Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, PR China.
Eur J Pharmacol. 2012 May 15;683(1-3):211-6. doi: 10.1016/j.ejphar.2012.03.010. Epub 2012 Mar 16.
Ranolazine is mainly used to treat patients with chronic stable angina in clinical practice. However, ranolazine does not lower significantly systemic blood pressure. The direct effect of ranolazine on vascular tone remains unknown. In the present study, we investigated the vascular effects and mechanisms of action of ranolazine in isolated rat intrarenal arteries. Rings of intrarenal arteries were mounted in a small vessel myography using two stainless steel wires for the measurement of isometric tension. L-type Ca²⁺ currents were recorded in isolated single renal arterial smooth muscle cells using patch clamp techniques in whole-cell mode. Ranolazine induced concentration-dependent relaxations in rings contracted with phenylephrine, but ranolazine failed to cause any relaxation in rings pre-contracted by U46619, 5-HT or endothelin-1. Ranolazine also induced relaxations in norepinephrine pre-contracted rings. Yohimbine failed to induce relaxation in rings pre-contracted by norepinephrine. Propranolol did not affect ranolazine-induced relaxation but the relaxant effect of ranolazine was much less than that of prazosin. Ranolazine-induced relaxations were slight but significantly attenuated by endothelial denudation. Partial inhibition was observed in endothelium-intact arteries exposed to a combination of iberiotoxin and apamin. Ranolazine at higher concentration (>30 μM) inhibited Ca²⁺-induced contraction in a noncompetitive manner. Ranolazine reduced L-type Ca²⁺ currents at potentials between -30 and 50 mV in isolated renal artery myocytes. Therefore it can be said that ranolazine has significant α₁-adrenergic receptor and weak calcium channel antagonistic effects in rat intrarenal arteries.
雷诺嗪主要用于临床治疗慢性稳定性心绞痛患者。然而，雷诺嗪并不会显著降低全身血压。雷诺嗪对血管张力的直接作用尚不清楚。在本研究中，我们研究了雷诺嗪在分离的大鼠肾内动脉中的血管作用和作用机制。使用两根不锈钢丝在小型血管肌动描记术（myography）中安装肾内动脉环，用于等长张力测量。使用全细胞模式下的膜片钳技术在分离的单个肾动脉平滑肌细胞中记录 L 型 Ca²⁺电流。雷诺嗪在与苯肾上腺素收缩的环中诱导浓度依赖性松弛，但雷诺嗪在由 U46619、5-HT 或内皮素-1 预收缩的环中没有引起任何松弛。雷诺嗪还诱导去甲肾上腺素预收缩的环松弛。育亨宾不能诱导去甲肾上腺素预收缩的环松弛。普萘洛尔对雷诺嗪诱导的松弛没有影响，但雷诺嗪的松弛作用比哌唑嗪小得多。雷诺嗪诱导的松弛作用虽然轻微，但内皮细胞剥脱后明显减弱。在暴露于 Iberiotoxin 和 Apamin 组合的完整内皮动脉中观察到部分抑制。在较高浓度（>30 μM）下，雷诺嗪以非竞争性方式抑制 Ca²⁺诱导的收缩。雷诺嗪在分离的肾动脉心肌细胞中降低了电位在-30 至 50 mV 之间的 L 型 Ca²⁺电流。因此可以说，雷诺嗪在大鼠肾内动脉中具有显著的α₁肾上腺素能受体和较弱的钙通道拮抗作用。
