Marquetant R, Brehm B, Strasser R H
Department of Cardiology, University of Heidelberg, Germany.
J Mol Cell Cardiol. 1992 May;24(5):535-48. doi: 10.1016/0022-2828(92)91842-s.
Chronic beta-blockade has evolved to an important therapeutic strategy in medicine. Not all its therapeutic effects may be explained by its direct action on the beta-adrenergic system. We therefore investigated if chronic beta-blockade in vivo or in isolated cell systems may modulate also inhibitory receptors of the adenylyl cyclase system. Chronic treatment with metoprolol for 6 days (10 mg/day) induced an increase of beta-adrenergic receptors in rat cardiac plasma membranes (53 +/- 8 vs 80 +/- 12 fmol/mg protein). Simultaneously the density of cardiac muscarinic M2 receptors decreased significantly from 150 +/- 17 to 110 +/- 12 fmol/mg protein without any change of the affinity of the receptors for their agonists or antagonists. By this mechanism chronic beta-blockade leads to an unexpected impairment of the muscarinic-mediated inhibition of the adenylyl cyclase. This transregulation of inhibitory receptors by chronic beta-blockade was not restricted to the heart but also reduced the muscarinic receptors of rat lung (35 +/- 4 vs 24 +/- 3 fmol/mg protein). Additionally, other inhibitory receptors of the adenylyl cyclase system such as the A1 adenosine receptors of rat brain were reduced by chronic beta-blockade (532 +/- 32 vs 444 +/- 26 fmol/mg protein). This transregulation of A1 adenosine receptors occurred only after chronic beta-blockade with the active stereoisomer (-)-metoprolol whereas the (+)-isomer was ineffective. The ability of the remaining A1 adenosine receptors to form the agonist-promoted high affinity state was unaltered. Their reduction, however, was sufficient to abolish the phenylisopropyl-mediated inhibition of the adenylyl cyclase. To evaluate if this regulation of various inhibitory receptors in different organs may represent a general cellular regulation mechanism, we investigated whether this transregulation also occurred in isolated cells. Isolated smooth muscle cells derived from the vas deferens (DDT1 MF-2) were cultivated in the presence of the beta-blocker atenolol (10(-5) M) for 3 days. Chronic beta-blockade in these isolated cells induced an increase of beta-adrenergic receptors and concomitantly a significant decrease of A1 adenosine receptors (460 +/- 42 vs 368 +/- 18 fmol/mg protein). The affinity of the A1 adenosine receptors for their agonists and antagonists and the ability of the remaining receptors to form the agonist-promoted high affinity state remained unaltered. In contrast, the reduction of receptor density greatly impaired the adenosine-mediated inhibition of the adenylyl cyclase. These data demonstrate that chronic beta-blockade leads to a functionally significant reduction of inhibitory receptors of the adenylyl cyclase system.(ABSTRACT TRUNCATED AT 400 WORDS)
慢性β受体阻滞剂已发展成为医学上一种重要的治疗策略。其所有治疗效果并非都能用对β-肾上腺素能系统的直接作用来解释。因此，我们研究了体内或分离细胞系统中的慢性β受体阻滞剂是否也可能调节腺苷酸环化酶系统的抑制性受体。用美托洛尔进行6天（10毫克/天）的慢性治疗可使大鼠心肌质膜中的β-肾上腺素能受体增加（53±8对80±12飞摩尔/毫克蛋白质）。同时，心脏毒蕈碱M2受体的密度从150±17显著降至110±12飞摩尔/毫克蛋白质，而受体对其激动剂或拮抗剂的亲和力没有任何变化。通过这种机制，慢性β受体阻滞剂会导致毒蕈碱介导的腺苷酸环化酶抑制出现意外损害。慢性β受体阻滞剂对抑制性受体的这种转调节作用并不局限于心脏，还会使大鼠肺中的毒蕈碱受体减少（35±4对24±3飞摩尔/毫克蛋白质）。此外，腺苷酸环化酶系统的其他抑制性受体，如大鼠脑的A1腺苷受体，也因慢性β受体阻滞剂而减少（532±32对444±26飞摩尔/毫克蛋白质）。A1腺苷受体的这种转调节作用仅在使用活性立体异构体（-）-美托洛尔进行慢性β受体阻滞剂治疗后出现，而（+）-异构体则无效。剩余A1腺苷受体形成激动剂促进的高亲和力状态的能力未改变。然而，其减少足以消除苯异丙基介导的腺苷酸环化酶抑制。为了评估不同器官中各种抑制性受体的这种调节是否可能代表一种普遍的细胞调节机制，我们研究了这种转调节是否也发生在分离的细胞中。在存在β受体阻滞剂阿替洛尔（10^-5摩尔/升）的情况下，培养来自输精管的分离平滑肌细胞（DDT1 MF-2）3天。这些分离细胞中的慢性β受体阻滞剂诱导β-肾上腺素能受体增加，同时A1腺苷受体显著减少（460±42对368±18飞摩尔/毫克蛋白质）。A1腺苷受体对其激动剂和拮抗剂的亲和力以及剩余受体形成激动剂促进的高亲和力状态的能力保持不变。相反，受体密度的降低极大地损害了腺苷介导的腺苷酸环化酶抑制。这些数据表明，慢性β受体阻滞剂会导致腺苷酸环化酶系统的抑制性受体在功能上显著减少。（摘要截短至400字）
