Turnbull Lynne, McCloskey Diana T, O'Connell Timothy D, Simpson Paul C, Baker Anthony J
Department of Medicine and Cardiovascular Research Institute, University of California and Veterans Affairs Medical Center, San Francisco, USA.
Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1104-9. doi: 10.1152/ajpheart.00441.2002. Epub 2002 Dec 5.
Two functional alpha(1)-adrenergic receptor (AR) subtypes (alpha(1A) and alpha(1B)) have been identified in the mouse heart. However, it is unclear whether the third known subtype, alpha(1D)-AR, is also present. To investigate this, we determined whether there were alpha(1)-AR responses in hearts from a novel mouse model lacking alpha(1A)- and alpha(1B)-ARs (double knockout) (ABKO). In Langendorff-perfused hearts, alpha(1)-ARs were stimulated with phenylephrine. For ABKO hearts, phenylephrine reduced left ventricular pressure and coronary flow (to 87 +/- 2% and 86 +/- 4% of initial, respectively, n = 11, P < 0.01). These effects were blocked by prazosin and 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-8-azaspirol[4,5]decane-7,9-dione] dihydrochloride, suggesting that alpha(1D)-AR-mediated responses were present. In contrast, right ventricular trabeculae from ABKO hearts did not respond to phenylephrine, suggesting that in ABKO perfused hearts, the effects of phenylephrine were not mediated by direct actions on cardiomyocytes. A novel finding was that alpha(1)-AR stimulation caused positive inotropy in the wild-type mouse heart, in contrast to negative inotropy observed in mouse cardiac muscle strips. We conclude that mouse hearts lacking alpha(1A)- and alpha(1B)-ARs retain functional alpha(1)-AR responses involving decreases of coronary flow and ventricular pressure that reflect alpha(1D)-AR-mediated vasoconstriction. Furthermore, alpha(1)-AR inotropic responses depend critically on the experimental conditions.
在小鼠心脏中已鉴定出两种功能性α(1)-肾上腺素能受体（AR）亚型（α(1A)和α(1B)）。然而，尚不清楚第三种已知亚型α(1D)-AR是否也存在。为了研究这一点，我们确定了来自缺乏α(1A)-和α(1B)-ARs的新型小鼠模型（双敲除）（ABKO）的心脏中是否存在α(1)-AR反应。在Langendorff灌注心脏中，用去氧肾上腺素刺激α(1)-ARs。对于ABKO心脏，去氧肾上腺素降低了左心室压力和冠状动脉流量（分别降至初始值的87±2%和86±4%，n = 11，P < 0.01）。这些作用被哌唑嗪和8-[2-[4-(2-甲氧基苯基)-1-哌嗪基]-8-氮杂螺[4,5]癸烷-7,9-二酮]二盐酸盐阻断，表明存在α(1D)-AR介导的反应。相比之下，ABKO心脏的右心室小梁对去氧肾上腺素无反应，这表明在ABKO灌注心脏中，去氧肾上腺素的作用不是通过对心肌细胞的直接作用介导的。一个新发现是，与在小鼠心肌条中观察到的负性肌力作用相反，α(1)-AR刺激在野生型小鼠心脏中引起正性肌力作用。我们得出结论，缺乏α(1A)-和α(1B)-ARs的小鼠心脏保留了功能性α(1)-AR反应，包括冠状动脉流量和心室压力的降低，这反映了α(1D)-AR介导的血管收缩。此外，α(1)-AR的变力反应严重依赖于实验条件。
