From the Departments of Clinical Neurosciences (R.P.W., H.S.M.) and
Medical Physics and Engineering (C.D.), King's College School of
Medicine and Dentistry and the Institute of Psychiatry; and the Centre for
Clinical Pharmacology, University College (P.V.), London, UK.
Correspondence to Dr Hugh Markus, Department of Neurology, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK. E-mail h.markus{at}iop.bpmf.ac.uk
Background and Purpose—Animal
studies suggest that nitric oxide (NO) is important in basal cerebral
blood flow (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 flow (ICA flow and CCA flow) and transcranial
Doppler ultrasound measurement of middle cerebral artery flow
velocity (MCA
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 flow 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
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
© 1998 American Heart Association, Inc.
Original Contributions
Nitric Oxide Synthase Inhibition in Humans Reduces Cerebral Blood Flow but Not the Hyperemic Response to Hypercapnia
). The pressor effect of L-NMMA was controlled for by
comparison with noradrenaline titrated to effect an
equivalent blood pressure elevation. . 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. 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.
Key Words: cerebrovascular circulation • nitric oxide • noradrenaline • ultrasonography, Doppler
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