NK1 receptor-mediated endothelium-dependent relaxation and contraction with different sensitivity to post-receptor signaling in pulmonary arteries.
In rabbit intrapulmonary arteries, substance P (SP) has been reported to induce endothelium-dependent relaxation (EDR) and endothelium-dependent contraction (EDC) via tachykinin NK(1) receptors, and endothelium-independent contraction (EIC) via tachykinin NK(2) receptors. The present study pharmacologically examined whether these opposite responses (EDR and EDC) are mediated by the same NK(1) receptor. Five tachykinin agonists, including septide, a reportedly atypical NK(1) agonist, caused concentration-dependent EDR in the presence of NK2 antagonist (SR-48968) + TXA2 synthetase inhibitor (ozagrel), which blocked EIC and EDC, in pre-contracted arteries, and concentration-dependent EDC in the presence of NK2 antagonist (SR-48968) + nitric oxide synthase inhibitor (l-N(G)-nitro-arginine methyl ester), which blocked EIC and EDR, in non-contracted arteries. The EC(50) values of these agonists for EDR were smaller than those for EDC, indicating that the affinities of NK(1) agonists to NK(1) receptors are different between EDR and EDC. However, the rank order of their potency for EDR and EDC was the same: SP = septide > SP methyl ester (SPME) > neurokinin A > neurokinin B. [Ala(5), beta-Ala(8)]-alpha-neurokinin fragment 4-10 (NK2 agonist) and senktide (NK3 agonist) caused no responses. Two structurally different NK(1) antagonists, CP-99994 and SR-140333, shifted the concentration-EDC and -EDR curves of SPME, a selective NK(1) agonist, and septide rightward and suppressed their maximal responses in a similar concentration-dependent manner, indicating that the affinities of NK(1) antagonists to NK1 receptors are similar between EDR and EDC. U-73122, a phospholipase C inhibitor, and thapsigargin, 2,5-di-tert-butylhydroquinone, and ruthenium red, all intracellular Ca2+ release blockers, inhibited SP-induced EDR and EDC. Effective concentrations of ionomycin (Ca2+ ionophore) causing EDR were also lower than those causing EDC. Taken together, SP-induced EDR and EDC are mediated by activation of the same NK1 receptor followed by an increase in intracellular Ca2+, and sensitivity to Ca2+ may be higher in the EDR than EDC pathway.
Miike
Tomohiro
T
Pharmacology Division, Radioisotope Research Center, Kyoto University, Kyoto 606-8501, Japan. miike@kyoto-pharm.co.jp
Shirahase
Hiroaki
H
Kanda
Mamoru
M
Kunishiro
Kazuyoshi
K
Kurahashi
Kazuyoshi
K
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D020128:Inhibitory Concentration 50; D007476:Ionophores; D008297:Male; D015288:Neurokinin A / Q000378:metabolism / Q000494:pharmacology; D015287:Neurokinin B / Q000378:metabolism / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D054801:Phosphoinositide Phospholipase C / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000502:physiology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors; D018042:Receptors, Neurokinin-3 / Q000819:agonists; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
D002121:Calcium Channel Blockers; D007476:Ionophores; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D013373:Substance P; C054725:septide; D015288:Neurokinin A; D015287:Neurokinin B; D019001:Nitric Oxide Synthase; D054801:Phosphoinositide Phospholipase C; D013930:Thromboxane-A Synthase; D011761:Pyrrolidonecarboxylic Acid