title: Dose-dependency of clonidine's effects in ascitic cirrhotic rats: comparison with α1-adrenergic agonist midodrine.
abstract: OBJECTIVE
  Sympathetic nervous system (SNS) activation decreases response to diuretics, but both α1-adrenoceptor agonists and sympatholytic α2-adrenoceptor agonists are recommended in the management of ascitic cirrhosis. We intend to compare the effects of increasing doses of clonidine (α2-agonist) vs. midodrine (α1-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 CCl(4) 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 CCl(4)) (G7). G1-G5 cirrhotic rats received daily, during the 11(th)-13(th) CCl(4) weeks: clonidine 0.3 μg only (G1), diuretics + clonidine 0.2 (G2), 0.5 (G3) or 1 μg (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 μg 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).
  
  
  CONCLUSIONS
  Low-dose α2-agonists improve natriuresis and reduce SNS function and hyper-aldosteronism without affecting arterial pressure in experimental ascitic cirrhosis treated with diuretics.
authors.affiliation: Division of Gastroenterology, Gradenigo Hospital, Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sansoè
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
authors.affiliation: Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Torino, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D001201:Ascites / Q000209:etiology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000008:administration & dosage / Q000009:adverse effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology; D008879:Midodrine / Q000008:administration & dosage / Q000009:adverse effects; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D012083:Renin / Q000097:blood; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D008879:Midodrine; D012083:Renin; D003000:Clonidine; D009638:Norepinephrine
keywords: ascites; cirrhosis complications; experimental cirrhosis; α-adrenoceptor agonists