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 [Pro(9)]substance P produced concentration-dependent contractions which were potentiated by either the removal of the vascular endothelium (E(max) = +106% and +72%, respectively) or by pretreatment with L-nitroarginine (100 mu M; 60 min before) (E(max) = +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 (pK(B) = 9.0) with 10-fold greater potency than [Pro(9)]substance P (pK(B) = 8.0). In preparations with intact endothelium both septide and [Pro(9)]substance P (from 0.1 to 100 nM) relaxed the noradrenaline(10 mu M) induced tone, and their effects were markedly reduced by(+/-)-CP-96,345 (100 nM). In noradrenaline-precontracted veins L-nitroarginine (100 mu M) 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 Ala(8)]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.