Rademaker Miriam T, Charles Christopher J, Nicholls M Gary, Richards A Mark
Christchurch Cardioendocrine Research Group, Christchurch School of Medicine, Christchurch, New Zealand.
Circ Heart Fail. 2009 Nov;2(6):532-40. doi: 10.1161/CIRCHEARTFAILURE.109.861336. Epub 2009 Sep 22.
Urocortin 2 (Ucn2), a novel peptide with therapeutic potential in heart failure, and diuretics have opposing effects on renal function and the renin-angiotensin-aldosterone system. Because any prospective new treatment is likely to be used in conjunction with standard diuretic therapy, it is necessary to investigate the combined effects of these agents.
Ucn2 and furosemide were administered for 3 hours, both singly and combined, in 7 sheep with pacing-induced heart failure. Compared with time-matched controls, separate Ucn2 and furosemide administration significantly increased urine output (furosemide>Ucn2), urine sodium (furosemide>Ucn2), potassium (furosemide>Ucn2), and creatinine excretion (Ucn2>furosemide) and creatinine clearance (Ucn2>furosemide). Compared with furosemide treatment alone, Ucn2+furosemide produced a further diuresis (P<0.05), natriuresis (P<0.05), and a sustained increase in creatinine excretion (P<0.05) and clearance (P<0.05), without additional potassium elimination. All active treatments reduced mean arterial pressure (Ucn2+furosemide=furosemide>Ucn2), left atrial pressure (Ucn2+furosemide>Ucn2>furosemide), and peripheral resistance (Ucn2+furosemide=Ucn2>furosemide), whereas only Ucn2, singly and in combination with furosemide, increased cardiac output and dP/dt(max). In contrast to the increase in plasma renin activity elicited by furosemide alone, Ucn2 and Ucn2+furosemide markedly reduced plasma renin activity. All active treatments decreased plasma aldosterone (Ucn2+furosemide=Ucn2>furosemide), whereas only Ucn2 and Ucn2+furosemide reduced vasopressin and natriuretic peptide concentrations.
Ucn2 cotreatment with furosemide enhanced hemodynamic and renal function and diuretic responsiveness (without additional potassium depletion) in experimental heart failure. Furthermore, Ucn2 reversed furosemide-induced increases in plasma renin activity and induced greater decreases in plasma aldosterone and vasopressin. These data indicate that adjunct Ucn2 therapy with diuretics in heart failure is beneficial.
尿皮质素2（Ucn2）是一种在心力衰竭治疗中具有潜在治疗价值的新型肽，与利尿剂对肾功能及肾素-血管紧张素-醛固酮系统具有相反的作用。由于任何一种潜在的新治疗方法都可能与标准利尿剂疗法联合使用，因此有必要研究这些药物的联合作用。
对7只因起搏诱发心力衰竭的绵羊单独及联合给予Ucn2和呋塞米3小时。与时间匹配的对照组相比，单独给予Ucn2和呋塞米均显著增加尿量（呋塞米>Ucn2）、尿钠（呋塞米>Ucn2）、钾（呋塞米>Ucn2）以及肌酐排泄量（Ucn2>呋塞米）和肌酐清除率（Ucn2>呋塞米）。与单独使用呋塞米治疗相比，Ucn2+呋塞米产生了进一步的利尿作用（P<0.05）、利钠作用（P<0.05），并使肌酐排泄量（P<0.05）和清除率（P<0.05）持续增加，且无额外的钾排泄。所有活性治疗均降低了平均动脉压（Ucn2+呋塞米=呋塞米>Ucn2）、左心房压（Ucn2+呋塞米>Ucn2>呋塞米）和外周阻力（Ucn2+呋塞米=Ucn2>呋塞米），而只有Ucn2单独及与呋塞米联合使用时增加了心输出量和dP/dt(max)。与单独使用呋塞米引起的血浆肾素活性增加相反，Ucn2和Ucn2+呋塞米显著降低了血浆肾素活性。所有活性治疗均降低了血浆醛固酮（Ucn2+呋塞米=Ucn2>呋塞米），而只有Ucn2和Ucn2+呋塞米降低了血管加压素和利钠肽浓度。
在实验性心力衰竭中，Ucn2与呋塞米联合治疗可增强血流动力学和肾功能以及利尿反应性（无额外的钾消耗）。此外，Ucn2可逆转呋塞米引起的血浆肾素活性增加，并使血浆醛固酮和血管加压素的降低幅度更大。这些数据表明，在心力衰竭中Ucn2与利尿剂联合治疗是有益的。
