Chronic hypoxia (CH)‐induced inflammation down‐regulates soluble guanylate cyclase (sGC) in rat carotid body

Abstract

sGC in oxygen‐sensitive carotid body type I cells is activated by the diffusible gas, nitric oxide (NO). In rats exposed to CH, sGC is down‐regulated, with a corresponding drop in NO‐stimulated production in cGMP. Moreover, CH induces an invasion of activated macrophages and the production of inflammatory cytokines in chemosensory tissue. The present study investigates the relationship between inflammation and the down‐regulation of sGC in type I cells. Quantitative PCR (qPCR) assays of carotid bodies from 7‐day CH (380 Torr) rats demonstrated a 50–500% increase in expression of cytokines interleukin‐1β (IL‐1β), IL‐6, and tumor necrosis factor‐α (TNFα). CH (7 days) elicited a >90% reduction in the expression of sGC. In contrast, animals concurrently treated with anti‐inflammatory drugs, ibuprofen (4mg/kg/day) or bosentan (200mg/kg/day), expressed normal levels of the sGC gene. sGC expression was reduced by 50% in normal type I cells cultured for 48 hrs in the presence of TNFα (50 ng/ml). However, exposure to TNFα did not alter the expression of the gene for tyrosine hydroxylase (TH). Our data indicate that a CHinduced increase in cytokine production directly influences the expression of sGC, a signaling molecule which mediates type I cell inhibition. Inflammation appears to be an important factor in the readjustment of chemoreceptor sensitivity following CH. USPHS Grants NS 12636 and NS 07938.