on September 24, 2009
Published online before print September 24, 2009, doi: 10.1161/CIRCHEARTFAILURE.108.798389
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Original Article |
Cardio-Renal Effects of the A1 Adenosine Receptor Antagonist SLV320 in Patients with Heart Failure
1 Kerckhoff-Klinik, Bad Nauheim, Germany;
2 IKlinicki Center Serbia, Belgrad, Serbia;
3 University Novi Sad, Sremska Kamenica, Serbia;
4 Clinical Centre Bezanijska Kosa, Zemum, Serbia;
5 Dedinje Cardiovascular Institute Milana Tepica 1, Belgrade, Serbia;
6 Stavanger Universitetssykehus, Stavanger, Norway;
7 Solvay Pharmaceuticals Research Laboratories, Hannover, Germany and Weesp, The Netherlands;
8 Charité, Berlin, Germany;
9 Solvay Pharma. Research Lab., Hannover, Germany;Weesp, Netherlands; Charité, Berlin, Germany
htthttp://www.ccr.charite.de/site/html/de/ag_hocher.htmlp://
* Corresponding author; email: berthold.hocher{at}charite.de
Background—Blocking the tubuloglomerular feedback mechanism with adenosine A1 receptor antagonists seems to improve diuresis and sodium excretion without compromising glomerular filtration rate in heart failure patients. However, direct cardiac effects of this compound class were not investigated so far.
Methods and Results—In total 111 patients (109 male/2 female) received a one-hour infusion of 5, 10, 15 mg SLV320, an adenosine A1 receptor antagonist, placebo or 40 mg furosemide, respectively. Mean age was 57.9 years, mean ejection fraction was 28.1%, Eighty-two patients were of NYHA class II, twenty-nine patients were of NYHA class III. Hemodynamic parameters (heart rate, blood pressure, PCWP, MPAP, SVR, RAP, and CO) were determined. Kidney function was assessed by cystatin C measurements, analysis of urine output and urine electrolytes. In addition, pharmacokinetics of SLV320 and ex vivo inhibition of adenosine A1 receptor activity was performed. SLV320 was well tolerated, no serious adverse events were observed. Heart rate, blood pressure, PCWP, MPAP, RAP, and CO was not altered by any dose of SLV320. PCWP was significantly (p=0.04) decreased by furosemide (-6.2±5.9 mmHg). SVR was significantly (p=0.04) increased in the furosemide group (+166.70±261.87 dynes/sec*cm-5), whereas all SLV320 groups showed no significant alterations of SVR. 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 significantly (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 post doing:SLV320 (10 mg and 15 mg) increased significantly sodium excretion and diuresis as compared to placebo during the 0 - 6 hours collection period post dosing.
Conclusions—SLV320 infusion shows no immediate effects on cardiac hemodynamics. SLV320 might improve glomerular filtration rate while simultaneously promoting natriuresis and diuresis.
Key Words: adenosine • diuretics • heart failure • kidney • cardio-renal syndrome
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