Background and purpose: Myocardial fibrosis is an unwanted effect associated with chronic renal failure. The adenosine system is involved in cardiac and renal function. Therefore, we investigated the novel selective adenosine A 1 receptor antagonist SLV320 focusing on its potential in preventing cardiomyopathy in rats with 5/6 nephrectomy. Experimental approach: Male Sprague-Dawley rats were allocated to 4 groups of 12 rats each: 5/6 nephrectomy (5/6 NX), 5/6 NX plus SLV320 (10 mg kg À1 d À1 mixed with food), sham and sham plus SLV320. Study duration was 12 weeks, blood pressure was assessed repeatedly. At study end kidney function was assessed, blood samples and hearts were taken for histology/immunohistochemistry. Pharmacological properties of SLV320 were assessed using receptor binding and enzyme assays and in vivo. Key results: SLV320 is a selective and potent adenosine A 1 antagonist in vitro (Ki ¼ 1 nM) with a selectivity factor of at least 200 versus other adenosine receptor subtypes. Functional A 1 antagonism was demonstrated in vivo. In rats with 5/6 NX SLV320 significantly decreased albuminuria by about 50%, but did not alter glomerular filtration rate (GFR). SLV320 normalized cardiac collagen I þ III contents in 5/6 NX rats. SLV320 prevented nephrectomy-dependent rise in plasma levels of creatinine kinase (CK), ALT and AST. Blood pressure did not differ between study groups. Conclusion: SLV320 suppresses cardiac fibrosis and attenuates albuminuria without affecting blood pressure in rats with 5/6 nephrectomy, indicating that selective A 1 receptor antagonists may be beneficial in uraemic cardiomyopathy.
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. Methods and 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 (Pϭ0.04) decreased by furosemide (Ϫ6.2Ϯ5.9 mm Hg). Systemic vascular resistance was significantly (Pϭ0.04) increased in the furosemide group (ϩ166.70Ϯ261.87 dynes ⅐ s Ϫ1 ⅐ cm
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