Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension
Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension
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DOI：
10.1124/jpet.118.253864
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发表时间：
2019-03-01
影响因子：
3.5
通讯作者：
Iglarz, Marc
中科院分区：
文献类型：
--
作者：
Trensz, Frederic;Bortolamiol, Celine;Iglarz, Marc
内皮素（ET）系统已成为高血压治疗的新靶点，尽管有几种药理学类别，包括肾素血管紧张素系统（RAS）阻滞剂，但医疗需求仍然存在。ET受体拮抗剂已在高血压的临床前模型中证实有效，特别是在低肾素条件下和高血压患者中。我们在两种实验性高血压模型：醋酸脱氧皮质酮（DOCA）-盐大鼠（低肾素模型）和自发性高血压大鼠[（SHR），正常肾素模型]中研究了一种有效的ETA/ETB双重受体拮抗剂aprocitentan（N-[5-（4-溴-苯基）-6-[2-[（5-溴-2-嘧啶基）氧基]乙氧基]-4-嘧啶基]-硫酰胺）对血压（BP）的药理学作用。我们还比较了其与RAS阻断剂（缬沙坦和依那普利）的组合与盐受体拮抗剂螺内酯与相同RAS阻断剂的组合对高血压大鼠血压和肾功能的影响。在清醒的DOCA-盐大鼠中，Aprocitentan在降低BP方面比SHR更有效。在DOCA-盐大鼠中，单次口服给予aprocitentan可诱导剂量依赖性和持久的BP降低，给予aprocitentan 4周可剂量依赖性降低BP（统计学显著性）和肾血管阻力，并降低左心室肥大（不显著）。在DOCA-盐大鼠和SHR中，Aprocitentan与缬沙坦和依那普利在降低BP方面具有协同作用，而螺内酯与这些RAS阻断剂具有相加作用。在限钠和依那普利下的高血压大鼠中，与螺内酯相比，添加丙托西替坦进一步降低血压而不引起肾损害。总之，ETA/ETB受体拮抗剂代表了一种有前途的高血压治疗方法，特别是低肾素特征，并可与RAS阻滞剂联合使用，而不会增加肾损害的风险。
The endothelin (ET) system has emerged as a novel target for hypertension treatment where a medical need persists despite availability of several pharmacological classes, including renin angiotensin system (RAS) blockers. ET receptor antagonism has demonstrated efficacy in preclinical models of hypertension, especially under low-renin conditions and in hypertensive patients. We investigated the pharmacology of aprocitentan (N-[5-(4-bromo-phenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrinnidinyl]-sulfannide), a potent dual ETA/ETB receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: deoxycorticosterone acetate (DOCA)-salt rats (lowrenin model) and spontaneously hypertensive rats [(SHR), normal renin model]. We also compared the effect of its combination with RAS blockers (valsartan and enalapril) with that of the combination of the mineraloreceptor antagonist spironolactone with the same RAS blockers on BP and renal function in hypertensive rats. Aprocitentan was more potent and efficacious in lowering BP in conscious DOCA-salt rats than in SHRs. In DOCA-salt rats, single oral doses of aprocitentan induced a dose-dependent and long-lasting BP decrease and 4-week administration of aprocitentan dose dependently decreased BP (statistically significant) and renal vascular resistance, and reduced left ventricle hypertrophy (nonsignificant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHRs while spironolactone demonstrated additive effects with these RAS blockers. In hypertensive rats under sodium restriction and enalapril, addition of aprocitentan further decreased BP without causing renal impairment, in contrast to spironolactone. In conclusion, ETA/ETB receptor antagonism represents a promising therapeutic approach to hypertension, especially with low-renin characteristics, and could be used in combination with RAS blockers, without increasing the risk of renal impairment.