Lessons learned from nitric oxide synthase knockout animals.

Nitric oxide (NO) is generated by 3 major isoforms of nitric oxide synthase (NOS) with complex and overlapping patterns of expression. This article presents several examples of how gene targeted mice lacking endothelial and neuronal isoforms have showed various roles of NO. Neuronal NOS knockout mice are resistant to global and focal cerebral ischemia, confirming a role for neuronal NO in cellular toxicity after stroke. Endothelial NOS knockout mice have increased susceptibility to stroke consistent with a vascular protective effect of NO. They are hypertensive and lack endothelium dependent relaxing factor activity. Analysis of cardiac function shows roles for NO in suppression of inotropic responses to beta-adrenergic agonists and in mediating basal diastolic relaxation. Endothelial NOS knockout mice respond to vascular injury with increased neointimal proliferation, consistent with a physiological role for NO to suppress smooth muscle cell proliferation.