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Prokinetic-like activity of erythromycin in rabbit isolated colon: a comparison with the gastric antrum
Erythromycin, a motilin receptor agonist, contracts gut muscle and exerts gastric prokinetic activity at least partly by facilitating enteric nerve activity. This is supported by studies in rabbit gastric antrum, where the dominant action of motilin was pre-junctional, leading to prolonged facilitation of cholinergically-mediated contractions; higher concentrations evoked short-lived, direct muscle contraction (Dass et al., 2003). In rabbit colon, motilin receptor agonists also directly contract the muscle (eg. Strunz et al., 1975; Deeportere et al., 1991) but there have been no studies to look for any ability to modulate nerve-mediated responses. We re-examined the actions of erythromycin in rabbit colon and compared the effects with those observed in the stomach. Circular muscle preparations ~10 mm x 3 mm were cut from the distal colon and gastric antrum of male 2-3 kg rabbits. These were suspended under 1g load for isometric recording and electrical field stimulation (EFS) in tissue baths containing Krebs solution (37ºC; 5 % CO2 in O2; Dass et al., 2003). The parameters of EFS provided the minimum intensity of stimulation which evoked clear, monophasic muscle contractions, sensitive to prevention by tetrodotoxin (1µM; n=2 each) and reduced in the presence of atropine (1µM; n=2 each). These were 50 v, 10 Hz, 0.5 ms width, 30 s duration every 60 s (stomach) and 50 v, 5 Hz, 0.5 ms width, 10 s duration every 40 s (colon). Concentration-response curves were constructed by non-cumulative dosing; 1 concentration/ preparation . Data are means ± SEM; students t-test. In the colon, erythromycin (0.1 µM – 10 µM) concentration-dependently increased EFS-evoked contractions; lower concentrations had no effects . The maximally-effective concentration (Emax) was 10 µM (contractions increased by 95.4 ± 20.5 %; n=4), the time to achieve Emax was 9.8 ± 4.8 min and the time for the response to decline by 50 % (t½; taken from when drug added) was 31 ± 7.9 min. In the stomach (0.1 µM – 10 µM), the Emax was 490 ± 117 % at 3 µM, the time to achieve Emax was 8.4 ± 2.0 min with a t½ of 24 ± 5.6 min. In the colon erythromycin at 10 µM only, also evoked a short-lived muscle contraction (50.8 ± 5.7 % of contraction to 1 µM carbachol (CCh); n=4), reaching Emax at 43.8 ± 6.8 s with a t½ of 149.0 ± 49.6 s. In the stomach erythromycin 10 µM increased muscle tension by 56.4 ± 32.6 % (n=6), the time to achieve Emax was 114.7 ± 39.6 s with a t½ of 642.8 ± 14.5 s; in the colon but not in the stomach, this activity was followed by an increase in spontaneous muscle contractility. Erythromycin 10 µM had no effects on contractions to a submaximally-effective concentration of CCh (1 µM) in colon or stomach; in the presence of erythromycin or vehicle, respectively, contractions were 83.4 ± 4.0 % vs. 87.5 ± 7.3 % of pre-drug contractions to CCh in the colon (P>0.05; n=3-4) and 105.1 ± 23 % vs. 78.85 ± 14.34 % in the antrum (P>0.05; n=3-4). These data suggest that as for the stomach, the dominant excitatory activity of erythromycin in rabbit colon is pre-junctional, leading to prolonged enhancement of cholinergic activity. A short-lived ability to contract the muscle is apparent only at high concentrations.
Dass NB., et al (2003) Br J Pharmacol., 140, 948 – 954. |
