Van Liefde I, Van Witzenburg A, Vauquelin G
Department of Protein Chemistry, Free University of Brussels (V.U.B.) Belgium.
J Pharmacol Exp Ther. 1992 Aug;262(2):552-8.
l-Isoproterenol has been proposed to stimulate lipolysis in rat epididymal adipocytes via atypical beta adrenergic receptors, whereas radioligand binding studies only revealed the presence of beta 1 adrenergic receptors on adipocyte membranes. We have made use of the unique properties of CGP12177 to evidence that both the beta 1 and the atypical beta adrenergic receptor subtypes are mediating the lipolytic response of rat epididymal adipocytes to l-isoproterenol. CGP12177, an antagonist with high affinity for beta 1 receptors, triggers lipolysis by specifically stimulating the atypical receptors. For this response, CGP12177 displays low potency (EC50 = 68 nM), but high intrinsic activity (94% relative to l-isoproterenol). At low concentrations (3 nM), CGP12177 inhibits the lipolytic response to 10 nM l-isoproterenol by 43%, indicating that at least this fraction of the response is beta 1 receptor-mediated. The response to BRL37344, which is a selective agonist for the atypical receptors, is not inhibited by CGP12177. The pA2 values of the beta adrenergic antagonists propranolol, metoprolol and atenolol were calculated from the rightward shifts that they impose on dose-response curves of both l-isoproterenol and CGP12177. With l-isoproterenol, these values (6.54, 5.83 and 5.07, respectively) are lower than those expected for beta 1 and beta 2 receptors, indicating that atypical receptors are also involved in the lipolytic response to this agonist. With CGP12177, the pA2 values of propranolol, metoprolol and atenolol are even lower (5.80, 5.03 and 4.06, respectively), and are likely to be a more accurate reflection of their affinities for the atypical receptors.
有人提出，左旋异丙肾上腺素可通过非典型β肾上腺素能受体刺激大鼠附睾脂肪细胞的脂肪分解，而放射性配体结合研究仅揭示脂肪细胞膜上存在β1肾上腺素能受体。我们利用了CGP12177的独特性质来证明，β1和非典型β肾上腺素能受体亚型均介导大鼠附睾脂肪细胞对左旋异丙肾上腺素的脂肪分解反应。CGP12177是一种对β1受体具有高亲和力的拮抗剂，它通过特异性刺激非典型受体来引发脂肪分解。对于这种反应，CGP12177的效能较低（EC50 = 68 nM），但内在活性较高（相对于左旋异丙肾上腺素为94%）。在低浓度（3 nM）时，CGP12177可使对10 nM左旋异丙肾上腺素的脂肪分解反应抑制43%，这表明至少该部分反应是由β1受体介导的。对非典型受体的选择性激动剂BRL37344的反应不受CGP12177的抑制。β肾上腺素能拮抗剂普萘洛尔、美托洛尔和阿替洛尔的pA2值是根据它们对左旋异丙肾上腺素和CGP12177剂量反应曲线的右移计算得出的。对于左旋异丙肾上腺素，这些值（分别为6.54、5.83和5.07）低于β1和β2受体预期的值，这表明非典型受体也参与了对该激动剂的脂肪分解反应。对于CGP12177，普萘洛尔、美托洛尔和阿替洛尔的pA2值甚至更低（分别为5.80、5.03和4.06），并且可能更准确地反映了它们对非典型受体的亲和力。
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