Differential effects of progesterone and its analogues on the contractility of the murine jejunum in vitro.
Epidemiological studies have demonstrated a higher prevalence of gastrointestinal motility disturbances in women compared with men. This may partly be due to the effects of sex hormones on smooth muscle cells. To further characterize the mechanisms by which sex hormones affect intestinal smooth muscle, we studied the effects of several structurally related progestins on intestinal contractility. Segments of the murine intestine oriented along the longitudinal axis were connected to force displacement transducers. We recorded the isometric tension generated by the murine jejunum spontaneously and after cholinergic stimulation. The baseline tension, amplitude of spontaneous contractions, and increase in tension after cholinergic stimulation were measured in the presence and absence of various steroid hormones. Progesterone dose dependently decreased the contractile activity of the murine jejunum. This effect occurred within less than 1 min and could not be inhibited by a specific blocker of the progesterone receptor, suggesting a nongenomic pathway. Experiments with several progestins demonstrated a stereoselectivity of this steroid hormone effect. This was most pronounced for dihydroprogesterone: the 5 alpha form did not affect intestinal contractility, while the stereoisomer 5 beta-dihydroprogesterone significantly inhibited smooth muscle tension. We conclude that progesterone significantly inhibits the contractility of the murine jejunum in vitro. The differential effects of various structural analogues argue against a nonspecific effect of the steroid hormones on the lipid bilayer with secondary functional alterations of membrane proteins. Rather, they suggest a specific interaction between the steroid hormone and a still unidentified protein that differs in its function and pharmacological profile from the known progesterone receptor.
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Department of Surgery, University of Iowa College of Medicine, Iowa City 52242, USA.
Yedidag
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Bielefeldt
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D004092:20-alpha-Dihydroprogesterone / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D007583:Jejunum / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D010277:Parasympathomimetics / Q000494:pharmacology; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006067:Gonanes; D006727:Hormone Antagonists; D010277:Parasympathomimetics; D004092:20-alpha-Dihydroprogesterone; D011374:Progesterone; D002217:Carbachol; C053238:onapristone