title: Characterization of the peripheral action of neurokinins and neurokinin receptor selective agonists on the rat cardiovascular system.
abstract: 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%) greater than NKB (17.5%) greater than 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 less than 0.05) greater vasodepressor response than SP, while the potency of the octapeptide NK-1 selective agonist [beta-Ala4, Sar9, Met(O2)11]SP (4-11) (316%) was not significantly different from SP. Conversely, the NK-2 selective agonist NKA (4-10) (less than 2%) caused only a small effect. The vasodepressor effect elicited by [MePhe7]NKB (112%) and [beta-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 less than 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 [beta-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 [beta-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.(ABSTRACT TRUNCATED AT 400 WORDS)
authors: Département de Physiologie, Faculté de Médecine, Université de Montréal, Québec, Canada.
authors: R
authors: R
authors: Couture
authors: O
authors: O
authors: Laneuville
authors: C
authors: C
authors: Guimond
authors: G
authors: G
authors: Drapeau
authors: D
authors: D
authors: Regoli
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D015288:Neurokinin A / Q000008:administration & dosage / Q000494:pharmacology*; D015287:Neurokinin B / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000648:ultrastructure; D010275:Parasympathetic Nervous System / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000502:physiology; D013610:Tachycardia / Q000139:chemically induced
chemical_list: D010446:Peptide Fragments; D011453:Prostaglandins; D017981:Receptors, Neurotransmitter; C062618:substance P, Sar(9)-Met(O2)(11)-; C061061:neurokinin B (4-10), beta-Asp(4)-Me-Phe(7)-; D013373:Substance P; D015288:Neurokinin A; D015287:Neurokinin B; C056408:neurokinin A(4-10)