Nitric oxide synthase inhibition in humans reduces cerebral blood flow but not the hyperemic response to hypercapnia

Background and Purpose-Animal studies suggest that nitric oxide (NO) is important in basal cerebral blood now (CBF) regulation and that it may mediate the vasodilatory response to carbon dioxide. We investigated its role in the human circulation using the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Methods-L-NMMA was administered as an intravenous bolus at three doses (1, 3, and 10 mg/kg). CBF was assessed by color velocity ultrasonic imaging of internal and common carotid artery volume now (ICA now and CCA now) and transcranial Doppler ultrasound measurement of middle cerebral artery now velocity (MCA nu). The presser effect of L-NMMA was controlled for by comparison with noradrenaline titrated to effect an equivalent blood pressure elevation. Results-L-NMMA produced a dose-dependent reduction in basal mean +/- SD CCA flow from 415.2 +/- 51.9 to 294 +/- 56.2 mL/min (at 10 mg/kg) and ICA now from 268.8 +/- 59.4 to 226.2 +/- 72.6 mL/min (P<.005 and P<.05, respectively, comparing areas under the dose-response curve). This was reversed by L-arginine. Mean +/- SD systemic blood pressure rose from 85.2 +/- 6.4 to 100.8 +/- 9.6 mm Hg (P<.01). There was no significant reduction in MCA nu. There was no significant change in the CBF response to either 6% or 8% carbon dioxide after L-NMMA. Noradrenaline produced a lesser fall in basal CCA flow (12.0%) but had a similar effect on the hypercapnic response. Conclusions-Basal NO release is important in controlling human CBF, but intravenously administered L-NMMA does not inhibit the hypercapnic hyperemic response in humans. The discrepancy between CBF and MCA nu after L-NMMA administration is consistent with MCA vasoconstriction. Neuronal NO synthase inhibition may be protective in stroke. However, our results suggest that nonselective NO synthase inhibitors such as L-NMMA should be used with caution because they reduce CBF.