Phorbol esters elicit Ca(2+)-dependent delayed contractions in diabetic rat aorta.
To determine whether diabetes alters vascular effects mediated by activation of protein kinase C, the contractions induced by phorbol esters were examined in aortic rings from rats with 8- to 12-weeks streptozotocin-induced diabetes and compared with those from age-matched control rats. In diabetic rat aorta, phorbol 12,13-dibutyrate (PDB) (> or = 30 nM) and 12-O-tetradecanoylphorbol 13-acetate (TPA) (300 nM) elicited a delayed, sharply developing rise in tension following an initial gradually developing contraction. In control rat aorta, these agents produced only an initial slowly developing contraction. Both the initial and the delayed contractile responses observed in diabetic aorta were completely abolished by pretreatment with 20 nM staurosporine, and the delayed phase of contraction was not seen in Ca(2+)-free medium or in the presence of 1 microM nifedipine. The concentration-response curves for the contractions induced by PDB revealed that PDB at concentrations > or = 30 nM produced significantly greater responses in diabetic aorta than in control aorta. In control aorta, exposure to Ca(2+)-free medium and pretreatment with 1 microM nifedipine shifted the concentration-response curves for PDB to the right without changing the maximal response. Under these conditions, there were no differences in the curves for PDB in control and diabetic aortas. These results suggest that the appearance of the delayed phase of contraction, possibly due to a delayed opening of Ca2+ channels, during activation of protein kinase C may be responsible for the enhanced contractile responses to phorbol esters in diabetic rat aorta.
Hattori
Y
Y
Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
Kawasaki
H
H
Fukao
M
M
Kanno
M
M
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001835:Body Weight; D002118:Calcium / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009929:Organ Size; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D010703:Phorbol Esters; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium