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1 Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM, USA
* To whom correspondence should be addressed. E-mail: njernigan{at}salud.unm.edu.
Recent studies from our laboratory indicate that pulmonary vasodilatory responses to exogenous nitric oxide (NO) are attenuated following chronic hypoxia (CH) and that this NO-dependent vasodilation is mediated by cGMP. Similarly, we have demonstrated that CH attenuates vasodilatory responses to the cGMP analog, 8-Br-cGMP. We hypothesized that attenuated pulmonary vasodilation to 8-Br-cGMP following CH is mediated by decreased protein kinase G-1 (PKG-1) expression/activity. Therefore, we examined vasodilatory responses to 8-Br-cGMP (1 µM) in isolated, saline-perfused lungs from normoxic and CH (4 wk at PB=380 mmHg) rats in the presence of the competitive PKG inhibitor Rp-8-Br-PET-cGMPS (30 µM) or the highly specific PKG inhibitor, KT-5823 (10 µM). PKG-1 expression and activity were determined in whole lung homogenates from each group, and vascular PKG-1 levels assessed by quantitative immunohistochemistry. PKG inhibition with either Rp-8-Br-PET-cGMPS or KT-5823 diminished vasodilatory responses to 8-Br-cGMP in lungs from both control and CH rats, thus indicating a role for PKG in mediating reactivity to 8-Br-cGMP in each group. However, in contrast to our hypothesis, PKG-1 levels were approximately 2-fold greater in lungs from CH rats vs. controls and further, this upregulation was localized to the vasculature. This correlates with an increase in PKG activity following CH. We conclude that PKG-1 is involved in 8-Br-cGMP mediated vasodilation, however, attenuated pulmonary vasodilation following CH is not associated with decreased expression/activity of PKG-1.
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