Inducible nitric oxide synthase (iNOS), an enzyme that produces toxic amounts of nitric oxide, is expressed in a number of brain pathologies, including cerebral ischemia. We used mice with a null mutation of the iNOS gene to study the role of iNOS in ischemic brain damage. Focal cerebral ischemia was produced by occlusion of the middle cerebral artery (MCA). In wild-type mice, iNOS mRNA expression in the post-ischemic brain begun between 24 and 48 hr peaked at 96 hr and subsided 7 d after MCA occlusion. iNOS mRNA induction was associated with expression of iNOS protein and enzymatic activity. In contrast, mice lacking the iNOS gene did not express iNOS message or protein after MCA occlusion. The infarct and the motor deficits produced by MCA occlusion were smaller in iNOS knockouts than in wild-type mice (p < 0.05). Such reduction in ischemic damage and neurological deficits was observed 96 hr after ischemia but not at 24 hr, when iNOS is not yet expressed in wild-type mice. The decreased susceptibility to cerebral ischemia in iNOS knockouts could not be attributed to differences in the degree of ischemia or vascular reactivity between wild-type and knockout mice. These findings indicate that iNOS expression is one of the factors contributing to the expansion of the brain damage that occurs in the post-ischemic period. iNOS inhibition may provide a novel therapeutic strategy targeted specifically at the secondary progression of ischemic brain injury.

Cerebral ischemia is followed by a local inflammatory response that is thought to participate in the extension of the tissue damage occurring in the postischemic period. However, the mechanisms whereby the inflammation contributes to the progression of the damage have not been fully elucidated. In models of inflammation, expression of the inducible isoform of nitric oxide synthase (iNOS) is responsible for cytotoxicity through the production of large amounts of nitric oxide (NO). In this study, therefore, we sought to establish whether iNOS is expressed in the ischemic brain. Rats were killed 6 h to 7 days after occlusion of the middle cerebral artery. iNOS expression in the ischemic area was determined by reverse-transcription polymerase chain reaction. Porphobilinogen deaminase mRNA was detected in the same sample and used for normalization. In the ischemic brain, there was expression of iNOS mRNA that began at 12 h, peaked at 48 h, and returned to baseline at 7 days (n = 3/time point). iNOS mRNA expression paralleled the time course of induction of iNOS catalytic activity, determined by the citrulline assay (17.4 +/- 4.4 pmol citrulline/micrograms protein/min at 48 h; mean +/- SD; n = 5 per time point). iNOS immunoreactivity was seen in neutrophils at 48-96 h after ischemia. The data provide molecular, biochemical, and immunocytochemical evidence of iNOS induction following focal cerebral ischemia. These findings, in concert with our recent demonstration that inhibition of iNOS reduces infarct volume in the same stroke model, indicate that NO production may play an important pathogenic role in the progression of the tissue damage that follows cerebral ischemia.

Transient focal ischemia leads to iNOS expression in postischemic brain. However, the spatial and temporal patterns of expression differ from those occurring in permanent ischemia: iNOS is induced earlier and predominantly in vascular cells rather than in neutrophils. Thus, the temporal profile and localization of postischemic iNOS expression depend on the nature of the ischemic insult. The finding that aminoguanidine reduces infarct size adds further support to the hypothesis that postischemic iNOS expression contributes to ischemic brain damage.

These results demonstrate that cerebral ischemia is also associated with iNOS expression in a minimally invasive model of transient MCA occlusion and that iNOS inhibition reduces focal ischemic damage. The findings support the hypothesis that nitric oxide produced by iNOS contributes to ischemic brain damage and that inhibition of iNOS may be a valuable tool in the management of cerebral ischemia.

Prinzmetal variant angina is characterized by angina secondary to coronary artery vasospasm, 1 typically at rest, associated with transient ST-segment deviations.2 Further diagnostic workup using angiography may reveal coronary arteries with or without atherosclerotic narrowings.1 Multiple sclerosis (MS) is typically a relapsing-remitting neurologic disorder involving demyelinated plaques, which slow or block conduction along nerves.3 Literature search reveals one case report indicating a causal relationship between these 2 diseases. 4 We present an additional case involving a 38-year-old patient who experienced Prinzmetal variant angina during a multiple sclerosis relapse. Case ReportA 38 year-old hospitalized woman was receiving an intravenous injection of meperidine for abdominal pain when she complained of severe chest pain and pressure that radiated to her neck, jaw, and left arm. She had mild shortness of breath and diaphoresis.The patient had been admitted 2 days earlier with nausea, vomiting, and abdominal pain after starting an oral prednisone taper for a recent MS exacerbation. Magnetic resonance imaging (MRI) on admission showed multiple foci of increased T 2 signal intensity, in the periventricular subcortical distribution, consistent with MS. Two new foci were seen in the right hemisphere, one in the centrum semiovale and another in the right inferior parietal lobe, just above the calcarine fissure. These demonstrated increased signal on the diffusion images, suggesting a more acute process of demyelination. The patient denied any previous episodes of chest pain as well as any cardiac history, hypertension, hypercholesterolemia, or respiratory problems. Past medical history included MS, depression, possible seizure disorder, tonsillectomy, and appendectomy. She was adopted, and her family history is unknown. Her usual medications include 150 mg of ranitidine twice daily, 50 mg of sertraline twice daily, 100 mg of amantadine twice daily, 100 mg of carbamazepine twice daily, norethindrone and ethinyl estradiol, propoxyphene napsylate as needed, and interferon ␤1a once per week. She was married with 2 children and she had smoked Ͻ1 pack of cigarettes per week for the prior 20 years. She rarely used alcohol, and she denied any drug use or herbal medications. Ten days before admission, she had lost her father to a stroke; his funeral was 3 days before admission.When examined, her temperature was 97.4°F, pulse was 50 to 70 beats/min, blood pressure was 130/70 mm Hg, respiratory rate was 20 breaths/ min with an oxygen saturation of 99% on 2 liters of O 2 via nasal cannula. In general, she was a pleasant, healthy woman who appeared moderately uncomfortable and anxious. Results of the examination were unremarkable.Her electrocardiogram showed 1-mm ST segment elevation in leads II, III, and aVF, suggesting an acute inferior myocardial infarction. Her chest radiograph was negative for acute processes. After administration of oxygen, aspirin, 0.4 mg of sublingual nitroglycerin, heparin, and intravenous morphine...