TACHYKININ NK1 RECEPTORS MEDIATE BOTH VASOCONSTRICTOR AND VASODILATORRESPONSES IN THE RABBIT ISOLATED JUGULAR-VEIN

We have characterized the receptor(s) mediating contraction and relaxa tion produced by tachykinins in the rabbit isolated jugular vein. The tachykinin NK1 receptor-selective agonists septide and [Pro(9)]substan ce P produced concentration-dependent contractions which were potentia ted by either the removal of the vascular endothelium (E(max) = +106% and +72%, respectively) or by pretreatment with L-nitroarginine (100 m u M; 60 min before) (E(max) = +123% and +71%, respectively). The tachy kinin NK1 receptor-selective antagonist, (+/-)-CP-96,345 phenyl)-methy l]-1-azabicyclo[2,2,2]octan-3-amine]) (10-300 nM) competitively antago nized septide (pK(B) = 9.0) with 10-fold greater potency than [Pro(9)] substance P (pK(B) = 8.0). In preparations with intact endothelium bot h septide and [Pro(9)]substance P (from 0.1 to 100 nM) relaxed the nor adrenaline(10 mu M) induced tone, and their effects were markedly redu ced 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 ine ffective, or produced small effects antagonized by (+/-)-CP-96,345 (10 0 nM), respectively. In conclusion, tachykinin NK1 receptors mediate b oth tachykinin-induced contraction and relaxation in the rabbit jugula r vein. This preparation, deprived of the endothelium or pretreated wi th L-nitroarginine, is suitable for evaluating tachykinin agonists or antagonists.