Decreased Protein Kinase G Activation by Disulfide‐Mediated Subunit Dimerization is Observed when Hypoxia Promotes Contraction of Bovine Pulmonary Arteries

Our laboratory had previously provided evidence that hydrogen peroxide (H 2 O 2 ) stimulates soluble guanylate cyclase under conditions where it relaxes isolated endothelium‐removed bovine pulmonary arteries (BPA), and that hypoxia promotes BPA contraction through suppressing relaxation by endogenous H 2 O 2 . Since it was reported that H 2 O 2 induces coronary relaxation associated with a NO/cGMP‐independent thiol oxidation/subunit dimerization activation of protein kinase G (PKG), we investigated if this mechanism participates in the contraction of BPA to hypoxia. BPA precontracted with 20 mM KCl showed decreased PKG dimerization in arteries exposed to hypoxia (PO 2 ~10 torr) versus BPA contracted under aerobic conditions (21% O 2 ). Hypoxia also promoted decreased phosphorylation of vasodilator‐stimulated phosphoprotein (VASP) at the serine‐239 site known to be mediated by PKG. Treatment of BPA with 1 mM dithiothreitol increased potassium contraction and abolished contraction to hypoxia, under conditions where it prevented PKG dimerization. Interestingly, serotonin was observed to increase PKG dimerization under hypoxic conditions in a manner which may be related to its oxidase activation‐associated promotion of pulmonary artery smooth muscle remodeling. Thus, attenuation of PKG activation by disulfide‐mediated dimerization appears to be a contributing factor to the contraction of BPA by hypoxia.