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This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/H2007    most recent 00600.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Winaver, J. Articles by Abassi, Z. Search for Related Content PubMed PubMed Citation Articles by Winaver, J. Articles by Abassi, Z.

Involvement of Rho kinase pathway in the mechanism of renal vasoconstriction and cardiac hypertrophy in rats with experimental heart failure

¹Department of Physiology and Biophysics, Faculty of Medicine, Technion, Israel Institute of Technology, and ²General Surgery A and ³Vascular Surgery, Rambam Medical Center, Haifa, Israel; and ⁴Cardiovascular Research, Orion Pharma-Orion Corp., Espoo, Finland

Submitted 6 June 2005 ; accepted in final form 12 December 2005

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.

Y-27632; congestive heart failure; renal hemodynamics; kidney