Differential effects of antimuscarinic agents on intestinal motility in the conscious dog.
In this study we investigated the effects of antimuscarinics with different selectivity on the intestinal migrating myoelectric complex (MMC) in five fasting, conscious dogs, chronically fitted with electrodes along the small bowel. Furthermore, we evaluated the chronotropic and mydriatic effects to assess the in vivo selectivity of the agents tested. Dose-response studies were performed with the following drugs administered i.v.: atropine, telenzepine (M1 antagonist), AF-DX 116 [11,2-(diethylamino)methyl-1-piperidinyl-acetyl-5,11-dihydro-6H-pyrido-2 ,3b- 1,4-benzodiazepine-6-one (M2 antagonist)] and 4-diphenylacetoxy-N- methylpiperidine methiodide (4-DAMP) (M3 antagonist). All the antimuscarinics tested dose-dependently increased the duration of the MMC period and inhibited spike activity, except low-dose telenzepine (3-10 nmol/kg), which shortened the MMC period and stimulated spike activity. High-dose telenzepine (> 100 nmol/kg) mimicked the inhibitory effect of atropine on the intestine. ED50 values for delay of MMC onset were 87,232, > 10,000 and 129 nmol/kg for atropine, telenzepine, AF-DX 116 and 4-DAMP, respectively. At doses lengthening the MMC period, atropine and 4-DAMP also induced tachycardia and mydriasis. At doses shortening the MMC period, telenzepine had no effect on pupil diameter or heart rate, except at the dose of 10 nmol/kg, which reduced heart rate. Finally, AF-DX 116, at doses inducing marked tachycardia, had a minor intestinal effect and no mydriatic effect. The present data are consistent with the hypothesis that both M1 and M3 receptors are involved in the regulation of the MMC: M1 receptors are probably located on an inhibitory pathway, whereas M3 receptors mediate excitatory stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)
de Ponti
F
F
Department of Internal Medicine and Therapeutics, University of Pavia, Italy.
Einaudi
A
A
Cosentino
M
M
D'Angelo
L
L
Lecchini
S
S
Frigo
G M
GM
Crema
A
A
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010276:Parasympatholytics / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000502:physiology*
D010276:Parasympatholytics; D010880:Piperidines; D011976:Receptors, Muscarinic; C046338:telenzepine; D010890:Pirenzepine; D001285:Atropine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; C048593:otenzepad