iNOS gene expression modulates microvascular responsiveness in endotoxin-challenged mice

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Immunology

Background:

• Septic shock involves vasodilation and reduced vasoconstrictor responsiveness.
• Nitric oxide (NO) overproduction via inducible nitric oxide synthase (iNOS) is implicated.
• Direct evidence linking iNOS expression to microvascular dysfunction in sepsis is needed.

Purpose of the Study:

• To investigate the role of iNOS gene expression in lipopolysaccharide (LPS)-induced microvascular hyporesponsiveness.
• To determine the effect of LPS on smooth muscle contraction and endothelial relaxation in mouse mesenteric arteries.
• To differentiate the contributions of iNOS and NO-independent pathways to sepsis-induced vasodilation.

Main Methods:

• Wild-type and iNOS knockout mice were challenged with LPS or saline.
• Mesenteric resistance arteries were isolated and pressurized ex vivo.
• Concentration-dependent responses to norepinephrine (vasoconstrictor) and acetylcholine (vasodilator) were measured.

Main Results:

• LPS significantly impaired norepinephrine-induced contraction in wild-type mice.
• iNOS knockout mice showed no impairment in contraction after LPS exposure.
• Aminoguanidine (iNOS inhibitor) partially restored contraction, suggesting a NO-independent role for iNOS.
• Endothelium-dependent relaxation was unaffected by LPS.

Conclusions:

• iNOS gene expression directly mediates the LPS-induced decrease in microvascular responsiveness to vasoconstrictors.
• iNOS plays a central role in the NO-independent effects of LPS on microvascular function.
• Endothelial nitric oxide synthase (eNOS) activity is not a primary factor in LPS-induced hyporesponsiveness in this model.