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)

Pharmacodynamic evaluation of Lys5, MeLeu9, Nle10-NKA(4–10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats

“…Tachykinins have been involved in regulation of vascular tone and blood flow as well as modulation of blood pressure and heart rate, with most effects being attributed to the NK 1 receptors (Couture et al 1989; Hoover et al 2000; Longmore et al 1997; Walsh and D 2006). There are numerous species differences in the expression of NK receptors, and in animal studies the depth and type of anesthesia influence cardiovascular parameters, such that effects on blood pressure and heart rate measured under anesthesia are not necessarily reflective of the awake state.…”

Characterization of NK1 and NK2 tachykinin receptors in guinea‐pig and rat bronchopulmonary and vascular systems

“…This observation may indicate the presence of NK2 receptors in the vascular system of the rat; moreover, NKA and a more selective NK2 receptor agonist, NKA(4 10), have been reported to be poorly hypotensive peptides (Couture et al, 1989). However, in the present study, the hypotensive effects evoked by NKA and [Lys5, MeLeu9,NLeu'1-NKAf4_l0) were not modified by the selective NK2 receptor antagonists, actinomycin D and SR48968, but were antagonized by the NK1 receptor antagonists, RP 67580 and CP-96,345.…”

Intracerebroventricular responses to neuropeptide γ in the conscious rat: characterization of its receptor with selective antagonists

“…NPy leads one to suggest that receptor sites must be localized in the circumventricular organs or in adjacent periventricular structures. A peripheral site of action is also unlikely since these peptides are vasodilators and reduce blood pressure after systemic administration (Couture et al, 1989; Decarie & Couture, 1992). The cardiovascular changes elicited by i.c.v.…”