Characterization of the peripheral action of neurokinins and neurokinin receptor selective agonists on the rat cardiovascular system

Summary The effects on mean arterial pressure (MAP) and heart rate (HR) of increasing doses (0.65–65 nmol/kg) of substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were measured after intravenous (i. v.) injection in urethane anaesthetized rats. Neurokinins (NKs) elicited a vasodepressor effect with the following rank order of potency: SP (100%) > NKB (17.5%) > NKA (10%). The two undecapeptide NK-1 selective agonists, [Pro⁹, Met(O₂)¹¹]SP (787%) and [Sar⁹, Met(O₂)¹¹]SP (697%), evoked a significantly (P < 0.05) greater vasodepressor response than SP, while the potency of the octapeptide NK-1 selective agonist [-Ala⁴, Sar⁹, Met(O₂)¹¹]SP (4–11) (316%) was not significantly different from SP. Conversely, the NK-2 selective agonist NKA (4–10) (<2%) caused only a small effect. The vasodepressor effect elicited by [MePhe⁷]NKB (112%) and [-Asp⁴, MePhe⁷]NKB (4–10) (92%), two NK-3 selective agonists, were not significantly different from that of SP. Senktide (1,095%) is the most potent NK-3 agonist, and is significantly (P < 0.01) more potent than SP. No cross-desensitization, of the vasodepressor response, was observed between NK-1 and NK-3 selective agonists. I. V. injection of 32.5 nmol/kg of NKA, NKA (4–10) and [-Ala⁴, Sar⁹, Met(O₂)¹¹]SP (4–11) raised HR, while NKB and the NK-3 selective agonists produced a rapid and marked bradycardia. SP and the two undecapeptide, NK-1 selective agonists, produced an initial increase in HR and a latent long-lasting bradycardia. The bradycardia elicited by [Sar⁹, Met(O₂)¹¹]SP (32.5 nmol/kg) was blocked by methylatropine, hexamethonium, indomethacin and by treatment with capsaicin or compound 48/80. Although the bradycardia elicited by [-Asp⁴, MePhe⁷]NKB (4–10) (32.5 nmol/kg) was also blocked by hexamethonium, methylatropine, and by bilateral vagotomy, it remained unaffected after indomethacin, or in rats pretreated with either capsaicin or compound 48/80. The drop in MAP produced by the NK-1 and NK-3 agonists were reduced by hexamethonium, methylatropine and bilateral vagotomy (NK-3 agonist), but remained unaffected by indomethacin, capsaicin, and compound 48/80. The tachycardia to NKA (4–10) (65 nmol/kg) was blocked entirely by sotalol or metoprolol and potentiated by hexamethonium. Guanethidine and bilateral adrenalectomy (48 h) failed to affect the tachycardia induced by the agonist, whereas the combination of both treatments abolished the response. Rats sympathectomized with 6-hydroxydopamine (48 h) reduced the increase in HR to NKA (4–10) only at 1 min post-administration. These results support the hypothesis that the vasodepressor action of SP is mediated by the direct activation of NK-1 receptors on vascular endothelium. NKs can accelerate HR by releasing catecholamines through activation of NK-1 and/or NK-2 receptors, on noradrenergic fibers and adrenal chromaffn cells. Furthermore NKs can exert a depressor effect on the cardiovascular system by producing a vagal reflex (Bezold-Jarisch reflex), following either the activation of NK-3 receptors located on capsaicin-insensitive sensory fibers, or by promoting the release of prostaglandins from mast cells (via a non-receptor mechanism) which in turn will stimulate capsaicin-sensitive sensory fibers.