Cytokine-mediated downregulation of vasopressin V1A receptors during acute endotoxemia in rats

The reduced pressure response to vasopressin during acute sepsis has directed our interest to the regulation of vasopressin V-1A receptors. Rats were injected with lipopolysaccharide for induction of experimental gram-negative sepsis. V-1A receptor gene expression was downregulated in the liver, lung, kidney, and heart during endotoxemia. Inasmuch as the concentrations of proinflammatory cytokines such as interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma were highly increased during sepsis, the influence of these cytokines on V-1A receptor expression was investigated in primary cultures of hepatocytes and in the aortic vascular smooth muscle cell line A7r5. V-1A receptor expression was downregulated by the cytokines in a nitric oxide-independent manner. Blood pressure dose-response studies after injection of endotoxin showed a diminished responsiveness to the selective V-1 receptor agonist Phe(2),Ile(3),Orn(8)-vasopressin. Our data show that sepsis causes a downregulation of V-1A receptors and suggest that this effect is likely mediated by proinflammatory cytokines. We propose that this downregulation of V-1A receptors contributes to the attenuated responsiveness of blood pressure in response to vasopressin and, therefore, contributes to the circulatory failure in septic shock.