Nitric oxide and focal cerebral ischemia: multiplicity of actions and diverse outcome.
The original observation that inhibitors of nitric oxide (NO) synthesis can antagonize glutamate toxicity in cell culture has led to extensive investigation of the role of NO in the pathophysiology of cerebral ischemic injury in vivo. However, studies of the efficacy of NO synthase inhibitors in models of focal cerebral ischemia have generated widely disparate findings, ranging from dramatic neuroprotection to exacerbation of ischemic damage. This review summarizes these studies and proposes that their apparently contradictory findings can be reconciled by viewing the results as a continuum of response that reflects the many and diverse physiological actions of NO. Thus, differences in experimental design between studies can alter the balance between these NO-controlled processes and result in the transformation of an overt neuroprotective effect of NO synthesis inhibition into one of exacerbation of ischemic injury. Thus, this review also identifies some of the most important physiological and pathophysiological functions of NO (and the consequences of their inhibition by NO synthase inhibitors) that may interact to determine outcome after a focal cerebral ischemic insult. A clearer appreciation of the potential therapeutic utility of both NO synthesis inhibitors and NO donors will emerge only when the complexity of their effects on mechanisms that interact to determine the extent of ischemic damage in vivo are more fully defined and understood.
Dawson
D A
DA
Wellcome Surgical Institute, University of Glasgow, Scotland.
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000502:physiology; D005609:Free Radicals; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000503:physiopathology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase; D016896:Treatment Outcome
D005609:Free Radicals; D009569:Nitric Oxide; D018698:Glutamic Acid; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases