Blocking central leukotrienes synthesis affects vasopressin release during sepsis

Area of Science:

• Neuroendocrinology
• Sepsis Pathophysiology
• Leukotriene Biology

Background:

• Vasopressinergic neurons contain cysteinyl-leukotriene C(4) (LTC(4)) synthase, an enzyme in cys-leukotriene synthesis.
• Cys-leukotrienes may regulate vasopressin secretion, but their role in sepsis-induced AVP release is unclear.

Purpose of the Study:

• To investigate the role of LTC(4) synthase in arginine vasopressin (AVP) release during experimentally induced sepsis.
• To evaluate the effect of a cys-LT synthesis inhibitor on sepsis outcomes and AVP regulation.

Main Methods:

• Male Wistar rats underwent cecal ligation and puncture (CLP) or sham operation after central administration of the LTC(4) synthase inhibitor (MK-886) or vehicle.
• Measurements included survival rates, plasma AVP, hematocrit, serum sodium, nitric oxide, plasma osmolality and protein, and blood pressure.
• Hypothalamic LTC(4) synthase content and neurohypophyseal AVP content were quantified.

Main Results:

• Central administration of MK-886 reduced mortality, blocked the initial increase in plasma AVP and hypothalamic LTC(4) synthase, and partially reversed the decrease in neurohypophyseal AVP.
• MK-886 abolished the drop in blood pressure during the initial phase of sepsis.
• The inhibitor reduced increases in serum nitric oxide and hematocrit but did not affect plasma protein or osmolality changes.

Conclusions:

• Central cys-LTs are involved in the vasopressin release observed during sepsis.
• Inhibition of cys-LT synthesis offers a potential therapeutic strategy for managing sepsis-induced AVP dysregulation and associated complications.