Tachykinin-stimulated small bowel myoelectric pattern: sensitization by NO inhibition, reversal by neurokinin receptor blockade.
Tachykinins stimulate motility whereas NO inhibits motility in the gastrointestinal tract.


OBJECTIVE
To investigate if inhibition of NO production sensitizes myoelectric activity to subthreshold doses of tachykinins in the small intestine of awake rats.


METHODS
Rats were supplied with a venous catheter and bipolar electrodes at 5, 15 and 25 cm distal to pylorus for electromyography of small intestine. The motor responses were evaluated using pattern recognition. Substance P and neurokinin A dose-dependently stimulated gut motility, with neurokinin A being more potent than substance P. Therefore, neurokinin A was chosen and administered under baseline conditions and 45-60 min after N(omega)-nitro-L-arginine (L-NNA) 1 mg kg(-1), with or without pretreatment with L-arginine 300 mg kg(-1). In addition, myoelectric activity effects of neurokinin A in conjunction with L-NNA were studied before and after administration of the tachykinin receptor antagonists, SR140333 (NK1), SR48968 (NK2) and SR142801 (NK3), each at 2.5 mg kg(-1).


RESULTS
Dose-finding studies verified 10 pmol kg(-1) min(-1) to be the threshold dose at which NKA caused phase II-like activity in a low percentage of experiments (12%, n=41). This dose was therefore used in combination with L-NNA for sensitization experiments of gut myoelectric activity. In experiments where NKA-induced no response, pretreatment with L-NNA led to phase II-like activity in 9 of 18 (50%, p<0.05) experiments. Co-administration of SR140333 and SR48968 abolished this effect.


CONCLUSIONS
NO counteracts the stimulatory effect of tachykinins on small bowel myoelectric activity in the rat. Inhibition of the L-arginine/NO pathway sensitizes the gut to tachykinin-stimulated motor activity.
Schmidt
Peter Thelin
PT
Gastroenterology Unit, Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden. Peter.Thelin.Schmidt@medks.ki.se
Bozkurt
Ayhan
A
Hellström
Per M
PM
D000818:Animals; D001120:Arginine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004576:Electromyography; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects*; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D018039:Receptors, Tachykinin; D015320:Tachykinins; D009569:Nitric Oxide; D013373:Substance P; D015288:Neurokinin A; D001120:Arginine; D019001:Nitric Oxide Synthase