Respiratory actions of tachykinins in the nucleus of the solitary tract: characterization of receptors using selective agonists and antagonists.
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.
Mazzone
S B
SB
School of Biomedical Science, University of Tasmania, P.O. Box 320, Launceston, Tasmania 7250, Australia.
Geraghty
D P
DP
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D008297:Male; D008845:Microinjections; D015288:Neurokinin A / Q000008:administration & dosage / Q000494:pharmacology; D015287:Neurokinin B / Q000008:administration & dosage / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors; D018039:Receptors, Tachykinin / Q000819:agonists* / Q000037:antagonists & inhibitors*; D015656:Respiratory Mechanics / Q000187:drug effects*; D017552:Solitary Nucleus / Q000187:drug effects*; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology; D015320:Tachykinins / Q000494:pharmacology*; D013990:Tidal Volume / Q000187:drug effects
D001549:Benzamides; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; D015320:Tachykinins; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; C073839:SR 48968; D015288:Neurokinin A; D015287:Neurokinin B; C091554:SR 142801