Low Dose L-NAME Reduces Infarct Volume in the Rat MCAO/Reperfusion Model

Abstract

In a variety of recent studies, inhibitors of nitric oxide (NO) synthesis have ameliorated neuronal injury during permanent focal cerebral ischemia, suggesting that NO may contribute to ischemic damage. In other studies, however, these inhibitors increased infarct volume during permanent middle cerebral artery occlusion (MCAO). One complication in these studies was that high-dose NO synthase inhibitors increased mean arterial blood pressure (MAP) by 20-30 mm Hg. Thus, it is possible that variations in the effects of NO synthesis inhibitors on infarct volume could be related to effects of these inhibitors on MAP and cerebral perfusion during or after ischemia. The present study compared the effects of control (Ringer's lactate solution) versus lowdose NO inhibition (0.1 mg/kg bolus followed by 0.01 mg/kg/min) on cerebral infarct volume using L-NAME (N^G-nitro-L-arginine methyl ester) administered during a 1-h baseline period, 3-h of MCAO, and 2 h of reperfusion in the spontaneously hypertensive rat. Infarct volume was determined using the TTC (2,3,5-triphenyltetrazolium chloride) method performed 5 h after onset of occlusion. L-NAME reduced infarct volume by 55%. In the control group (n = 7), infarct volume measured 116 ± 4 (SEM) mm³ which was 29 ± 1% of the left hemispheric volume (400.5 ± 0.3 mm³). In the L-NAME group (n = 7), infarct volume measured 53 ± 8 mm³ which was only 13 ± 2% of the left hemispheric volume (400.4 ± 0.5 mm³). No significant differences in MAP (in mm Hg) were noted between groups during baseline (control 140 ± 4; L-NAME 131 ± 3), MCAO (control 134 ± 2; L-NAME 135 ± 1), or reperfusion (control 120 ± 2; L-NAME 114 ± 2). These findings suggest an important role for NO during cerebral ischemic injury. The absence of an increase in MAP during L-NAME infusion suggests that the protective effect of inhibition of NO synthesis was not mediated by an increase in cerebral perfusion secondary to systemic hypertension. Of potential clinical importance is the observation that low-dose NO inhibition may substantially lessen ischemic brain injury.