Tachykinin receptors mediate atropine-resistant rat duodenal reflex contractions in vivo.
The study aimed to establish the possible role of tachykinins as mediators of atropine-resistant reflex contractions evoked by balloon distension in the proximal duodenum of urethane-anesthetized, guanethidine (34 mumol/kg s.c.)-pretreated rats. Distension of the balloon with a small amount (0.2-0.3 ml) of saline induced the appearance of phasic rhythmic contractions (about 11 mmHg in amplitude) which were promptly suppressed by either atropine (3 mumol/kg i.v.) or hexamethonium (28 mumol/kg i.v.). Despite the continuous i.v. infusion of atropine (2 mumol/h), low-amplitude rhythmic phasic contractions recovered, which were promptly suppressed by hexamethonium, to indicate the involvement of an atropine-resistant excitatory reflex. The amplitude of these atropine-resistant contractions was increased to about 4-5 mmHg by further distension of the balloon (0.4-0.6 ml) : under these conditions, the atropine-resistant contractions undergo a progressive fading. The fading was prevented by i.v. administration of the nitric oxide (NO) synthase inhibitor, L-nitroarginine methyl ester (L-NAME, 55 mumol/h), to provide a suitable baseline (amplitude of contractions was 7-8 mmHg) for studying the effect of tachykinin receptor antagonists. I.v. administration of the selective tachykinin NK2 receptor antagonists, MEN 10,627 (10-100 nmol/kg) and SR 48968 (100-300 nmol/kg) or of the selective NK1 antagonist SR 140333 (100 nmol/kg), at doses which do not affect the duodenal contractions induced by acetylcholine (5.5 mumol/kg i.v.), produced a prompt and long lasting suppression of the atropine-resistant reflex duodenal contractions produced by balloon distension in urethane-anesthetized rats, whilst SR-48965 (300 nmol/kg), the enantiomer of SR-48968 devoid, of NK2 receptor blocking activity, was without effect. I.v. administration of the selective NK1 receptor agonists [Sar9] substance P sulfone and septide or of the NK2 receptor selective agonist, [beta Ala8] neurokinin A(4-10) produced dose-dependent contractions of the duodenum. SR 140333 (100 nmol/kg i.v.) selectively antagonized the duodenal contractions produced by [Sar9] substance P sulfone and septide without affecting those produced by [beta Ala8] neurokinin A(4-10). On the other hand, MEN 10,627 (30-100 nmol/kg i.v.) and SR 48968 (100-300 nmol/kg i.v.) but not SR 48965 (300 nmol/kg i.v.) antagonized, at a comparable extent, duodenal contractions induced by both the selective NK2 and NK1 receptor agonists. We conclude that endogenous tachykinins are involved in mediating atropine-resistant reflex contractions evoked by distension of the rat duodenum in vivo: both NK1 and NK2 receptors are activated by endogenous ligands to produce NANC contractions of rat duodenum in vivo. However, the contractile response to i.v. administered NK1 receptor agonists, [Sar9] substance P sulfone and septide, may involve the release of mediators producing smooth muscle contraction via NK2 receptors.
Giuliani
S
S
Pharmacology Department, Research Laboratories, Menarini Ricerche, Florence, Italy.
Tramontana
M
M
Lecci
A
A
Maggi
C A
CA
D000704:Analysis of Variance; D000818:Animals; D001285:Atropine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D002404:Catheterization; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D018039:Receptors, Tachykinin / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology
D001549:Benzamides; D004791:Enzyme Inhibitors; D018727:Muscarinic Antagonists; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D018039:Receptors, Tachykinin; C090951:MEN 10627; D013373:Substance P; C073839:SR 48968; C054725:septide; D001285:Atropine; D015288:Neurokinin A; D011761:Pyrrolidonecarboxylic Acid; D019331:NG-Nitroarginine Methyl Ester