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Chronic hypoxia attenuates cGMP-dependent pulmonary vasodilation
Nikki L Jernigan1, Thomas C Resta
1Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-5218, USA. njernigan@salud.unm.edu
Summary
Chronic hypoxia reduces nitric oxide (NO) vasodilation in female rats by increasing cGMP breakdown and decreasing vascular smooth muscle sensitivity to cGMP, not by altering soluble guanylyl cyclase levels.
Area of Science:
- Physiology
- Cardiovascular Research
- Pulmonary Hypertension
Background:
- Chronic hypoxia (CH) typically enhances nitric oxide (NO)-mediated pulmonary vasodilation.
- However, studies show reduced responses to external NO in female rats after CH.
- This suggests underlying mechanisms affecting the NO-cGMP pathway.
Purpose of the Study:
- To investigate the mechanisms behind the attenuated NO-dependent pulmonary vasodilation in female rats following CH.
- To test the hypothesis involving soluble guanylyl cyclase (sGC) activity, phosphodiesterase type 5 (PDE5) degradation, or vascular smooth muscle (VSM) cGMP sensitivity.
Main Methods:
- Isolated, saline-perfused lungs from CH and normoxic female rats were used.
- Vasodilatory responses to NO donors and dissolved NO were measured.
- sGC expression and activity were assessed via Western blotting and cGMP radioimmunoassay.
- Effects of PDE5 inhibitors (dipyridamole, T-1032) and 8-bromoguanosine 3'5'-cyclic monophosphate were evaluated.
Main Results:
- CH rats showed attenuated vasodilation to NO donors and dissolved NO compared to normoxic rats.
- Pulmonary sGC expression and activity were not decreased in CH rats.
- Selective PDE5 inhibitors enhanced NO-dependent reactivity in CH lungs but did not fully restore vasodilation.
- CH similarly inhibited responses to 8-bromoguanosine 3'5'-cyclic monophosphate.
Conclusions:
- Attenuated NO-dependent pulmonary vasodilation in CH is not due to reduced sGC expression.
- Increased cGMP degradation by PDE5 and decreased VSM sensitivity to cGMP are the likely mechanisms.
- These findings highlight altered cGMP signaling in pulmonary vascular adaptation to chronic hypoxia in females.