Cholesterol depletion enhances both spontaneous and agonist-evoked uterine smooth muscle contractions in a reversible manner.

In experiments designed to determine the consequence of cholesterol depletion on relaxation signaling in the uterus, we treated isolated strips of guinea pig myometrium in organ baths with beta-methyl cyclodextrin (beta-MeCD) to remove cholesterol expecting suppression of spontaneous activity and uncoupling of agonist specific relaxation as we have shown in vascular muscle (Circulation Research 91:292-299, 2002). Treatment of myometrium with 15 mM beta-MeCD for 15 min led to enhancement of spontaneous activity that was further increased following a second beta-MeCD treatment. beta-MeCD treated tissues developed increased force on top of that already present basally when stimulated by OT, but reached the same maximum as control tissues. Washout of OT relaxed control but not beta-MeCD pretreated tissues. When cholesterol depleted tissues were repleted with cholesterol using a water-soluble preparation, they immediately relaxed to baseline. Overloading of cholesterol to beta-MeCD-naive tissues suppressed spontaneous contractions and diminished responses to OT. These findings suggest that cholesterol selectively uncouples relaxation signaling. We propose that myometrial activity may be altered in women acutely by changes in serum cholesterol and that understanding the distinctions between myometrial smooth muscle and other smooth muscles may reveal heretofore unknown therapeutic targets for the treatment of uterine dysfunction.