Mitrovic Veselin, Seferovic Petar, Dodic Slobodan, Krotin Mirjana, Neskovic Aleksander, Dickstein Kenneth, de Voogd Hanka, Böcker Christiane, Ziegler Dieter, Godes Michael, Nakov Roumen, Essers Hans, Verboom Cees, Hocher Berthold
Kerckhoff-Klinik, Department of Cardiology and Cardiosurgery, Bad Nauheim, Germany.
Circ Heart Fail. 2009 Nov;2(6):523-31. doi: 10.1161/CIRCHEARTFAILURE.108.798389. Epub 2009 Sep 24.
Blocking the tubuloglomerular feedback mechanism with adenosine A1 receptor antagonists seems to improve diuresis and sodium excretion without compromising the glomerular filtration rate in patients with heart failure. However, the direct cardiac effects of this compound class have not been investigated to date.
In total, 111 patients (109 men and 2 women) received a 1-hour infusion of 5, 10, and 15 mg SLV320, an adenosine A1 receptor antagonist, placebo, or 40 mg furosemide. Mean age was 57.9 years, mean ejection fraction was 28.1%, 82 patients were of New York Heart Association class II, and 29 patients were of New York Heart Association class III. Hemodynamic parameters (heart rate, blood pressure, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, systemic vascular resistance, right atrial pressure, and cardiac output) were determined. Kidney function was assessed by cystatin C measurements and by analysis of urine output and urine electrolytes. In addition, pharmacokinetics of SLV320 and ex vivo inhibition of adenosine A1 receptor activity were performed. SLV320 was well tolerated, and no serious adverse events were observed. Heart rate, blood pressure, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, right atrial pressure, and cardiac output were not altered by any dose of SLV320. Pulmonary capillary wedge pressure was significantly (P=0.04) decreased by furosemide (-6.2+/-5.9 mm Hg). Systemic vascular resistance was significantly (P=0.04) increased in the furosemide group (+166.70+/-261.87 dynes . s(-1) . cm(-5)), whereas all SLV320 groups showed no significant alterations of systemic vascular resistance. Changes from baseline cystatin C plasma concentrations decreased after 10 mg SLV320 (-0.093+/-0.137 mg/L, P=0.046), whereas furosemide resulted in a significant (P=0.03) increase of cystatin C (+0.052+/-0.065 mg/L) versus baseline. All values represent mean changes+/-SD from baseline at 3 hours postdosing: SLV320 (10 and 15 mg) increased significantly sodium excretion and diuresis compared with placebo during the 0- to 6-hour collection period postdosing.
SLV320 infusion shows no immediate effects on cardiac hemodynamics. SLV320 might improve glomerular filtration rate while simultaneously promoting natriuresis and diuresis. Clinical Trial Registration- clinicaltrials.gov Indentifier: NCT00160134.
对于心力衰竭患者，使用腺苷A1受体拮抗剂阻断肾小管球反馈机制似乎可改善利尿和钠排泄，且不影响肾小球滤过率。然而，这类化合物对心脏的直接作用迄今尚未得到研究。
总共111例患者（109例男性和2例女性）接受了1小时的5毫克、10毫克和15毫克SLV320（一种腺苷A1受体拮抗剂）、安慰剂或40毫克呋塞米静脉输注。平均年龄为57.9岁，平均射血分数为28.1%，82例患者为纽约心脏协会II级，29例患者为纽约心脏协会III级。测定血流动力学参数（心率、血压、肺毛细血管楔压、平均肺动脉压、全身血管阻力、右心房压和心输出量）。通过胱抑素C测量以及尿量和尿电解质分析评估肾功能。此外，还进行了SLV320的药代动力学和腺苷A1受体活性的体外抑制实验。SLV320耐受性良好，未观察到严重不良事件。任何剂量的SLV320均未改变心率、血压、肺毛细血管楔压、平均肺动脉压、右心房压和心输出量。呋塞米使肺毛细血管楔压显著降低（P = 0.04）（-6.2±5.9毫米汞柱）。呋塞米组全身血管阻力显著增加（P = 0.04）（+166.70±261.87达因·秒-1·厘米-5），而所有SLV320组全身血管阻力均无显著变化。10毫克SLV320后，胱抑素C血浆浓度相对于基线的变化降低（-0.093±0.137毫克/升，P = 0.046），而呋塞米导致胱抑素C相对于基线显著增加（P = 0.03）（+0.052±0.065毫克/升）。所有数值均代表给药后3小时相对于基线的平均变化±标准差：在给药后0至6小时收集期内，与安慰剂相比，SLV320（10毫克和15毫克）显著增加了钠排泄和尿量。
输注SLV320对心脏血流动力学无即时影响。SLV320可能在促进尿钠排泄和利尿的同时改善肾小球滤过率。临床试验注册 - clinicaltrials.gov标识符：NCT00160134。
