Increased contractile responses to endothelin-1 and U46619 via a protein kinase C-mediated nifedipine-sensitive pathway in diabetic rat aorta.
To determine how diabetes alters vasocontractile responses to endothelin-1 (ET-1) and the thromboxane A2-mimetic U46619 (9,11-dideoxy-9alpha,11alpha-methanoepoxyprostaglandin F2alpha) and to explore the possible mechanisms of the altered responses, contractions produced by these agonists were examined in aortic rings from rats with 8- to 12-weeks streptozotocin-induced diabetes in comparison with those from age-matched control rats. ET-1 (> or = 1 nM) and U46619 (> or = 100 nM) induced significantly greater contractions in diabetic aorta. The enhanced contractile responses of diabetic aorta to these agonists were abolished in the presence of 1 microM nifedipine, resulting in no significant difference in the maximum responses between control and diabetic aortas. Pretreatment with 1 microM calphostin C or 20 nM staurosporine caused marked reductions in contractions induced by ET-1 and U46619 in both control and diabetic aortas, and the difference in the maximum contractile responses to these agonists between control and diabetic aortas were eliminated by their treatment. These results suggest that chronic diabetes enhances aortic contractions induced by ET-1 and U46619 and the enhanced contractions are possibly due to an increased Ca2+ influx through transmembrane Ca2+ channels resulting from increased protein kinase C-activated process.
Hattori
Y
Y
Department of Pharmacology, Hokkaido University School of Medicine Sapporo, Japan.
Kawasaki
H
H
Kanno
M
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011493:Protein Kinase C; D009543:Nifedipine