Batenburg Wendy W, van Esch Joep H M, Garrelds Ingrid M, Jorde Ulrich, Lamers Jos M J, Dekkers Dick H W, Walther Thomas, Kellett Elaine, Milligan Graeme, van Kats Jorge P, Danser A H Jan
Department of Pharmacology, The Netherlands.
J Hypertens. 2006 Jul;24(7):1355-63. doi: 10.1097/01.hjh.0000234116.17778.63.
To investigate whether renin-angiotensin system blockade might underlie the favorable metabolic effects of the nonselective beta + alpha1-adrenoceptor blocker carvedilol as compared with the selective beta1-adrenoceptor blocker metoprolol.
Human coronary microarteries (HCMAs), obtained from 32 heart valve donors, were mounted in myographs.
Angiotensin II and the alpha1-adrenoceptor agonist phenylephrine constricted HCMAs to maximally 63 +/- 10 and 46 +/- 15% of the contraction to 100 mmol/l K. Neither carvedilol, metoprolol, the nonselective beta-adrenoceptor antagonist propranolol, nor the alpha1-adrenoceptor antagonist prazosin affected the constrictor response to angiotensin II. alpha1-adrenoreceptors and beta-adrenoceptors are thus not involved in the direct constrictor effects of angiotensin II. When added to the organ bath at a subthreshold concentration, angiotensin II greatly amplified the response to phenylephrine. Both carvedilol and the angiotensin II type 1 (AT1) receptor antagonist irbesartan inhibited this angiotensin II-induced potentiation. Furthermore, carvedilol blocked the angiotensin II-induced amplification of phenylephrine-induced inositol phosphate accumulation in cardiomyocytes.
AT1-alpha1-receptor crosstalk, involving inositol phosphates, sensitizes HCMAs to alpha1-adrenoceptor agonists. Our results suggest that, in the presence of an increased sympathetic tone, carvedilol provides AT1 receptor blockade via its alpha1-adrenoceptor blocking effects. This could explain the favorable effects of carvedilol versus metoprolol.
研究与选择性β1肾上腺素能受体阻滞剂美托洛尔相比，肾素-血管紧张素系统阻断是否是非选择性β+α1肾上腺素能受体阻滞剂卡维地洛产生良好代谢效应的基础。
从32名心脏瓣膜供体获取的人冠状动脉微血管（HCMAs），安装在肌张力测定仪上。
血管紧张素II和α1肾上腺素能受体激动剂去氧肾上腺素使HCMAs收缩至最大为100 mmol/l钾引起收缩的63±10%和46±15%。卡维地洛、美托洛尔、非选择性β肾上腺素能受体拮抗剂普萘洛尔或α1肾上腺素能受体拮抗剂哌唑嗪均不影响对血管紧张素II的收缩反应。因此，α1肾上腺素能受体和β肾上腺素能受体不参与血管紧张素II的直接收缩效应。当以阈下浓度加入器官浴时，血管紧张素II极大地增强了对去氧肾上腺素的反应。卡维地洛和血管紧张素II 1型（AT1）受体拮抗剂厄贝沙坦均抑制这种血管紧张素II诱导的增强作用。此外，卡维地洛阻断了血管紧张素II诱导的心肌细胞中去氧肾上腺素诱导的肌醇磷酸积累的放大。
涉及肌醇磷酸的AT1-α1受体串扰使HCMAs对α1肾上腺素能受体激动剂敏感。我们的结果表明，在交感神经张力增加的情况下，卡维地洛通过其α1肾上腺素能受体阻断作用提供AT1受体阻断。这可以解释卡维地洛与美托洛尔相比的有利作用。
