CHARACTERIZATION OF THE RECEPTOR MEDIATING RELAXATION TO SUBSTANCE-P IN CANINE MIDDLE CEREBRAL-ARTERY - NO EVIDENCE FOR INVOLVEMENT OF SUBSTANCE-P IN NEUROGENICALLY MEDIATED RELAXATION
Cm. Stubbs et al., CHARACTERIZATION OF THE RECEPTOR MEDIATING RELAXATION TO SUBSTANCE-P IN CANINE MIDDLE CEREBRAL-ARTERY - NO EVIDENCE FOR INVOLVEMENT OF SUBSTANCE-P IN NEUROGENICALLY MEDIATED RELAXATION, British Journal of Pharmacology, 105(4), 1992, pp. 875-880
1 The aim of this study was to characterize the neurokinin receptor wh
ich mediates relaxation of dog isolated middle cerebral artery by the
use of selective agonists and antagonists and to establish whether sub
stance P is involved in the neurogenically mediated relaxant response
in this vessel. 2 Substance P caused concentration-related, endotheliu
m-dependent relaxations of dog isolated middle cerebral artery, contra
cted with prostaglandin F2-alpha. The selective NK1 receptor agonists,
GR73632 and substance P methyl ester (SPOMe), also caused relaxation
with similar maximum effects to those of substance P. GR73632 and SPOM
e were approximately 20 times and 6 times less potent respectively tha
n substance P. The selective NK2 and NK3 receptor agonists, GR64349 an
d senktide, were only weakly active in causing relaxation being at lea
st 425 times and 245 times less potent respectively than substance P.
3 The selective NK1 receptor antagonist, GR82334, was a potent, specif
ic, competitive antagonist of the relaxant effects of substance P. In
contrast, the selective NK2 receptor antagonist, R396 (10-mu-M) had no
effect on the response to substance P. 4 Electrical field stimulation
of dog isolated middle cerebral artery, contracted with prostaglandin
F2-alpha, caused neurogenically mediated, non-adrenergic non-choliner
gic (NANC) relaxations. These NANC relaxations were unaffected by endo
thelium removal, GR82334 (10-mu-M) or by capsaicin (10-mu-M) treatment
. However, the nitric oxide synthesis inhibitor, L-N(G)-monomethyl arg
inine methyl ester (L-NMMA) (100-mu-M) markedly attenuated the respons
e to electrical stimulation. 5 These results suggest that substance P
causes relaxation of dog isolated middle cerebral artery via activatio
n of NK1 receptors. However, substance P does not appear to be involve
d in NANC neurotransmission. In contrast, the marked inhibitory effect
of L-NMMA on NANC relaxations implicates nitric oxide in NANC neurotr
ansmission in this vessel.