Lessons from genetically engineered animal models IV. Nitric oxide synthase gene knockout mice

Nitric oxide is a ubiquitous molecule implicated in a variety of biological processes. The specific action of nitric oxide depends on its enzymatic so urces, namely neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS) , and inducible NOS (iNOS), each having distinct tissue localization. Conve ntional pharmacological antagonists could not distinguish these enzymes or provide models of chronic nitric oxide depletion in whole animals. Several lines of knockout mice have been generated to distinguish the roles of nitr ic oxide from each enzyme: nitric oxide from nNOS is a major inhibitory neu rotransmitter, nitric oxide from eNOS regulates blood flow under physiologi cal conditions, and nitric oxide from iNOS causes hypotension during severe inflammatory conditions. Moreover, the nitric oxides from each isoform hav e different roles in tissue injury and inflammation. Studies of NOS-deficie nt animals,have also identified redundant and compensatory pathways and rev ealed the consequences of life-long deficiency of these enzymes. The nNOS-d eficient mice develop gastric dilation and stasis, the eNOS-deficient mice develop hypotension and lack vasodilatory responses to injury, and iNOS-def icient mice are more susceptible to inflammatory damage but more resistant to septic shock.