Inhibition by Female Sex Steroids of Peristalsis in the Guinea Pig Small Intestine

Abstract

Aims: The effects of steroid hormones on propulsive peristalsis in the intestine were investigated in order to compare their adverse effect profile on this clinically most important motor pattern. Methods: Peristalsis in isolated segments of the guinea pig small intestine was triggered by luminal distension and recorded via the peristalsis-associated changes of the intraluminal pressure. Drug effects on muscular activity were investigated in a circular muscle preparation of the ileum. Results: Estradiol and progesterone, but not testosterone, hydrocortisone or cholesterol (each at 3–30 µM), caused a prompt and concentration-related increase in the peristaltic pressure threshold at which propulsive muscle contractions were elicited. Mifepristone (RU-486; 30 µM) did not prevent the inhibitory effect of progesterone, but blocked peristalsis per se. Pharmacological blockade of inhibitory neural pathways with N^G-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), naloxone (opioid receptor antagonist), apamin or suramin plus pyridoxal phosphate-6-azophenyl-2′,4′-disulphonic acid (P2 purinoceptor blockers) counteracted the inhibitory effect of submaximally (10 µM), but not maximally (30 µM), effective concentrations of progesterone. Estradiol and progesterone depressed circular muscle contractions evoked by cholecystokinin octapeptide to a larger degree than responses to the tachykinin NK₁ receptor agonist GR-73,632. Conclusion: The peristaltic motor inhibition caused by sex steroids at micromolar concentrations arises primarily from a depressant action on intestinal muscle activity and may be particularly relevant for high-dose regimens of mifepristone.