Selective iNOS inhibition enhances spontaneous gallbladder motility in the Australian possum.
Gallbladder inflammation is a common and painful disease. Inducible nitric oxide synthase (iNOS) plays a major role in inflammatory diseases, and iNOS inhibitors are being developed as therapeutic agents. Reports are inconsistent regarding iNOS expression in normal gallbladder. The aim of this study was to determine the effect of iNOS inhibition on spontaneous gallbladder motility. mRNA extracted from normal possum gallbladders was analysed by PCR. Gallbladder contractility was evaluated using a highly selective iNOS inhibitor AR-C102222AA (AR-C) in in vitro muscle strips (0.1-10 000 microm) and in vivo (0.1-30 micromol kg(-1)) experiments. Gene expression analysis revealed the presence of iNOS mRNA in normal gallbladder (n = 3). In vitro, AR-C (0.1-1000 micromol L(-1)) produced a concentration-dependent increase in spontaneous gallbladder contractile activity and basal tension (P < 0.05; n = 6). The maximum effect was a 1.8-fold increase in activity and 2.1-fold increase in basal tension. Pretreatment of muscle strips with tetrodotoxin (1 micromol L(-1)) did not block the AR-C-induced response (n = 5). In vivo, AR-C (30 micromol kg(-1), i.v.) increased gallbladder contraction frequency (P < 0.05; n = 8). These data suggest that iNOS is continually expressed in the normal gallbladder, which presumably releases low levels of nitric oxide and in turn may modulate spontaneous gallbladder motility. AR-C may be a beneficial treatment for patients suffering from acute cholecystitis.
Woods
C M
CM
Department of General and Digestive Surgery, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia.
Sandstrom
P
P
Bond
M
M
Michael
M
M
Svanvik
J
J
Toouli
J
J
Saccone
G T P
GT
D000818:Animals; D002764:Cholecystitis / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism*; D016473:Gallbladder Emptying / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D016133:Polymerase Chain Reaction; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D048330:Trichosurus
C489944:AR C102222AA; D004791:Enzyme Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II