Regulation of gall bladder motility by the arginine-nitric oxide pathway in guinea pigs.
Nitric oxide (NO) synthesised from L-arginine is an intercellular messenger in various biological actions including endothelial dependent relaxation and inhibition of platelet aggregation. This study explored the role of the L-arginine-NO pathway in the regulation of gall bladder motility. Intraluminal gall bladder pressure was recorded in anaesthetised guinea pigs in response to cholecystokinin or bethanechol before and after treatment with specific NO synthase inhibitors (NG-nitro-L-arginine, NG-nitro-L-arginine methyl ester, or NG-monomethyl-L-arginine), or with an NO donor (sodium nitroprusside). Baseline gall bladder pressure significantly increased after treatment with the NO synthase inhibitors. Responses to cholecystokinin (0.025-1.25 nmol/kg) were significantly enhanced after treatment with NG-nitro-L-arginine methyl ester and lasted two to threefold longer than in control experiments. The effect of the inhibitor both on resting pressure and on cholecystokinin induced changes was reversed by L-arginine but not by D-arginine. Pretreatment with the inhibitors also induced a significant enhancement of the response to bethanechol. On the other hand, sodium nitroprusside abolished the response to low dose cholecystokinin and reduced the response to a high dose by about 80%. In vitro experiments with isolated gall bladder strips showed a significant enhancement of the contractile response to cholecystokinin or bethanechol after preincubation with the NO synthase inhibitor. Calcium dependent activity of NO synthase was detected in fresh homogenates from gall bladder tissue and incubation with endotoxin induced considerable calcium independent activity. These findings support the existence of a key L-arginine-nitric oxide pathway regulating gall bladder contraction.
Mourelle
M
M
Digestive System Research Unit, Hospital General Vall d'Hebron, Autonomous University of Barcelona, Spain.
Guarner
F
F
Molero
X
X
Moncada
S
S
Malagelada
J R
JR
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D001626:Bethanechol Compounds / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D009599:Nitroprusside / Q000494:pharmacology; D011312:Pressure; D015290:Second Messenger Systems / Q000502:physiology*; D019323:omega-N-Methylarginine
D001626:Bethanechol Compounds; D004731:Endotoxins; D009599:Nitroprusside; D019335:Nitroarginine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D002766:Cholecystokinin; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester