Böhm M, Ettelbrück S, Flesch M, van Gilst W H, Knorr A, Maack C, Pinto Y M, Paul M, Teisman A C, Zolk O
Klinik III für Innere Medizin der Universität zu Köln, Germany.
Cardiovasc Res. 1998 Oct;40(1):146-55. doi: 10.1016/s0008-6363(98)00099-6.
Treatment with the beta-blocker carvedilol leads to an improvement of outcome and ejection fraction in heart failure. These effects occur without affecting the number of beta-adrenergic receptors, as determined in right ventricular biopsies from patients with heart failure. This study was aimed at investigating the effects of carvedilol on beta-adrenergic signal transduction alterations in a model of left ventricular pressure overload, which is characterized by sympathetic activation and a desensitized beta-adrenergic signal transduction.
Transgenic rats with overexpression of renin [TG(mREN2)27] were treated with carvedilol (30 micrograms/kg) or held under control conditions and were compared with Sprague-Dawley rats. Myocardial beta-adrenoceptors (125I-labeled iodocyanopindolol binding), Gi alpha (pertussis toxin labeling), Gs alpha-activity (reconstitution into cyc--S49 membranes) and adenylyl cyclase activity were measured. Blood pressure and heart rate, increase in heart rate during sacrifice and pressure rate products were determined.
beta-Adrenoceptors were downregulated and Gi alpha-protein levels were significantly increased, producing a desensitization of basal, isoprenaline- and guanine nucleotide-stimulated adenylyl cyclase activity compared to controls. Carvedilol reduced heart rate, blood pressure and pressure rate product in TG(mREN2)27. Carvedilol did not restore biochemical alterations, but even further reduced beta-adrenoceptor numbers and adenylyl cyclase. It exhibited a two affinity state, guanine nucleotide-sensitive binding to cardiac beta-adrenergic receptors similar to isoprenaline but different from metoprolol.
Carvedilol did not restore beta-adrenergic signal transduction at concentrations producing antiadrenergic effects in vivo. This effect might be due to an atypical guanine nucleotide-dependent interaction with beta-adrenergic receptors. Thus, ancillary properties could explain the recently reported beneficial effects in patients with heart failure independent from an upregulation of beta-adrenergic receptors.
使用β受体阻滞剂卡维地洛治疗可改善心力衰竭患者的预后及射血分数。正如在心力衰竭患者右心室活检中所确定的那样，这些作用的发生并未影响β肾上腺素能受体的数量。本研究旨在调查卡维地洛对左心室压力超负荷模型中β肾上腺素能信号转导改变的影响，该模型的特征为交感神经激活及β肾上腺素能信号转导脱敏。
将肾素过表达的转基因大鼠[TG(mREN2)27]用卡维地洛（30微克/千克）治疗或维持在对照条件下，并与Sprague-Dawley大鼠进行比较。测量心肌β肾上腺素能受体（125I标记的碘氰吲哚洛尔结合）、Giα（百日咳毒素标记）、Gsα活性（重组到cyc--S49膜中）及腺苷酸环化酶活性。测定血压、心率、处死期间心率增加及压力心率乘积。
与对照组相比，β肾上腺素能受体下调，Giα蛋白水平显著升高，导致基础、异丙肾上腺素及鸟嘌呤核苷酸刺激的腺苷酸环化酶活性脱敏。卡维地洛降低了TG(mREN2)27大鼠的心率、血压及压力心率乘积。卡维地洛并未恢复生化改变，反而进一步减少了β肾上腺素能受体数量及腺苷酸环化酶。它表现出两种亲和力状态，与异丙肾上腺素类似但与美托洛尔不同，对心脏β肾上腺素能受体具有鸟嘌呤核苷酸敏感性结合。
在体内产生抗肾上腺素能作用的浓度下，卡维地洛并未恢复β肾上腺素能信号转导。这种作用可能是由于与β肾上腺素能受体的非典型鸟嘌呤核苷酸依赖性相互作用。因此，辅助特性可以解释最近报道的卡维地洛在心力衰竭患者中独立于β肾上腺素能受体上调的有益作用。
