Postnatal maturation and hypoxic acclimatization modulate PKG‐mediated activation of BK channels in ovine cerebral arteries

Abstract

NO‐dependent relaxation of ovine cerebral arteries is enhanced during postnatal maturation but is attenuated by acclimatization to high altitude. Because NO‐mediated vasorelaxation is mediated by activation of PKG, which in turn activates large conductance BK channels, we hypothesized that the effects of both maturation and chronic hypoxia on NO‐dependent relaxation are mediated by modulation of PKG effects on BK channels. In middle cerebral arteries from normoxic and chronically hypoxic fetal and adult sheep, iberiotoxin (IBTX, an inhibitor of BK channels) enhanced the maximum contractile response to 5HT ≈10% in both age groups, but 8pCPT‐cGMP (8pCPT, a PKG activator) decreased this response ≈15% in fetal and ≈20% in adult arteries. Addition of 8pCPT followed by IBTX produced responses similar to controls in both age groups. In arteries treated with cumulative log dose increases of IBTX before or after incubation with 8pCPT, IBTX significantly enhanced basal tone ≈40% in both age groups. Preincubation with 8pCPT attenuated the contractile responses to IBTX by ≈70% in fetal and ≈90% in adult arteries. Addition of 8pCPT following maximum responses to IBTX decreased tone ≈30% in fetal and ≈40% in adult arteries. These results indicate that PKG enhances BK channel activity more in adult than fetal arteries, and markedly less in hypoxic than normoxic arteries.Supported by USPHS Grants HL54120, HD31266, & HL64867.