The role of nitric oxide in interleukin-2 therapy induced hypotension.
Nitric oxide is an uncharged free radical that mediates a range of physiologic processes in the vasculature. As a principal determinant of vascular tone, the overproduction of nitric oxide has been implicated in the pathogenesis of sepsis- and cytokine-induced hypotension. The enzyme that produces nitric oxide, nitric oxide synthase, exists in three isoforms. One of the three isoforms, inducible nitric oxide synthase, is expressed in many cell types only after stimulation by cytokines and/or endotoxin. Compared to the constitutive nitric oxide synthase enzymes, the inducible enzyme generates larger quantities of nitric oxide for longer periods. Expression of the inducible isoform in vitro requires stimulation by a mixture of cytokines including interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. These proinflammatory cytokines are known mediators of sepsis and are also produced in the serum of cancer patients during interleukin-2 therapy, thereby leading to excessive production of nitric oxide. Interleukin-2 therapy is associated with a spectrum of cardiovascular toxicities and hemodynamic alterations that are indistinguishable from those seen in septic shock. Many of these hemodynamic effects have been linked to the overproduction of nitric oxide via a cytokine-inducible nitric oxide pathway. In this regard, inhibition of nitric oxide synthesis represents a novel approach to limit the cardiovascular toxicity associated with interleukin-2 therapy and to improve its therapeutic index. Clinical trials to evaluate the efficacy of nitric oxide synthase inhibitors in reversing the hypotension associated with IL-2 therapy are now underway.
Shahidi
H
H
Rush-Presbyterian-St. Luke's Medical Center, Section of Hematology/Oncology, Chicago, Illinois, USA.
Kilbourn
R G
RG
D000818:Animals; D004790:Enzyme Induction; D006801:Humans; D007022:Hypotension / Q000139:chemically induced*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II
D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II