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1 Department of Cell Biology and Physiology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
* To whom correspondence should be addressed. E-mail: tresta{at}salud.unm.edu.
Pulmonary vascular smooth muscle (VSM) sensitivity to nitric oxide (NO) is enhanced in pulmonary arteries from rats exposed to chronic hypoxia (CH) compared to controls. Furthermore, in contrast to control arteries, relaxation to NO following CH is not reliant on a decrease in VSM intracellular free calcium ([Ca2+]i). We hypothesized that enhanced NOdependent pulmonary vasodilation following CH is a function of VSM myofilament Ca2+ desensitization via inhibition of the RhoA/Rho kinase (ROK) pathway. To test this hypothesis, we compared the ability of the NO donor, spermine NONOate, to reverse VSM tone generated by UTP; the ROK agonist, sphingosylphosphorylcholine; or the protein kinase C (PKC) activator, phorbol-12-myristate-13-acetate in Ca2+-permeabilized, endothelium-denuded pulmonary arteries (150-300 µm inner diameter) from control and CH (4 wk at 0.5 atm) rats. Arteries were loaded with fura-2AM to continuously monitor VSM [Ca2+]i. We further examined effects of NO on levels of GTP-bound RhoA and ROK membrane translocation as indices of enzyme activity in arteries from each group. We found that spermine NONOate reversed Y-27632-sensitive Ca2+ sensitization and inhibited both RhoA and ROK activity in vessels from CH rats, but not control animals. In contrast, spermine NONOate was without effect on PKC-mediated vasoconstriction in either group. We conclude that CH mediates a shift in NO-signaling to promote pulmonary VSM Ca2+ desensitization through inhibition of RhoA/ROK.
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