From the Department of Pharmacology, The University of Melbourne,
Parkville, Victoria, Australia.
Correspondence to Christopher G. Sobey, PhD, Department of Pharmacology, the University of Melbourne, Parkville, Victoria 3052, Australia. E-mail c.sobey{at}pharmacology.unimelb.edu.au
Background and
Purpose—Protease-activated receptors (PARs) are a family
of G-protein–coupled receptors activated by a tethered ligand
amino acid sequence within the amino terminal that is revealed by
site-specific proteolysis. In the vascular endothelium,
activation of PAR-2 by treatment with trypsin or by using the amino
acid ligand sequence (SLIGRL) produces
endothelium-dependent relaxation of isolated
noncerebral vascular segments. In this study, we first tested whether
PAR-2 activation produces cerebral vasodilatation in vivo and then
examined whether PAR-2–mediated vasodilatation is dependent on the
production of nitric oxide.
Methods—Concentration-dependent vasodilator effects of the PAR-2
agonist peptide SLIGRL and trypsin were examined on the basilar artery
using a cranial window in anesthetized rats. In addition, the
vasodilator effects of SLIGRL, acetylcholine (ACh), and sodium
nitroprusside (SNP) were examined in the absence and presence of
NG-nitro-L-arginine (L-NNA), an
inhibitor of nitric oxide synthase, and
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
(ODQ), an inhibitor of soluble guanylate
cyclase.
Results—Baseline diameter of the basilar artery averaged
239±4 µm. Under control conditions, SLIGRL (10–6
to 10–4 mol/L) and trypsin (0.01 to 10 U/mL) produced
concentration-dependent vasodilator responses. In time-control
experiments, SLIGRL (3x10–6 and 10–5 mol/L),
ACh (10–6 and 10–5 mol/L), and SNP
(10–8 and 10–7 mol/L) elicited reproducible
dilatation of the basilar artery. In another group of rats, L-NNA
(10–4 mol/L) markedly inhibited dilator responses to both
SLIGRL (13±3% versus 1±1% and 39±7% versus 11±2%; both
P<0.05) and ACh (8±1% versus 0±0% and 13±2%
versus 3±1%; both P<0.05). By contrast, responses to
SNP were significantly augmented after treatment with L-NNA
(P<0.05 versus control), indicating that
inhibitory effects of L-NNA were specific for responses
mediated by endogenous nitric oxide. Furthermore, in
another group ODQ (10-5 mol/L) inhibited responses to
SLIGRL to a degree similar to that seen with L-NNA, consistent
with a mechanism of PAR-2–mediated vasodilatation that involves
activation of guanylate cyclase by nitric oxide.
Conclusions—To the best of our knowledge, this study is the first
to examine whether PAR-2–mediated vasodilatation is functional in
cerebral arteries and is also the first to directly assess the effects
of PAR-2 activation on vascular tone in vivo. The results suggest that
activation of PAR-2 is an effective and powerful vasodilator mechanism
in cerebral arteries in vivo. Cerebral vasodilator responses to PAR-2
activation are mediated by nitric oxide and are likely to be
endothelium dependent.
Anesthesia
Research Mayo Clinic,
Rochester, Minnesota
© 1998 American Heart Association, Inc.
Original Contributions
Activation of Protease-Activated Receptor-2 (PAR-2) Elicits Nitric Oxide–Dependent Dilatation of the Basilar Artery In Vivo
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