The effects of flosequinan on endothelin-1-induced changes in inositol 1,4,5-trisphosphate levels and protein kinase C activity in rat aorta.
In rat aorta endothelin-1 (10(-8) M) induces significant increases in inositol 1,4,5-trisphosphate (IP3) levels after a 30 s exposure. An increase in particulate protein kinase C activity is also observed at 30 s with a second peak of activity occurring after 10 min. Flosequinan, at concentrations of 10(-6) M or greater, inhibits these endothelin-1-induced changes in both IP3 and particulate protein kinase C activity in the absence of changes in either cyclic GMP or cyclic AMP. It is likely therefore that flosequinan inhibits the transduction mechanisms between the endothelin-1 receptor and hydrolysis of phosphatidylinositol 4,5-bisphosphate, possibly at the level of a G-protein. These results provide a mechanism to explain the vasodilator effects of flosequinan observed in vitro.
Lang
D
D
Department of Pharmacology and Therapeutics, University of Wales College of Medicine, Cardiff, UK.
Lewis
M J
MJ
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D016232:Endothelins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007293:Inosine Triphosphate / Q000378:metabolism*; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*
D016232:Endothelins; D009124:Muscle Proteins; D011804:Quinolines; D014665:Vasodilator Agents; D007293:Inosine Triphosphate; C047316:flosequinan; D000242:Cyclic AMP; D011493:Protein Kinase C; D006152:Cyclic GMP