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Articles in PresS, published online ahead of print January 18, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00273.2001
Submitted on July 19, 2001
Accepted on January 16, 2002
1 Cell Biology and Physiology, University of New Mexico, Albuquerque, NM, USA
* To whom correspondence should be addressed. E-mail: tresta{at}salud.unm.edu.
Chronic hypoxia (CH) augments endothelium-derived nitric oxide-dependent pulmonary vasodilation, however, responses to exogenous nitric oxide (NO) are reduced following CH in female rats. We hypothesized that CH-induced attenuation of NO-dependent pulmonary vasodilation is mediated by downregulation of vascular smooth muscle (VSM) soluble guanylyl cyclase (sGC) expression and/or activity, increased cGMP degradation by phosphodiesterase type 5 (PDE-5), or decreased VSM sensitivity to cGMP. Experiments demonstrated attenuated vasodilatory responsiveness to the NO donors S-nitroso-N-acetyl penicillamine (SNAP) and spermine NONOate and to arterial boluses of dissolved NO solutions in isolated, saline-perfused lungs from CH vs. normoxic female rats. In additional experiments, the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-
]quinoxalin-1-one (ODQ), blocked vasodilation to NO donors in lungs from each group. However, CH was not associated with decreased pulmonary sGC expression or activity as assessed by Western blotting and cGMP radioimmunoassay, respectively. Consistent with our hypothesis, the selective PDE-5 inhibitors, dipyridamole and T-1032, augmented NO-dependent reactivity in lungs from CH rats, while having little effect in lungs from normoxic rats. However, the attenuated vasodilatory response to NO in CH lungs persisted following PDE-5 inhibition. Furthermore, CH similarly inhibited vasodilatory responses to 8-Br-cGMP. We conclude that attenuated NO-dependent pulmonary vasodilation following CH is not likely mediated by decreased sGC expression, but rather, to increased cGMP degradation by PDE-5 and decreased pulmonary VSM reactivity to cGMP.
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