From the Laboratory of Cerebrovascular Biology and Stroke, Department of
Neurology, University of Minnesota Medical School, Minneapolis, Minn.
Correspondence to C. Iadecola, MD, Department of Neurology, University of Minnesota Medical School, Box 295 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. E-mail iadec001{at}maroon.tc.umn.edu
Background—The mechanisms regulating
the cerebellar microcirculation during neural activity are poorly
understood. One of the major neural inputs to the cerebellar cortex is
the climbing fiber (CF), a pathway that uses excitatory amino acids,
including glutamate, as a transmitter. We studied whether CF activation
increases cerebellar blood flow (BFcrb) and, if so, we investigated the
role of glutamate receptors, nitric oxide (NO) and cGMP, in the
response.
Methods—The CF were activated by harmaline administration
(40 mg/kg, IP) in halothane-anesthetized rats with a cranial
window placed over the cerebellar vermis. BFcrb was monitored by a
laser-Doppler probe, and arterial pressure and blood
gases were controlled.
Results—With Ringer superfusion, harmaline produced sustained
increases in BFcrb that peaked 20 minutes after administration
(+115±13%; n=6; P<.05). The increases in BFcrb were
substantially reduced by superfusion with tetrodotoxin (10
µmol/L; -91±5%; n=5; P<.05 from Ringer). The
response was also attenuated by the
Conclusions—Activation of the CF system increases BFcrb. The
response depends on activation of glutamate receptors and is in large
part mediated by NO via stimulation of soluble guanylyl cyclase.
Glutamate receptors NO and cGMP are important factors in the mechanisms
of functional hyperemia in cerebellar cortex.
Department
of Internal Medicine,
Cardiovasular Division,
University of Iowa College of Medicine,
Iowa City, Iowa
© 1998 American Heart Association, Inc.
Original Contributions
Activation of Cerebellar Climbing Fibers Increases Cerebellar Blood Flow
Role of Glutamate Receptors, Nitric Oxide, and cGMP
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor
inhibitor
2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)-quinoxaline (100
µmol/L; -70±6%; P<.05; n=5), but not by the
N-methyl-D-aspartate receptor blocker
2-amino-5-phosphonopentanoic acid (500 µmol/L;
P>.05; n=5). The response was attenuated by the
nonselective NO synthase (NOS) inhibitor
nitro-L-arginine (1 mmol/L; -73±5%; n=6) or by 7-NI
(50 mg, IP; -71±5%; n=5), a relatively selective neuronal NOS
inhibitor. The soluble guanylyl cyclase
inhibitor
1H-1,2,4oxadiazolo[4,3-a]quinoxalin-1-one (100
µmol/L) attenuated the response to harmaline (-73±5;
P<.05; n=6) but not to superfusion with
adenosine (P>.05; n=5) or 8-bromo–cGMP
(P>.05; n=5).
Editorial Comment
Role of Glutamate Receptors, Nitric Oxide, and cGMP
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