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vol.29 número2Efectividad del uso combinado de un inhibidor de Rho Kinasa y de un antagonista del receptor de angiotensina II en la prevención de hipertrofia ventricular en ratas hipertensas índice de autoresíndice de materiabúsqueda de artículos
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Revista chilena de cardiología

versión On-line ISSN 0718-8560

Resumen

JALIL, Jorge; NOVOA, Ulises; MORA, Italo  y  OCARANZA, María Paz. Vascular gene overexpression of NADPH oxydase in experimental hypertension is only reduced by direct Rho kinase inhibition. Rev Chil Cardiol [online]. 2010, vol.29, n.2, pp.233-241. ISSN 0718-8560.  http://dx.doi.org/10.4067/S0718-85602010000200009.

Background: Rho kinase (ROCK) activity promotes vasoconstriction and pathological vascular remodeling in experimental hypertension. Our working hypothesis is that ROCK inhibition could be an attractive target to prevent vascular remodeling in hypertension. Objectives: We evaluated vascular TGF beta, the genic expression of NADPH oxydase (a vascular oxidative stress source) and its dependency from ROCK activation in experimental hypertension in the rat. Methods: Five experimental groups were compared. Hypertension was induced by the administration of salt and deoxycorticosterone acetate (DOCA, 100 mg/Kg, weekly) to unilaterally nephrectomized rats. Unilaterally nephrectomized rats were used as controls (controls). DOCA rats were randomized to receive either Fasudil (a ROCK inhibitor, 50 mg/Kg/day) or candesartan (CAND, 10 mg/Kg/day for 3 weeks), starting 3 weeks after surgery. The other group received fasudil (25 mg/Kg/day) plus CAND (5 mg/Kg/day) for 3 weeks. After treatment, phosphorilated MYPT1 (a ROCK target expressing ROCK activation) was measured in aortic wall rings by Western Blot. We also determined TGF-beta (Western Blot), p22 Phox and gp 91subnits of NADPH oxydase mRNA (RT-PCR) and the number of ED1 infammatory cells. Results: In DOCA rats, SBP increased to 172 ± 7 mm Hg (p < 0,05), and returned to normal values after 3 weeks with candesartan, fasudil or both combined. In these rats, ROCK activity in aorta was increased 4 times (p < 0,05) and returned to control values in the 3 groups receiving treatment. p22 Phox and gp 91subnits of NADPH oxydase mRNA were increased by 80 and 90%, respectively (p<0,05). These changes were reduced to control values in rats receiving fasudil and candesartan + fasudil. Gene expression of TGF-beta increased 4 times, and the number of ED1 cells increased 6 times in the DOCA rats and returned to normal values in the groups treated with fasudil or candesartan + fasudil. Conclusion: Antihypertensive treatment was able to prevent infammation and gene over expression of TGF beta at the vascular wall level. NADPH oxydase over-expression was normalized only after the direct inhibition of ROCK by a specifc ROCK inhibitor.

Palabras clave : vascular NADPH oxydase; Rho kinase.

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