5-HT4 receptor agonists enhance both cholinergic and nitrergic activities in human isolated colon circular muscle.
Previous studies have demonstrated mixed inhibitory and facilitatory effects of 5-hydroxytryptamine-4 (5-HT(4)) receptor agonists on electrical field stimulation (EFS)-induced responses in human isolated colon. Here we report three types of responses to EFS in human isolated colon circular muscle: monophasic cholinergic contraction during EFS, biphasic response (nitrergic relaxation during EFS followed by cholinergic contraction after termination of EFS) and triphasic response (cholinergic contraction followed by nitrergic relaxation during EFS and a tachykininergic contraction after EFS). The effects of two 5-HT(4) receptor agonists, prucalopride and tegaserod were then investigated on monophasic responses only. Each compound inhibited contractions during EFS in a concentration-dependent manner. In the presence of N(omega)-nitro-l-arginine methyl ester (l-NAME) however, prucalopride and tegaserod enhanced the contractions in a concentration-dependent manner. In strips where the tone was elevated with substance-P and treated with scopolamine, EFS-induced relaxations were enhanced by the two agonists. The above observed effects by the two agonists were abolished by 5-HT(4) receptor antagonist SB-204070. The two agonists did not alter the tone raised by substance-P in the presence of scopolamine and l-NAME and did not affect carbachol-induced contractions in the presence of tetrodotoxin. These results suggest that in the circular muscle of human colon, 5-HT(4) receptor agonists simultaneously facilitate the activity of neurones which release the inhibitory and excitatory neurotransmitters, nitric oxide and acetylcholine respectively.
Cellek
S
S
Neurology and Gastroenterology Centre of Excellence in Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK. selim.2.cellek@gsk.com
John
A K
AK
Thangiah
R
R
Dass
N B
NB
Bassil
A K
AK
Jarvie
E M
EM
Lalude
O
O
Vivekanandan
S
S
Sanger
G J
GJ
D000109:Acetylcholine / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001572:Benzofurans / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009924:Organ Culture Techniques; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors; D012601:Scopolamine / Q000494:pharmacology; D058828:Serotonin 5-HT4 Receptor Agonists; D013373:Substance P / Q000494:pharmacology
D001572:Benzofurans; D004791:Enzyme Inhibitors; D007211:Indoles; D018727:Muscarinic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D058828:Serotonin 5-HT4 Receptor Agonists; C406662:prucalopride; D009569:Nitric Oxide; D013373:Substance P; C105050:tegaserod; D012601:Scopolamine; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester