Effects of Lubiprostone, a Novel GI Chloride Channel Activator, on Isolated Smooth Muscle

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Purpose: Lubiprostone (L) is a novel bicyclic fatty acid that selectively stimulates GI ClC-2 chloride channels. Fatty acids induce relaxation or contraction of smooth muscle, depending on tissue type. This study compares the activity of L on smooth muscle with that of other fatty acids. Methods: The agonist activity of L via prostaglandin (PG) receptors was assessed by measuring ileum longitudinal smooth muscle contraction (EP1 receptor), ileum circular smooth muscle twitch inhibition (EP2 receptor), vas deferens twitch inhibition (EP3 receptor), or iris sphincter contraction (FP receptor). Activity was expressed as a percentage of activity of PGE2 or PGF2α. The ability of L to elicit contractile activity in isolated uterine muscle in the nulliparous rat was compared to PGE1. Guinea pig tracheal strips were used to assess relaxing activity. L was tested at 10−9-10−5M. Isolated rat ileum was examined for L- and acetylcholine (ACh)-induced contractions (10−9-10−5M). Results: At 10,000 nM, L elicited only 54% and 23.4% of the maximal activity of PGE2 or PGF2α on PG EP1 or FP receptors, respectively. L was significantly less potent than PGE2 or misoprostol in inhibiting PG EP2 receptor-mediated ileum circular smooth muscle twitch. IC50 values of PGE2, misoprostol, and L were 52.2nM, 29.9nM, and 581.4nM, respectively. In guinea pig vas deferens, the IC50 value of PGE3 receptor-mediated twitch inhibition for L (40.6nM) was 20–40 times less than that of PGE2 (1.9nM) or misoprostol (0.9nM). In isolated rat uterus, L had no effect on spontaneous contractions at concentrations up to 10−8M. At L concentrations of 10−7, 10−6, and 10−5M, contractile tension increased by 16.8% (p < 0.05), 18.4% (p < 0.01), and 41.3% (p < 0.01), respectively, with contractile frequency at the highest dose approximately 2.4 times the pretreatment frequency. PGE1 increased contractile tension at 10−8-10−5M (25.4%-50.8%), indicating that L has 10-fold lower contractile activity than PGE1. L had no effect on guinea pig trachea at any concentration tested, in contrast to alprostadil and ornoprostil, which have reported effects at concentrations as low as 10−9M. In isolated rat ileum, L had no effect at 10−9 and 10−8M, and 19.4% and 46.5% at 10−7 and 10−6M, respectively, of maximal contraction induced by 10−6M ACh. Conclusions: Lubiprostone has no pharmacologically relevant activity on prostaglandin receptors or various smooth muscle tissues.