Differences in the effects of tachykinin NK1 receptor antagonists: neuronal versus smooth muscle tissues

The effects of three tachykinin NK1 receptor antagonists (L-668,169, (+/-)-RP 67580, and (+/-)-CP 96.345) were examined for their ability to antagonise responses evoked by substance P O-methyl ester (a selective NK1 receptor agonist) in isolated neuronal tissue (rat superior cervical ganglia and guinea-pig locus coeruleus) and smooth muscle tissues (rat urinary bladder and guinea-pig ileum longitudinal muscle/myenteric plexus). (+/-)-RP 67580 was similarly effective in antagonising responses in both rat superior cervical ganglia and urinary bladder (estimated pKa value = 7.4 for both tissues); however, (+/-)-CP 96,345 was 50-fold less effective in antagonising responses in guinea-pig locus coeruleus than in ileum longitudinal muscle/myenteric plexus (estimated pKa values = 7.6 and 9.3 respectively). It is suggested that the differential effects of (+/-)-CP 96,345 may reflect the existence of a population of NK1 receptors within guinea-pig locus coeruleus that are less sensitive to the effects of this NK1 receptor antagonist.