Tachykinin receptors mediating contractions of oestrogen-primed rat uterus: classification using non-peptide antagonists.
1. The aim of the present study was to characterize the tachykinin receptors mediating contractions of the uterus from the oestrogen-primed rat. Apparent pKB values versus mammalian tachykinins and some subtype-selective agonists were determined for the non-peptide NK1, NK2 and NK3 receptor antagonists SR 140333, SR 48968 and SR 142801, respectively. 2. Apparent pKB values for SR 48968 tested at concentrations of 3, 10 and 30 nmol/L versus neurokinin (NKA, [Lys5MeLeu9Nle10] NKA(4-10) and [Nle10] NKA(4-10) were 8.79, 9.44 and 9.33, respectively, indicating activation of an NK2 receptor and, in the case of NKA, the possible activation of an additional receptor subtype. SR 48968 (30 nmol/L) did not affect responses to NKB (1 mumol/L), senktide (30 nmol/L), substance P (SP; 100 nmol/L) or [Sar9Met(O2)11] SP (100 nmol/L), indicating its selectivity at this concentration. 3. SR 140333 (1-100 nmol/L) reduced the effects of the NK1-preferring agonists SP and [Sar9Met(O2)11] SP, indicating the presence of NK1 receptors. The pKB estimate versus [Sar9Met(O2)11] was 9.01. SR 140333 (100 nmol/L) did not affect responses to NK2 and NK3 receptor-preferring agonists. 4. SR 142801 (100 nmol/L to 1 mumol/L) produced small rightward shifts in the log concentration-response curves to NKB, yielding an apparent pKB value of 7.0. At 1 mumol/L, SR 142801 reduced responses to the NK2 agonists, suggesting some non-selectivity at this concentration. 5. Taken together, these data provide strong evidence that tachykinin-induced contractions of the uterus of the oestrogen-primed rat are mediated by NK2 receptors, with some contribution from NK1 receptors.
Fisher
L
L
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Pennefather
J N
JN
D000818:Animals; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015288:Neurokinin A / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000502:physiology*; D018042:Receptors, Neurokinin-3 / Q000187:drug effects / Q000502:physiology; D018039:Receptors, Tachykinin / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology / Q000502:physiology*; D015320:Tachykinins / Q000494:pharmacology / Q000502:physiology; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology*
D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; D015320:Tachykinins; D013373:Substance P; D004958:Estradiol; D015288:Neurokinin A