Azizi Michel, Ménard Joël, Bissery Alvine, Guyene Than-Tam, Bura-Rivière Alessandra
Université Paris Descartes, Faculté de Médecine, Paris, France.
Clin J Am Soc Nephrol. 2007 Sep;2(5):947-55. doi: 10.2215/CJN.00360107. Epub 2007 Aug 8.
An AT1 receptor antagonist induces a counterregulatory renin release whose intensity and duration reflect the magnitude of the renin-angiotensin blockade. We investigated whether a renin inhibitor may neutralize this counterregulation and amplify the effects of AT1 receptor antagonists.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In 12 normotensive male individuals who were on a high-sodium diet, a double-blind, placebo-controlled, randomized, crossover design was used to study the hormonal and BP effects of single oral administrations of 300 mg of the renin inhibitor aliskiren, 320 mg of valsartan, and a combination of these two drugs, each at half dosage (150 mg of aliskiren and 160 mg of valsartan).
Valsartan (320 mg) increased plasma renin activity and angiotensin I and angiotensin II levels, but 300 mg of aliskiren decreased them for 48 h. Aliskiren (300 mg) stimulated immunoreactive renin release more strongly than 320 mg of valsartan, decreased urinary aldosterone excretion for longer than 320 mg of valsartan, and had a similar BP-lowering effect as 320 mg of valsartan. In combination, 150 mg of aliskiren neutralized the valsartan (160 mg)-induced increase in plasma angiotensins for 48 h. The renin and aldosterone effects of the combination of 150 mg of aliskiren and 160 mg of valsartan were similar to those of 300 mg of aliskiren and greater than those of 320 mg of valsartan. When plasma drug concentrations were taken into account, the combination of 150 mg of aliskiren and 160 mg of valsartan had a synergistic effect on renin release. The BP-lowering effect of 150 mg of aliskiren and 160 mg of valsartan was similar to that of 300 mg of aliskiren and 320 mg of valsartan at peak but was more prolonged.
The stronger and longer lasting effects on plasma active renin and urinary aldosterone of aliskiren, alone or in combination, demonstrate a more effective blockade of the renin-angiotensin system than that obtained with 320 mg of valsartan alone.
AT1受体拮抗剂可诱导肾素的代偿性释放，其强度和持续时间反映了肾素 - 血管紧张素阻断的程度。我们研究了肾素抑制剂是否可以抵消这种代偿调节并增强AT1受体拮抗剂的作用。
设计、地点、参与者及测量方法：在12名高钠饮食的正常血压男性个体中，采用双盲、安慰剂对照、随机、交叉设计，研究单次口服300毫克肾素抑制剂阿利吉仑、320毫克缬沙坦以及这两种药物各半量组合（150毫克阿利吉仑和160毫克缬沙坦）对激素和血压的影响。
缬沙坦（320毫克）可提高血浆肾素活性以及血管紧张素I和血管紧张素II水平，但300毫克阿利吉仑可使其在48小时内降低。300毫克阿利吉仑比320毫克缬沙坦更强烈地刺激免疫反应性肾素释放，降低尿醛固酮排泄的时间比320毫克缬沙坦更长，且降压效果与320毫克缬沙坦相似。联合使用时，150毫克阿利吉仑可在48小时内抵消缬沙坦（160毫克）诱导的血浆血管紧张素升高。150毫克阿利吉仑与160毫克缬沙坦联合使用对肾素和醛固酮的作用与300毫克阿利吉仑相似，且大于320毫克缬沙坦。考虑血浆药物浓度时，150毫克阿利吉仑与160毫克缬沙坦联合使用对肾素释放具有协同作用。150毫克阿利吉仑与160毫克缬沙坦的降压效果在峰值时与300毫克阿利吉仑和320毫克缬沙坦相似，但持续时间更长。
阿利吉仑单独或联合使用对血浆活性肾素和尿醛固酮具有更强且更持久的作用，表明其对肾素 - 血管紧张素系统的阻断比单独使用320毫克缬沙坦更有效。
