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Vol. 288, Issue 2, 671-678, February 1999
The R. W. Johnson Pharmaceutical Research Institute Spring
House, Pennsylvania (B.P.D., W.C., R.J.S., A.L.D., C.K.D., L.dG.,
P.A.G.);
General Atomics Court, San Diego, California (W.F., K.N.); and
Department of Immunology, The Scripps Research Institute, La Jolla,
California (R.D.Y.)
We developed mice deficient in protease-activated receptor-2 (PAR-2) or
PAR-1 to explore the pathophysiological functions of these receptors.
In this report, we evaluated mean arterial pressure and heart rate (HR)
changes in response to PAR-1 or PAR-2 activation in anesthetized
wild-type (WT), PAR-1-deficient (PAR-1-/-), and
PAR-2-deficient (PAR-2-/-) mice. In WT mice, TFLLRNPNDK, a
PAR-1 selective activating peptide, caused hypotension and HR decreases
at 1 µmol/kg. TFLLRNPNDK also caused secondary hypertension following
L-NAME pretreatment. These responses were absent in
PAR-1
/ mice. In WT mice, SLIGRL, a PAR-2 selective
activating peptide, caused hypotension without changing HR at 0.3 µmol/kg. SLIGRL did not induce hypertension following
N
-nitrol-arginine-methyl ester-HCl
(L-NAME). The response to SLIGRL was absent in
PAR-2-/- mice. SFLLRN, a nonselective receptor activating
peptide caused hypotension and HR decreases in WT mice at 0.3 µmol/kg, as well as secondary hypertension following
L-NAME. SFLLRN still induced hypotension in
PAR-1/ mice, but HR decrease and secondary hypertension
following L-NAME were absent. The hypotensive and
bradycardic responses to SFLLRN and TFLLRNPNDK in
PAR-2/ mice were accentuated compared with WT mice. By
using mouse strains deficient in either PAR-1 or PAR-2, we confirmed
the in vivo specificity of TFLLRNPNDK and SLIGRL as respective
activating peptides for PAR-1 and PAR-2, and the distinct hemodynamic
responses mediated by activation of PAR-1 or PAR-2. Moreover, the
accentuated response to PAR-1 activation in PAR-2-deficient mice
suggests a compensatory response and potential receptor cross-talk.
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