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We hypothesized that enhanced NO-dependent pulmonary vasodilation following CH is a function of VSM myofilament Ca<jats:sup>2+<\/jats:sup> 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 Ca<jats:sup>2+<\/jats:sup>-permeabilized, endothelium-denuded pulmonary arteries (150- to 300-\u03bcm inner diameter) from control and CH (4 wk at 0.5 atm) rats. Arteries were loaded with fura-2 AM to continuously monitor VSM [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>. We further examined effects of NO on levels of GTP-bound RhoA and ROK membrane translocation as indexes of enzyme activity in arteries from each group. We found that spermine NONOate reversed Y-27632-sensitive Ca<jats:sup>2+<\/jats:sup> 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 Ca<jats:sup>2+<\/jats:sup> desensitization through inhibition of RhoA\/ROK. <\/jats:p>","DOI":"10.1152\/ajplung.00196.2004","type":"journal-article","created":{"date-parts":[[2004,8,14]],"date-time":"2004-08-14T01:33:19Z","timestamp":1092447199000},"page":"L1220-L1229","source":"Crossref","is-referenced-by-count":72,"title":["Chronic hypoxia augments protein kinase G-mediated Ca<sup>2+<\/sup> desensitization in pulmonary vascular smooth muscle through inhibition of RhoA\/Rho kinase signaling"],"prefix":"10.1152","volume":"287","author":[{"given":"Nikki L.","family":"Jernigan","sequence":"first","affiliation":[{"name":"Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-0001"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjimen R.","family":"Walker","sequence":"additional","affiliation":[{"name":"Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-0001"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Resta","sequence":"additional","affiliation":[{"name":"Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-0001"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000111804.34509.94"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000074202.19612.8C"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(92)90148-C"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1002\/1097-4652(200009)184:3<409::AID-JCP16>3.0.CO;2-K"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103206200"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1186\/rr74"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00090.2003"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.274.2.H672"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.171299298"},{"key":"R10","doi-asserted-by":"crossref","unstructured":"Gopalakrishna R, Chen ZH, and Gundimeda U. 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