Antagonism by (D-Pro2, D-Trp7,9)-substance P of the cerebrovascular dilatation induced by substance P

The effects of (D-Pro2, D-Trp7,9)-substance P, a structural analogue of substance P, were examined in two models on cerebrovascular responses to substance P(SP) in cats; in vitro using segments of the middle cerebral artery and in situ by microapplication of the peptides close to pial arterioles. (D-Pro2, D-Trp7,9)-SP in concentrations up to 6.6 x 10(-6) M was without significant effect upon isolated middle cerebral arteries under normal conditions and in arteries contracted with prostaglandin F2 alpha. SP caused concentration-dependent relaxations of middle cerebral arteries contracted by prostaglandin F2 alpha (mean +/- SE; EC50: 2.0 +/- 1.6 x 10(-9) M). The presence of (D-Pro2, D-Trp7,9)-SP shifted the concentration-response curve of SP towards higher concentrations without significantly effecting the maximum response of the arteries to SP. A relaxation by 24.2 +/- 4.0% (n = 6) was obtained in prostaglandin F2 alpha contracted arteries by increasing the potassium concentration with 2 mM in the buffer solution. This response to potassium was unaltered in the presence of 6.6 x 10(-6)M of (D-Pro2, D-Trp7,9)-SP (25.0 +/- 7.1%, n = 5). Perivascular microapplication of SP around individual pial arterioles in situ effected dose-dependent increases in vascular calibre (mean response 14.5 +/- 2% with SP, 10(-7)M). The concomitant perivascular administration of (D-Pro2, D-Trp7,9)-SP (6.6 x 10(-6)M), which alone did not alter the arteriolar calibre, attenuated significantly the cerebrovascular response to SP (mean response 1.5 +/- 3.2%). On the basis of the agonist-antagonist relation found, these observations point to the possibility of a specific SP receptor site in cerebral arteries and arterioles.