title: Mechanism of relaxation and interaction with nitric oxide of the soluble guanylate cyclase stimulator BAY 41-2272 in mouse gastric fundus and colon.
abstract: BAY 41-2272 is a heme-dependent nitric oxide-independent soluble guanylate cyclase (sGC) stimulator, but its relaxant effect in vascular, respiratory and urogenital tissue is only partially dependent on sGC activation. As its mechanism of action has not been studied in the gastrointestinal tract, it was investigated in mouse gastric fundus and colon. Circular smooth muscle strips were mounted in organ baths under non-adrenergic non-cholinergic (NANC) conditions for isometric force recording and cGMP levels were determined using an enzyme immunoassay kit. BAY 41-2272 induced concentration-dependent relaxation in both tissues and increased cGMP levels. The sGC inhibitor ODQ totally inhibited this BAY 41-2272-induced increase of cGMP, but only partially reduced the corresponding relaxation. The PDE-5 inhibitor sildenafil had no effect on BAY 41-2272-induced responses. The NO synthase inhibitor L-NAME caused a significant decrease in BAY 41-2272-induced responses in colonic strips. Electrical field stimulation in the presence of BAY 41-2272 induced increased NANC relaxation in fundus, while in colon, rebound contraction at the end of the stimulation train was no longer visible. This suggests synergy with endogenously released NO. Responses to BAY 41-2272 were not significantly influenced by apamin, charybdotoxin or ouabain, excluding interaction with small, intermediate and large conductance Ca(2+)-activated K(+) channels and with Na(+)-K(+)-ATPase. Under depletion of intracellular calcium, CaCl(2)-induced contractions were significantly reduced by BAY 41-2272 in an ODQ-insensitive way. The present study demonstrates that BAY 41-2272 exerts its relaxing effect in mouse gastric fundus and colon partially through a cGMP-dependent mechanism and at least one additional cGMP-independent mechanism involving Ca(2+)-entry blockade.
authors.affiliation: Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, Ghent, Belgium.
authors.forename: Sarah M R
authors.initials: SM
authors.lastname: Cosyns
authors.forename: Romain A
authors.initials: RA
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005748:Gastric Fundus / Q000187:drug effects* / Q000502:physiology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000502:physiology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D010069:Oxadiazoles / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011720:Pyrazoles; D011725:Pyridines; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester