Guinea pig ileum motility stimulation elicited by N-formyl-Met-Leu-Phe (fMLF) involves neurotransmitters and prostanoids.
In guinea-pig ileum (GPI), the chemotactic peptide N-formyl-Met-Leu-Phe-OH (fMLF) possesses spasmogenic properties through the activation of formyl peptide receptors (FPRs). Despite this, the mediators involved remain to be elucidated. fMLF (1nM-1μM) induced a dose-dependent contraction of GPI (EC(50)=24nM), that is blocked by pre-treatment with the FPRs antagonist Boc(2). The pre-treatment with tetrodotoxin (TTX) atropine or with SR140333 reduced the fMLF-induced contraction, whereas with hexamethonium, MEN10627, SB222200, mepyramine, cimetidine, thioperamide or methysergide did not produce any effect. With DuP697 pre-treatment, but not with piroxicam, reduced the fMLF-induced contraction. After stimulation with 24nM fMLF, a strong increase in the PGE(2) levels was observed. Finally, the concomitant blocking of the NK(1) receptor, the muscarinic receptors and COX-2 abolished the GPI contractions induced by fMLF. fMLF induced a concentration-dependent contraction of guinea-pig jejunum (EC(50)=11nM), proximal colon (EC(50)=3.5nM) and distal colon (EC(50)=2.2nM), with a time-course similar to that observed in GPI. In these preparations as well, the co-administration of atropine, SR140333 and DuP697 abolished the contractions induced by fMLF. Intraperitoneal injection of fMLF (0.1 or 1μmol/kg) enhanced the gastrointestinal motility in mice, abolished by the co-administration of atropine, SR140333 and DuP697. In conclusion, we showed that fMLF exerts spasmogenic actions on guinea-pig intestine both in vitro and in vivo through the release of acetylcholine and substance P from myenteric motorneurons and through prostanoids, probably from the inflammatory cells of the enteric immune system.
Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, viale Regina Elena 299, 00161 Rome, Italy.
Mariantonella
M
Colucci
Marica
M
Mastriota
Francesco
F
Maione
Amalia
A
Di Giannuario
Nicola
N
Mascolo
Maura
M
Palmery
Cinzia
C
Severini
Mauro
M
Perretti
Stefano
S
Pieretti
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D005772:Gastrointestinal Transit / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology*; D041741:Lower Gastrointestinal Tract / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010894:Piroxicam / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism*; D011812:Quinuclidines / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D041742:Upper Gastrointestinal Tract / Q000187:drug effects / Q000502:physiology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents; D009842:Oligopeptides; D010880:Piperidines; D011453:Prostaglandins; D011812:Quinuclidines; D013876:Thiophenes; D010894:Piroxicam; C085215:SR 140333; D013779:Tetrodotoxin; D009240:N-Formylmethionine Leucyl-Phenylalanine; C033373:butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine; D001285:Atropine; C064874:DuP 697; D015232:Dinoprostone