title: Progesterone inhibits gallbladder motility through multiple signaling pathways.
abstract: Progesterone (P) has an inhibitory effect on the contractility of gastrointestinal smooth muscle, including the gallbladder. Since P levels are elevated during pregnancy, a biliary stasis may develop during pregnancy that is characterized by an increase in the fasting and residual volumes and by a decrease in emptying capacity. This study investigates the effect of P and two metabolites on contraction in guinea pig gallbladder strips. P induced a concentration-dependent relaxation in guinea pig gallbladder strips precontracted with cholecystokinin octapeptide (CCK). Pretreatment of gallbladder strips with P (50 microM) also reduced the amount of CCK-induced tension. Nifedipine (1 microM) produced a similar effect. Pretreatment of the strips with PKA inhibitor 14--22 amide myristolated (180 nM) or the PKG inhibitor KT5823 (1.2 microM) either separately or in combination significantly reduced the amount of P-induced relaxation. Rp-cAMPs (0.1mM) or H-89 (10 microM) separately or in combination significantly reduced the P-effect; however, the combination of agents produced the largest reduction. Genistein (1 microM), an inhibitor of protein tyrosine kinases, significantly (p<0.01) reduced the amount of P-induced relaxation. The use of strontium in the Kreb's solution as a substitute for Ca(2+) significantly (p<0.01) reduced the amount of CCK-induced tension. Pretreatment of the strips with 2-APB (26 microM), an inhibitor of IP(3,) induced Ca(2+) release, produced a significant (p<0.01) reduction in P-induced relaxation. We conclude that P inhibits gallbladder motility rapidly by nongenomic actions of the hormone. Several pathways that include tyrosine kinase and PKA/cAMP activity may mediate this effect.
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alta., Canada T6G 2H7. lkline@ualberta.ca
authors.forename: L W
authors.initials: LW
authors.lastname: Kline
authors.forename: E
authors.initials: E
authors.lastname: Karpinski
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000494:pharmacology; D004092:20-alpha-Dihydroprogesterone / Q000494:pharmacology; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000172:deficiency; D002227:Carbazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D016473:Gallbladder Emptying / Q000187:drug effects / Q000502:physiology*; D019833:Genistein / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013324:Strontium / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D001896:Boron Compounds; D002227:Carbazoles; D002352:Carrier Proteins; D007211:Indoles; D007546:Isoquinolines; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C477818:myristoylated protein kinase A inhibitor amide 14-22; C073601:KT 5823; D004092:20-alpha-Dihydroprogesterone; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; D002766:Cholecystokinin; D019833:Genistein; C109986:2-aminoethoxydiphenyl borate; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D009543:Nifedipine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium; D013324:Strontium