title: Involvement of Rho kinase pathway in the mechanism of renal vasoconstriction and cardiac hypertrophy in rats with experimental heart failure.
abstract: Rho-dependent kinases serve as downstream effectors of several vasoconstrictor systems, the activities of which are upregulated in congestive heart failure (CHF). We evaluated renal and cardiac effects of Y-27632, a highly selective Rho kinase inhibitor, in an experimental model of volume-overload CHF. Effects of acute administration of Y-27632 (0.3 mg/kg) on renal hemodynamic and clearance parameters and effects of chronic treatment (10.0 mg.kg(-1).day(-1) for 7 days via osmotic minipumps) on cardiac hypertrophy and cumulative Na+ excretion were studied in male Wistar rats with aortocaval fistula and control rats. The Y-27632-induced decrease in renal vascular resistance (from 40.4 +/- 4.6 to 26.0 +/- 3.1 resistance units, P < 0.01) in CHF rats was associated with a significant increase in total renal blood flow (+34%) and cortical and medullary blood flow (approx +37 and +27%, respectively). These values were significantly higher than those in control rats and occurred despite a decrease in mean arterial pressure (-15 mmHg). Despite the marked renal vasodilatory effect, Y-27632 did not alter glomerular filtration rate and renal Na+ excretion. Chronic administration of Y-27632 did not alter daily or cumulative renal Na+ excretion in CHF rats but was associated with a significant decrease in heart-to-body weight ratio, an index of cardiac hypertrophy: 0.32 +/- 0.007, 0.46 +/- 0.017, and 0.37 +/- 0.006% in control, CHF, and CHF + Y-27632 rats, respectively. The findings suggest that Rho kinase-dependent pathways are involved in the mechanisms of renal vasoconstriction and cardiac hypertrophy in rats with volume-overload heart failure. Selective blockade of these signaling pathways may be considered an additional tool to improve renal perfusion and attenuate cardiac hypertrophy in heart failure.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine, Technion, Isreal Institute of Technology, Haifa, Israel.
authors.forename: Joseph
authors.initials: J
authors.lastname: Winaver
authors.forename: Elena
authors.initials: E
authors.lastname: Ovcharenko
authors.forename: Irit
authors.initials: I
authors.lastname: Rubinstein
authors.forename: Konstantin
authors.initials: K
authors.lastname: Gurbanov
authors.forename: Piero
authors.initials: P
authors.lastname: Pollesello
authors.forename: Bishara
authors.initials: B
authors.lastname: Bishara
authors.forename: Aaron
authors.initials: A
authors.lastname: Hoffman
authors.forename: Zaid
authors.initials: Z
authors.lastname: Abassi
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000503:physiopathology*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000098:blood supply* / Q000503:physiopathology*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D015398:Signal Transduction; D014661:Vasoconstriction; D054460:rho-Associated Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases