Sex Differences in Sepsis‐Induced Nitric Oxide and EDHF Signaling Pathways in Rat Pulmonary Artery

Abstract

Sepsis still remains a major cause of hospital infection related deaths in the US. Pulmonary manifestation of sepsis is characterized by pulmonary hypertension, pulmonary edema and refractory hypoxemia. Pulmonary hypertension is associated with abnormal regulation of vascular tone in sepsis. Evidence exists that males are more susceptible to sepsis than females. The objective of present study was to elucidate the influence of gender on endothelial function, particularly with reference to nitric oxide (NO) and endothelium‐derived hyperpolarizing factor (EDHF) signaling pathways in pulmonary artery of septic rats. Sepsis was induced in rats by cecal ligation and puncture (CLP). To determine the effect of sepsis‐induced alteration in the NO and EDHF signaling pathways in both sexes, arterial relaxation was measured using isometric tension experiments. Results demonstrate that in control animals the potency but not the amplitude of the response to the vasoconstrictor, phenylephrine, was significantly greater in the pulmonary arteries from female than male rats. Sepsis caused a significant reduction in the efficacy of phenylephrine in pulmonary arteries from either sex. In controls, acetylcholine (ACh) was more potent in dilating pulmonary arteries from female than male rats and sepsis identically inhibited ACh‐induced relaxations in both male and female animals. Sepsis completely abolished the EDHF response in pulmonary arterial rings from both sexes. Pre‐treatment with L‐NAME (eNOS inhibitor) and indomethacin (prostacyclin inhibitor) significantly increased the basal tone of pulmonary arterial rings from female rats and was significantly reduced in sepsis. However, L‐NAME and indomethacin did not alter the basal tone of pulmonary artery from both control and septic male rats. Real time PCR analysis of mRNA expression revealed that sepsis decreased IKCa, SKCa1, and SKCa2 mRNA expression levels in female rats and IKCa and SKCa2 mRNA expression levels in male rats. SKCa1 SKCa1 mRNA expression levels did not change in male rats while sepsis had no effect on SKCa3 mRNA expression levels in both sexes. In conclusion, the results of the present study suggest that sepsis‐induced alteration in the reactivity of pulmonary artery is gender dependent. This can be attributed to a decrease in NO but predominantly EDHF‐mediated vasorelaxation resulting from a significant decrease in expression of endothelium localized potassium channels.