Dose-dependency of clonidine's effects in ascitic cirrhotic rats: comparison with alpha 1-adrenergic agonist midodrine

摘要

Background & Aims: Sympathetic nervous system (SNS) activation decreases response to diuretics, but both alpha 1-adrenoceptor agonists and sympatholytic alpha 2-adrenoceptor agonists are recommended in the management of ascitic cirrhosis. We intend to compare the effects of increasing doses of clonidine (alpha 2-agonist) vs. midodrine (alpha 1-agonist) in advanced cirrhosis. Methods: Renal function, mean arterial pressure (MAP), and hormonal status were measured in rats with ascitic cirrhosis due to 13-week CCl4 administration (groups G1-G5), in control rats (Gc), and in rats with ascitic cirrhosis untreated (G6) or treated with daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K+-canrenoate during the 11 th-13 th weeks of CCl4) (G7). G1-G5 cirrhotic rats received daily, during the 11th-13th CCl4 weeks: clonidine 0.3 lg only (G1), diuretics + clonidine 0.2 (G2), 0.5 (G3) or 1 mu g (G4), and diuretics + midodrine 1 mg/kg b. w. (G5). Results: Cirrhotic rats in G1 or G2 had higher glomerular filtration rate, renal plasma flow and natriuresis than cirrhotic rats treated with diuretics (G7) (all P < 0.05). The addition of clonidine 0.2 lg to diuretics (G2 vs. G7) reduced serum norepinephrine (169 +/- 71 ng/L vs. 523 +/- 88 ng/L) and plasma renin activity (12 +/- 3 ng/ml/h vs. 25 +/- 5 ng/ml/h) (all P < 0.05). Midodrine did not improve the renal performance in ascitic rats treated with diuretics. In comparison to absolute cirrhotic controls (G6), MAP was lower in G4 and higher in G5 (all P < 0.05). Conclusion: Low-dose alpha 2-agonists improve natriuresis and reduce SNS function and hyper-aldosteronism without affecting arterial pressure in experimental ascitic cirrhosis treated with diuretics.