Respiratory actions of tachykinins in the nucleus of the solitary tract: characterization of receptors using selective agonists and antagonists

Abstract

1. The respiratory response to microinjection of tachykinins and analogues into the commissural nucleus of the solitary tract (cNTS) of urethane-anaesthetized rats was investigated in the presence and absence of selective tachykinin NK(1), NK(2) and NK(3) antagonists (RP 67580, SR 48968 and SR 142801, respectively). 2. All tachykinins, except for the selective NK(2) agonist, [Nle(10)]-NKA(4-10), increased tidal volume (VT). The rank potency order of naturally-occurring tachykinins was neurokinin A (NKA)> or =substance P (SP)>>NKB, whereas the rank order for selective analogues was senktide> or = septide>> [Sar(9),Met(O(2))(11)]-SP>>[Nle(10)]-NKA(4-10). Septide (NK(1)-selective) and senktide (NK(3)-selective) were 22 fold more potent (pD(2) approximately 12) at stimulating VT than SP (pD(2) approximately 10.5). 3. Tachykinin agonists produced varying degrees of respiratory slowing, independent of changes in VT. At doses producing maximum stimulation of VT, agonists induced either a mild (<10 breaths min(-1) decrease; SP and septide), moderate (10 - 25 breaths min(-1) decrease; NKA, NKB and [Sar(9),Met(O(2)]-SP) or severe ( approximately 40 breaths min(-1) decrease; senktide) bradypnoea. [Nle(10)]-NKA(4-10) produced a dose-dependent bradypnoea without affecting VT. 4. RP 67580 significantly attenuated the VT response to SP (33 pmol) and NKA (10 pmol) but not NKB (100 pmol). In the presence of RP 67580, the mild bradypnoeic response to NKB was significantly enhanced whereas SP and NKA induced a bradyapnea which was not observed in the absence of RP 67580. SR 48968 had no effect on the VT response to SP or NKB, markedly enhanced the VT response to NKA and completely blocked the bradypnoeic response to [Nle(10)]-NKA(4-10). Only SR142801 attenuated the VT response to NKB. 5. The present data suggest that all three tachykinin receptors (NK(1), NK(2) and NK(3)) are present in the cNTS and are involved in the central control of respiration.

Figure 1

Respiratory response to microinjection of low, medium and high doses of SP (a,b,c), [Nle¹⁰-NKA(4-10) (d,e,f) and senktide (g,h,i) into the cNTS of spontaneously breathing, urethane-anaesthetized rats. Each point represents the mean tidal volume (VT), frequency (f) or minute ventilation (VE) of 3–5 rats. Vertical lines show the s.e.mean. Where error bars are not obvious, they are within the symbol.

Figure 2

Log dose-response curves for naturally-occurring tachykinins (a–c) and receptor-selective synthetic agonists (d–f), microinjected into the cNTS of spontaneously breathing, urethane-anaesthetized rats. Each point is the mean maximum agonist-induced change in tidal volume (ΔVT), frequency (Δf) or minute ventilation (ΔVE) of 3–8 rats. Vertical lines show the s.e.mean. Where error bars are not obvious, they are within the symbol.

Figure 3

Effect of the NK₁, NK₂ and NK₃ receptor antagonists, RP 67580 (165 pmol), SR 48968 (165 pmol) and SR 142801 (165 pmol), respectively, on tidal volume (VT) and respiratory frequency (f) responses to microinjection of SP (33 pmol) into the cNTS of spontaneously breathing, urethane-anaesthetized rats. SP was injected into the cNTS at time zero (first arrow) and 80 min (third arrow). Ten minutes prior to the second injection of SP, vehicle (25% ethanol in normal saline) or RP 67580 (a,b), SR 48968 (c,d) or SR 142801 (e,f) were injected (second arrow). Values are the mean of four rats. Vertical lines show s.e.mean. Where error bars are not obvious, they are within the symbol.

Figure 4

Effect of the NK₁, NK₂ and NK₃ receptor antagonists, RP 67580 (50 pmol), SR 48968 (50 pmol) and SR 142801 (50 pmol), respectively, on tidal volume (VT) and respiratory frequency (f) responses to microinjection of NKA (10 pmol) into the cNTS of spontaneously breathing, urethane-anaesthetized rats. NKA was injected into the cNTS at time zero (first arrow) and 80 min (third arrow). Ten minutes prior to the second injection of NKA, vehicle (25% ethanol in normal saline) or RP 67580 (a,b), SR 48968 (c,d) or SR 142801 (e,f) were injected (second arrow). Values are the mean of four rats. Vertical lines show s.e.mean. Where error bars are not obvious, they are within the symbol.

Figure 5

Effect of the NK₁, NK₂ and NK₃ receptor antagonists, RP 67580 (500 pmol), SR 48968 (500 pmol) and SR 142801 (500 pmol), respectively, on tidal volume (VT) and respiratory frequency (f) responses to microinjection of NKB (100 pmol) into the cNTS of spontaneously breathing, urethane-anaesthetized rats. NKB was injected into the cNTS at time zero (first arrow) and 80 min (third arrow). Ten minutes prior to the second injection of NKB, vehicle (25% ethanol in normal saline) or RP 67580 (a,b), SR 48968 (c,d) or SR 142801 (e,f) were injected (second arrow). Values are the mean of four rats. Vertical lines show s.e.mean. Where error bars are not obvious, they are within the symbol.