Chronic Hypoxia Attenuates cGMP‐dependent protein kinase (PKG)‐Mediated Vasorelaxation by Depressing BK Potassium Channel Activity in Cerebral Arteries

Abstract

OBJECTIVEChronic hypoxia attenuates the ability of PKG to induce vasorelaxation in serotonin‐contracted ovine carotids, and more so in fetal than adult arteries. The present investigation examines the hypothesis that alterations in the BK channel and other PKG kinase substrates contribute to hypoxic attenuation of PKG‐dependent vasorelaxation in term fetal and adult ovine cerebral arteries.METHODSAdult and fetal sheep were maintained under normoxic (140±2 days at sea level) or hypoxic (140±2 days at 3820 meters elevation) conditions. PKG‐induced vasorelaxation was quantified by measuring changes in contractile force of middle cerebral artery segments using graded doses of serotonin in the presence or absence of the BK channel inhibitor iberiotoxin (100 nM) and/or the PKG activator 8‐pCPT‐cGMP (30 μM).RESULTSTotal PKG‐induced vasorelaxation was significantly less in hypoxic (8.9% fetal, 8.1% adult) than in normoxic (33.3% fetal, 26.3% adult) cerebral arteries. Corresponding values for BK‐independent PKG‐induced vasorelaxation were also less in hypoxic (6.3% fetal, 10.0% adult) than normoxic (28.7% fetal, 18.2% adult) cerebral arteries. For BK‐dependent PKG‐induced vasorelaxation, these values again were less in hypoxic (2.2% fetal, 1.8% adult) than normoxic (4.7% fetal, 8.1% adult) arteries.CONCLUSIONHypoxic attenuation of PKG‐induced vasorelaxation in ovine cerebral arteries was attributable to a reduced influence of PKG on the BK channel. Non‐BK channel mediators of vasorelaxation exhibited similar attenuation but of lesser magnitude. Fetal cerebral arteries were most affected by hypoxic stress.This work was supported by NIH Grants HL‐54120, HD‐31266, HL‐64867 and NS‐076945.