Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
Am J Physiol Heart Circ Physiol. 2013 Apr 1;304(7):H946-53. doi: 10.1152/ajpheart.00822.2012. Epub 2013 Jan 25.
α1-Adrenergic receptors (α1-ARs) elicit a negative inotropic effect (NIE) in the mouse right ventricular (RV) myocardium but a positive inotropic effect (PIE) in the left ventricular (LV) myocardium. Effects on myofilament Ca(2+) sensitivity play a role, but effects on Ca(2+) handling could also contribute. We monitored the effects of α1-AR stimulation on contraction and Ca(2+) transients using single myocytes isolated from the RV or LV. Interestingly, for both the RV and LV, we found heterogeneous myocyte inotropic responses. α1-ARs mediated either a PIE or NIE, although RV myocytes had a greater proportion of cells manifesting a NIE (68%) compared with LV myocytes (36%). Stimulation of a single α1-AR subtype (α1A-ARs) with a subtype-selective agonist also elicited heterogeneous inotropic responses, suggesting that the heterogeneity arose from events downstream of the α1A-AR subtype. For RV and LV myocytes, an α1-AR-mediated PIE was associated with an increased Ca(2+) transient and a NIE was associated with a decreased Ca(2+) transient, suggesting a key role for Ca(2+) handling. For RV and LV myocytes, α1-AR-mediated decreases in the Ca(2+) transient were associated with increased Ca(2+) export from the cell and decreased Ca(2+) content of the sarcoplasmic reticulum. In contrast, for myocytes with α1-AR-induced increased Ca(2+) transients, sarcoplasmic reticulum Ca(2+) content was not increased, suggesting that other mechanisms contributed to the increased Ca(2+) transients. This study demonstrates the marked heterogeneity of LV and RV cellular inotropic responses to stimulation of α1-ARs and reveals a new aspect of biological heterogeneity among myocytes in the regulation of contraction.
α1-肾上腺素能受体（α1-AR）在小鼠右心室（RV）心肌中引起负性肌力作用（NIE），但在左心室（LV）心肌中引起正性肌力作用（PIE）。肌球蛋白丝 Ca2+敏感性的作用，但 Ca2+处理的作用也可能有贡献。我们使用从 RV 或 LV 分离的单个心肌细胞监测 α1-AR 刺激对收缩和 Ca2+瞬变的影响。有趣的是，对于 RV 和 LV，我们发现心肌细胞的变力反应存在异质性。α1-AR 介导 PIE 或 NIE，尽管 RV 心肌细胞表现出 NIE 的细胞比例（68%）高于 LV 心肌细胞（36%）。使用选择性激动剂刺激单一 α1-AR 亚型（α1A-AR）也引起了变力反应的异质性，表明异质性源于 α1A-AR 亚型下游的事件。对于 RV 和 LV 心肌细胞，α1-AR 介导的 PIE 与 Ca2+瞬变增加相关，而 NIE 与 Ca2+瞬变减少相关，表明 Ca2+处理在其中起着关键作用。对于 RV 和 LV 心肌细胞，α1-AR 介导的 Ca2+瞬变减少与细胞内 Ca2+外排增加和肌浆网 Ca2+含量减少有关。相比之下，对于 α1-AR 诱导的 Ca2+瞬变增加的心肌细胞，肌浆网 Ca2+含量没有增加，这表明其他机制有助于增加 Ca2+瞬变。本研究表明，刺激 α1-AR 引起 LV 和 RV 细胞变力反应存在明显的异质性，并揭示了心肌细胞在收缩调节中生物异质性的一个新方面。
