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1 Department of Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
2 Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland; Dublin Molecular Medicine Centre, Dublin, Ireland
3 Department of Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland; Dublin Molecular Medicine Centre, Dublin, Ireland
* To whom correspondence should be addressed. E-mail: paul.mcloughlin{at}ucd.ie.
Pulmonary arteries (PA) are resistant to the vasodilator effects of extracellular acidosis observed in systemic vessels; the mechanism underlying this difference between the systemic and pulmonary circulations has not previously 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 (up to 3µM) induced a greater relaxation in precontracted PA rings than in aortic rings. In PA rings stimulated by PE, the activation of RhoA was greater than in the aorta. Normocapnic acidosis (NA) induced a smaller relaxation in pre-contracted PA than in aorta. However, in the presence of nifedipine and thapsigargin, when phenylephrine-induced contraction was predominantly mediated by Rho-kinase, the relaxant effect of NA was reduced and similar in both vessel types. Furthermore in presence of Y-27632, NA induced a greater relaxation in both PA and aorta, which was then similar in both vessels. Finally, in -toxin permeabilised 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 the PA than in the 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.
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