剂诱导的钙反应是通过何种受体亚型介导的。我们采用fura 2方法测量细胞内游离钙浓度，并通过放射性配体结合试验确定受体状态。Ang II（10^(-12)至10^(-7) mol/L）对对照Wistar-Kyoto大鼠的心肌细胞钙水平无影响，但在SHR的心肌细胞中以剂量依赖方式显著增加（P <.01）细胞内游离钙浓度。SHR心肌细胞中Ang II的总结合和特异性结合增加（P <.05）。尽管Ang II受体密度无显著变化，但10^(-7)至10^(-5) mol/L Ang II引起的SHR成纤维细胞钙反应显著降低（P <.01）。血管紧张素-1型受体阻滞剂氯沙坦（1 μmol/L）阻断了Ang II刺激的钙瞬变，而血管紧张素-2型受体阻滞剂PD 123319则无作用。高血压组和对照组的心肌细胞和成纤维细胞中，ET-1和芋螺毒素S6c诱导的钙反应无差异。总之，在SHR肥厚心脏的心肌细胞和成纤维细胞中，Ang II和ET-1以细胞特异性方式引发不同的反应。在SHR的心肌细胞中可检测到通过血管紧张素-1型受体介导的Ang II效应，而SHR的成纤维细胞对Ang II的反应减弱，且ET-1相关作用在两组大鼠的细胞中相似。在遗传性高血压压力超负荷相关的肥厚心脏中，Ang II对心肌细胞的刺激表明，Ang II可调节SHR心肌细胞的功能，但不能调节Wistar-Kyoto大鼠心肌细胞的功能，而ET-1的心脏作用不会随高血压的发展而改变。
