Participation of hepatic α/β-adrenoceptors and AT1 receptors in glucose release and portal hypertensive response induced by adrenaline or angiotensin II

It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (∝1- and β-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ∝1-AR and β-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ∝1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of β-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between β-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.既往研究已证实，血管紧张素II（angiotensin II, AII）对肝脏的血流动力学效应可被氯沙坦（losartan）完全阻断，而其诱导的葡萄糖释放过程则受氯沙坦部分影响。血管紧张素II 1型（AT1）受体与肾上腺素能（α1和β型）受体（AR）同属G蛋白超家族，二者的信号通路均可介导糖原分解与葡萄糖释放。采用特异性拮抗剂阻断上述两类受体后，可观测到AR与AT1-R之间存在交互调控关系。本研究采用离体灌流大鼠肝脏模型，探究在AT1受体拮抗剂氯沙坦、α1-AR拮抗剂哌唑嗪（prazosin）以及β-AR拮抗剂普萘洛尔（propranolol）共同存在时，AII与肾上腺素（adrenaline, Adr）所诱导的血流动力学与代谢应答变化。所有所用拮抗剂均可削弱肾上腺素诱导的血流动力学反应。氯沙坦可完全阻断AII诱导的血流动力学反应，而单独使用AR拮抗剂则无此类阻断效果；当联合使用两类拮抗剂时，血流动力学反应出现进一步下降。肾上腺素诱导的代谢应答主要由α1-AR介导。氯沙坦可显著削弱肾上腺素诱导的血流动力学反应，这一结果证实了AT1-R参与了该效应的调控。AII诱导的代谢应答可被普萘洛尔抑制，提示β-AR参与了该过程。当同时阻断两类AR时，血流动力学与代谢应答均出现累积性减弱。上述结果表明，两类AR均可能参与介导AII的生物学效应。肝细胞内β-AR与AT1-R信号通路之间存在的潜在信号串扰现象仍有待进一步研究，且在设计特异性靶向药物时应将该交互调控关系纳入考量。