Tachykinin NK1 receptors mediate both vasoconstrictor and vasodilator responses in the rabbit isolated jugular vein

We have characterized the receptor(s) mediating contraction and relaxation produced by tachykinins in the rabbit isolated jugular vein. The tachykinin NK1 receptor-selective agonists septide and [Pro9]substance P produced concentration-dependent contractions which were potentiated by either the removal of the vascular endothelium (Emax = +106% and +72%, respectively) or by pretreatment with L-nitroarginine (100 microM; 60 min before) (Emax = +123% and +71%, respectively). The tachykinin NK1 receptor-selective antagonist, (+/-)-CP-96,345 ([2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2,2,2]octan-3-amine]) (10-300 nM) competitively antagonized septide (pKB = 9.0) with 10-fold greater potency than [Pro9]substance P (pKB = 8.0). In preparations with intact endothelium both septide and [Pro9]substance P (from 0.1 to 100 nM) relaxed the noradrenaline-(10 microM) induced tone, and their effects were markedly reduced by (+/-)-CP-96,345 (100 nM). In noradrenaline-precontracted veins L-nitroarginine (100 microM) reversed the tachykinin-induced vasodilation into a contraction, providing evidence for the involvement of nitric oxide in this response. The tachykinin NK3 and NK2 receptor-selective agonists senktide and [beta Ala8]neurokinin A-(4-10) were either ineffective, or produced small effects antagonized by (+/-)-CP-96,345 (100 nM), respectively. In conclusion, tachykinin NK1 receptors mediate both tachykinin-induced contraction and relaxation in the rabbit jugular vein. This preparation, deprived of the endothelium or pretreated with L-nitroarginine, is suitable for evaluating tachykinin agonists or antagonists.