Concomitant Angiotensin AT1 Receptor Antagonism and Neprilysin Inhibition Produces Omapatrilat-like Antihypertensive Effects Without Promoting Tracheal Plasma Extravasation in the Rat
Concomitant Angiotensin AT1 Receptor Antagonism and Neprilysin Inhibition Produces Omapatrilat-like Antihypertensive Effects Without Promoting Tracheal Plasma Extravasation in the Rat
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DOI：
10.1097/fjc.0b013e318210fc7e
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发表时间：
2011-04-01
影响因子：
3
通讯作者：
Hegde, Sharath S.
中科院分区：
文献类型：
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作者：
Hegde, Laxminarayan G.;Yu, Cecile;Hegde, Sharath S.
奥马曲拉等药物对血管紧张素转换酶（ACE）和脑啡肽酶（NEP）的双重抑制可产生上级抗高血压疗效，但会导致血管性水肿的高发生率。我们研究了双重抑制血管紧张素AT（1）受体（ARB）和NEP（ARB-NEPI，缬沙坦-坎多沙曲）是否提供了与奥马曲拉相似的疗效，而没有血管性水肿的风险。使用基于荧光的酶测定法（ACE、NEP、氨肽酶P）或竞争结合测定法（AT（1））测定测试化合物对靶的活性。通过测量大鼠血管紧张素-升压反应的抑制和心房利钠肽诱导的尿环磷酸鸟苷（cGMP）输出的增强来定量体内靶点（ACE，AT（1，）和NEP）的参与。使用气管血浆外渗（TPE）作为替代，以评估化合物促进上呼吸道血管性水肿的倾向。分别在自发性高血压大鼠和脱氧皮质酮醋酸盐高血压大鼠中测定了肾素依赖性和非依赖性状态下的降压疗效。施用omapatrilat和联合施用缬沙坦和坎多曲阻断血管紧张素诱导的血管加压反应和增强心房利钠肽诱导的尿cGMP输出增加。在自发性高血压大鼠中，缬沙坦、omapatrilat和缬沙坦-坎沙曲联合用药均能降低血压至相似程度，而坎沙曲无效。在醋酸去氧皮质酮大鼠中，奥马曲拉、坎多沙三和缬沙坦-坎多沙三联合用药可降低血压，但缬沙坦不能。抗高血压剂量的omapatrilat可显著增加TPE;相比之下，缬沙坦、坎沙曲或其联合用药不会增加TPE。用缓激肽B2拮抗剂艾替班特预处理可消除omapatrilat诱导的TPE，但不能消除其抗高血压作用。在NEP抑制的背景下，通过ARB和ACE抑制对肾素-血管紧张素系统的抑制显示出相似的降压疗效，但对缓激肽代谢和TPE产生不同的影响，表明血管性水肿的风险降低。因此，双重AT（1）受体阻滞剂和NEP抑制剂是一种潜在的有吸引力的方法，可以保留奥马曲拉的优良抗高血压作用，但具有上级安全性。
Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy but cause high incidence of angioedema. We examined whether dual inhibition of angiotensin AT(1) receptor (ARB) and NEP (ARB-NEPI, valsartan-candoxatril) provides similar efficacy to omapatrilat without the risk of angioedema. Activity of test compounds at the targets was assayed using fluorescence-based enzyme assays (ACE, NEP, aminopeptidase P) or competition binding assays (AT(1)). Target engagement in vivo (ACE, AT(1,) and NEP) was quantified by measuring inhibition of angiotensin-pressor responses and potentiation of atrial natriuretic peptide-induced urinary cyclic guanosine monophosphate (cGMP) output in rats. Tracheal plasma extravasation (TPE) was used as a surrogate to assess propensity of compounds to promote upper airway angioedema. Antihypertensive efficacy in renin-dependent and -independent states was measured in spontaneously hypertensive rats and deoxycorticosterone acetate salt hypertensive rats, respectively. Administration of omapatrilat and coadministration of valsartan and candoxatril blocked angiotensin induced vasopressor responses and potentiated atrial natriuretic peptide-induced increase in urinary cGMP output. In spontaneously hypertensive rats, valsartan, omapatrilat, and valsartan-candoxatril combination all produced reduction in blood pressure to a similar extent, whereas candoxatril was ineffective. In deoxycorticosterone acetate rats, omapatrilat, candoxatril, and valsartan-candoxatril combination but not valsartan produced reduction in blood pressure. Antihypertensive doses of omapatrilat produced robust increases in TPE; by contrast, valsartan, candoxatril, or their combination did not increase TPE. Pretreatment with icatibant, a bradykinin B2 antagonist, abolished omapatrilat-induced TPE but not its antihypertensive effects. On the background of NEP inhibition, suppression of the renin-angiotensin system through ARB and ACE inhibition shows a similar antihypertensive efficacy but exerts differential effects on bradykinin metabolism and TPE indicative of reduced risk of angioedema. Thus, dual AT(1) receptor blockade and NEP inhibition is potentially an attractive approach to retain the excellent antihypertensive effects of omapatrilat but with a superior safety profile.