Differences in circular muscle contraction and peristaltic motor inhibition caused by tachykinin NK1 receptor agonists in the guinea-pig small intestine.
The tachykinin NK1 receptor agonist substance P methyl ester (SPOME) impedes intestinal peristalsis by releasing nitric oxide (NO) from inhibitory motor neurones. Since NK1 receptor agonists differ in their receptor interaction, we set out to compare a range of NK1 receptor agonists including SPOME, septide and GR-73 632 in their effects on propulsive peristalsis and circular muscle activity in the guinea-pig isolated small intestine. SPOME (100-300 nM) inhibited peristalsis by a rise of the pressure threshold at which peristaltic waves were triggered, whereas septide and GR-73 632 (30-300 nM) interrupted peristalsis by causing circular muscle spasms. Separate experiments showed that all three NK1 receptor agonists caused contraction of the circular muscle, which was enhanced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (300 mM) and the P2X purinoceptor antagonist suramin (300 mM). In contrast, tetrodotoxin (300 nM) augmented the contractile effect of septide and GR-73 632 but not that of SPOME. It is concluded that the motor response to NK1 receptor agonists involves release of NO and adenosine triphosphate from inhibitory motor neurones. However, the NK1 receptor agonists differ in the mechanism by which they cause inhibitory transmitter release, which corresponds to differences in their antiperistaltic action.
Shahbazian
A
A
Department of Experimental and Clinical Pharmacology, University of Graz, Austria.
Holzer
P
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D007421:Intestine, Small / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009046:Motor Neurons / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology* / Q000633:toxicity; D010528:Peristalsis / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D011812:Quinuclidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000819:agonists* / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000819:agonists; D018042:Receptors, Neurokinin-3 / Q000819:agonists; D012844:Sincalide / Q000494:pharmacology; D013035:Spasm / Q000139:chemically induced; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology* / Q000633:toxicity; D013498:Suramin / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D010880:Piperidines; D058919:Purinergic P2 Receptor Antagonists; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C054724:senktide; C068032:GR 73632; C068031:neurokinin A (3-10), lysyl(3)-glycyl(8)-R-lactam-leucine(9)-; C085215:SR 140333; D009569:Nitric Oxide; D013373:Substance P; D013779:Tetrodotoxin; D013498:Suramin; C033611:substance P, methyl ester-; C054725:septide; D015288:Neurokinin A; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D012844:Sincalide; D011761:Pyrrolidonecarboxylic Acid; D019331:NG-Nitroarginine Methyl Ester