Facilitatory effects of selective agonists for tachykinin receptors on cholinergic neurotransmission: evidence for species differences.
1. Exogenous tachykinins modulate cholinergic neurotransmission in rabbit and guinea-pig airways. We have investigated the effect of selective tachykinin receptor agonists and antagonists on cholinergic neurotransmission evoked by electrical field stimulation (EFS) of bronchial rings in rabbit, guinea-pig and human airways in vitro to assess which type of tachykinin receptor is mediating this facilitatory effect. 2. Bronchial rings were set up for isometric tension recording. Contractile responses to EFS (60 V, 0.4 ms, 2 Hz for 10 s every min) and exogenous acetylcholine (ACh) were obtained and the effects of selective tachykinin agonists and antagonists were investigated. 3. In rabbit bronchi the endogenous tachykinins, substance P (SP) and neurokinin A (NKA) (10 nM) potentiated cholinergic responses to EFS (by 287.6 +/- 121%, P < 0.01 and 181.4 +/- 56.5%, P < 0.001 respectively). 4. The NK1 receptor selective agonist, [Sar9]SP sulphone (10 nM) evoked a maximal facilitatory action on cholinergic responses of 334.9 +/- 63% (P < 0.01) (pD2 = 8.5 +/- 0.06) an effect which was blocked by the selective NK1-receptor antagonist, CP 96,345 (100 nM) (P < 0.05) but not by the NK2 receptor antagonist, MEN 10,376 (100 nM). The NK2 receptor selective agonist, [beta Ala8]NKA(4-10) (10 nM), produced a maximum enhancement of 278 +/- 83.5% (P < 0.01) (pD2 = 8.7 +/- 0.1) an effect which was blocked by MEN 10,376 (100 nM) (P < 0.05) and not by CP 96,345. [MePhe7]NKB, an NK3 receptor selective agonist was without effect. 5. The rank order of potency of NK2 receptor antagonists against enhancement of cholinergic responses by [Beta Ala8]NKA(4-10) was MEN 10,376> L 659,877> R 396. This pattern together with the observation of the full agonist activity of MDL 28,564 indicates that the NK2 receptors in the rabbit bronchus are similar to those which are present in the rabbit pulmonary artery.6. Neither [Sar9]SP sulphone (5 nM) nor [Beta Ala8]NKA(4- 10) (1 nM) had any effect on contractile responses to ACh (10 MicroM) suggesting a pre-junctional mechanism of action.7. By contrast, in guinea-pig bronchi only the NK1-receptor agonist [Sar9]SP sulphone (3 nM) was effective in enhancing cholinergic neurotransmission but the effect was relatively small (maximal enhancement 25.7 +/- 5.5%, P<0.01). In human bronchial rings all the selective neurokinin agonists were without effect on cholinergic neurotransmission.8. These results suggest that tachykinins may play an important role in modulating cholinergic neurotransmission in rabbit (via NK1 and NK2 receptors) and guinea-pig airways (via NK1 receptor) but have no demonstrable effect on human airways
Belvisi
M G
MG
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Patacchini
R
R
Barnes
P J
PJ
Maggi
C A
CA
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000294:innervation; D002211:Capsaicin / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D011817:Rabbits; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D015320:Tachykinins / Q000494:pharmacology / Q000502:physiology*
D010446:Peptide Fragments; D018039:Receptors, Tachykinin; D013450:Sulfones; D015320:Tachykinins; C062618:substance P, Sar(9)-Met(O2)(11)-; C064218:neurokinin A (4-10), beta-Ala(8)-; D013373:Substance P; D015288:Neurokinin A; D002211:Capsaicin