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Rho GTPases in Lung Physiology and Disease

Effect of changes in pH on wall tension in isolated rat pulmonary artery: role of the RhoA/Rho-kinase pathway

¹Department of Physiology, ²Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research and the ³Dublin Molecular Medicine Centre, University College, Dublin 2, Ireland

Submitted 15 September 2003 ; accepted in final form 28 January 2004

Pulmonary arteries (PA) are resistant to the vasodilator effects of extracellular acidosis in systemic vessels; the mechanism underlying this difference between systemic and pulmonary circulations has not been elucidated. We hypothesized that RhoA/Rho-kinase-mediated Ca²⁺ sensitization pathway played a greater role in tension development in pulmonary than in systemic vascular smooth muscle and that this pathway was insensitive to acidosis. In arterial rings contracted with the ₁-agonist phenylephrine (PE), the Rho-kinase inhibitor Y-27632 (3 µM) induced greater relaxation in precontracted PA rings than in aortic rings. In PA rings stimulated by PE, the activation of RhoA was greater than in aorta. Normocapnic acidosis (NA) induced a smaller relaxation in precontracted PA than in aorta. However, in the presence of nifedipine and thapsigargin, when PE-induced contraction was predominantly mediated by Rho-kinase, the relaxant effect of NA was reduced and similar in both vessel types. Furthermore, in the presence of Y-27632, NA induced a greater relaxation in both PA and aorta, which was similar in both vessels. Finally, in -toxin-permeabilized smooth muscle, PE-induced contraction at constant Ca²⁺ activity was inhibited by Y-27632 and unaffected by acidosis. These results indicate that Ca²⁺ sensitization induced by the RhoA/Rho-kinase pathway played a greater role in agonist-induced vascular smooth muscle contraction in PA than in aorta and that tension mediated by this pathway was insensitive to acidosis. The predominant role of the RhoA/Rho-kinase pathway in the pulmonary vasculature may account for the resistance of this circulation to the vasodilator effect of acidosis observed in the systemic circulation.

vascular smooth muscle; acidosis; RhoA; calcium sensitization; Y-27632

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