The diacylglycerol kinase inhibitor, R 59022, suppresses contractility of intestinal smooth muscle.
R 59022, a compound which causes the accumulation of diacylglycerol by inhibition of the enzyme diacylglycerol kinase, was tested for its effect on stimulated motor activity of the longitudinal muscle from the guinea-pig ileum. Motor responses to histamine were very potently inhibited by R 59022 (greater than or equal to 0.03 microM), which confirms its known activity as a histamine receptor antagonist. Contractions elicited by acetylcholine, substance P, or K+ depolarization were also concentration dependently depressed by R 59022 (1-30 microM); further analysis showed that substance P was antagonized in a non-competitive manner. R 59022 was significantly more active to block the tonic than the phasic component of the contractile response to K+ depolarization. The Ca2+-induced activation of the contractile apparatus in chemically skinned muscle strips was depressed by similar concentrations of R 59022 (3-30 microM). These data indicate that R 59022 suppresses the contractile activity of intestinal smooth muscle at an intracellular site of action but it is not yet clear whether this action can be accounted for by the accumulation of diacylglycerol and subsequent stimulation of protein kinase C.
Lippe
I T
IT
University of Graz, Department of Experimental and Clinical Pharmacology, Austria.
Holzer
P
P
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D019852:Diacylglycerol Kinase; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010716:Phosphatidylinositols / Q000378:metabolism; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D013373:Substance P / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*
D010716:Phosphatidylinositols; D010972:Platelet Activating Factor; D011744:Pyrimidinones; D013844:Thiazoles; D013373:Substance P; D006632:Histamine; C047505:R 59022; D010770:Phosphotransferases; D019852:Diacylglycerol Kinase; D000109:Acetylcholine; D002118:Calcium