Cardio-renal effects of the A1 adenosine receptor antagonist SLV320 in patients with heart failure.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Mitrovic
Veselin
V
Kerckhoff-Klinik, Department of Cardiology and Cardiosurgery, Bad Nauheim, Germany.
Seferovic
Petar
P
Dodic
Slobodan
S
Krotin
Mirjana
M
Neskovic
Aleksander
A
Dickstein
Kenneth
K
de Voogd
Hanka
H
Böcker
Christiane
C
Ziegler
Dieter
D
Godes
Michael
M
Nakov
Roumen
R
Essers
Hans
H
Verboom
Cees
C
Hocher
Berthold
B
D058916:Adenosine A1 Receptor Antagonists; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003510:Cyclohexanes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D005665:Furosemide / Q000627:therapeutic use; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D009318:Natriuresis / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects*
D058916:Adenosine A1 Receptor Antagonists; D002317:Cardiovascular Agents; D003510:Cyclohexanes; D004232:Diuretics; D006574:Heterocyclic Compounds, 2-Ring; D043682:Receptor, Adenosine A1; C523961:SLV320 compound; D005665:Furosemide