Diacylglycerol lipase and the contractile action of epidermal growth factor-urogastrone: evidence for distinct signal pathways in a single strip of gastric smooth muscle.
In guinea pig gastric longitudinal muscle preparations, wherein epidermal growth factor-urogastrone (EGF-URO) causes contraction via the generation of arachidonate-derived prostaglandins, the specific diacylglycerol lipase (DG lipase) inhibitor, U57,908 (formerly designated RHC 80267) completely blocked EGF-URO and transforming growth factor-alpha (TGF-alpha)-mediated contraction, without affecting contractions caused by other agonists such as bradykinin, prostaglandin F2 alpha or arachidonic acid (AA). In contrast, the contractile actions of EGF-URO and TGF-alpha on the gastric circular muscle component, present in the same tissue strip as the longitudinal muscle preparation, were unaffected by concentrations of U57,908 that maximally inhibited contraction in the longitudinal muscle preparation. We conclude that in the longitudinal muscle preparation, EGF-URO acts not by the activation of phospholipase A2, but rather via the metabolism of diacylglycerol by DG lipase, thereby liberating arachidonic acid for the synthesis of contractile prostanoids. We also conclude that, even in the same tissue, the effects of EGF-URO on anatomically different components (longitudinal muscle versus circular muscle) can be mediated via two quite distinct signal transduction pathways.
Yang
S G
SG
Department of Pharmacology and Therapeutics, University of Calgary, Faculty of Medicine, Alberta, Canada.
Saifeddine
M
M
Chuang
M
M
Severson
D L
DL
Hollenberg
M D
MD
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003512:Cyclohexanones / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006168:Guinea Pigs; D007124:Immunoenzyme Techniques; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism* / Q000494:pharmacology
D001095:Arachidonic Acids; D003512:Cyclohexanones; D016211:Transforming Growth Factor alpha; D016718:Arachidonic Acid; D004815:Epidermal Growth Factor; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D015237:Dinoprost; D010741:Phospholipases A; D008071:Lipoprotein Lipase; D054467:Phospholipases A2