Hershberger R E, Feldman A M, Bristow M R
Department of Medicine, University of Utah School of Medicine, Salt Lake City.
Circulation. 1991 Apr;83(4):1343-51. doi: 10.1161/01.cir.83.4.1343.
Receptors that couple via the stimulatory G protein, Gs, to adenylate cyclase and to a positive inotropic response have been extensively investigated in falling human heart. In contrast, much less is known about receptors, such as the A1-adenosine receptor, that couple to adenylate cyclase via the inhibitory G protein, Gi, to give a negative inotropic response. Activation of such Gi-coupled receptors might worsen heart failure. Furthermore, alpha Gi is increased in failing human ventricular myocardium, which may enhance inhibitory receptor coupling to adenylate cyclase.
A1-Adenosine receptor inhibition of adenylate cyclase was examined in crude particulate preparations derived from 12 nonfailing and 12 failing human left ventricles. Experimental conditions were designed for maximal inhibitory responses. Dose-response curves were performed with the selective A1-adenosine receptor agonist R-phenylisopropyl-adenosine (R-PIA). No differences in nonfailing versus failing heart were observed for basal adenylate cyclase activity (49.0 +/- 4.1 versus 45.7 +/- 2.6 pmol cyclic AMP/min/mg), maximal R-PIA-mediated inhibition (31.1 +/- 2.6 versus 30.2 +/- 1.6 pmol cyclic AMP/min/mg), ED50 (R-PIA x 10(-7) 1.28 +/- 0.10 versus 1.36 +/- 0.08), or slope (1.06 +/- 0.06 versus 1.03 +/- 0.10), respectively. Furthermore, fluoride, forskolin, and manganese adenylate cyclase activation were not different in failing heart, which is consistent with no change in the catalytic unit of adenylate cyclase. The inhibitory G protein alpha Gi, as quantitated by pertussis toxin-catalyzed ADP-ribosylation, was increased in failing heart (105.7 +/- 5.8 versus 132.7 +/- 3.4 optical density units, p less than 0.003). Basal adenylate cyclase activity was reduced in failing heart (7.8 +/- 0.8 versus 4.5 +/- 0.4 pmol cyclic AMP/min/mg, p less than 0.005) with assay conditions designed to assess G protein effects.
The A1-adenosine receptor pathway exerts a major inhibitory effect on human myocardial adenylate cyclase activity. Although alpha Gi was increased in failing heart, A1-adenosine receptor inhibition of adenylate cyclase was not altered in preparations of failing versus nonfailing human ventricular myocardium.
通过刺激性G蛋白Gs与腺苷酸环化酶偶联并产生正性变力反应的受体，已在衰竭的人类心脏中得到广泛研究。相比之下，对于诸如A1 - 腺苷受体等通过抑制性G蛋白Gi与腺苷酸环化酶偶联并产生负性变力反应的受体，人们了解得要少得多。此类与Gi偶联的受体激活可能会使心力衰竭恶化。此外，在衰竭的人类心室心肌中，αGi增加，这可能会增强抑制性受体与腺苷酸环化酶的偶联。
在源自12例非衰竭和12例衰竭人类左心室的粗制微粒体制剂中，检测了A1 - 腺苷受体对腺苷酸环化酶的抑制作用。实验条件设计为产生最大抑制反应。使用选择性A1 - 腺苷受体激动剂R - 苯异丙基腺苷（R - PIA）绘制剂量 - 反应曲线。在非衰竭心脏与衰竭心脏之间，未观察到基础腺苷酸环化酶活性（49.0±4.1对45.7±2.6 pmol环磷酸腺苷/分钟/毫克）、最大R - PIA介导的抑制作用（31.1±2.6对30.2±1.6 pmol环磷酸腺苷/分钟/毫克）、半数有效量（R - PIA×10⁻⁷ 1.28±0.10对1.36±0.08）或斜率（1.06±0.06对1.03±0.10）存在差异。此外，在衰竭心脏中，氟化物、福斯可林和锰对腺苷酸环化酶的激活作用并无差异。这与腺苷酸环化酶催化单位未发生变化一致。通过百日咳毒素催化的ADP - 核糖基化定量检测的抑制性G蛋白αGi，在衰竭心脏中增加（105.7±5.8对132.7±3.4光密度单位，p＜0.003）。在设计用于评估G蛋白效应的检测条件下，衰竭心脏中的基础腺苷酸环化酶活性降低（7.8±0.8对4.5±0.4 pmol环磷酸腺苷/分钟/毫克，p＜0.005）。
A1 - 腺苷受体途径对人类心肌腺苷酸环化酶活性发挥主要抑制作用。尽管在衰竭心脏中αGi增加，但在衰竭与非衰竭人类心室心肌制剂中，A1 - 腺苷受体对腺苷酸环化酶的抑制作用未发生改变。
