PHORBOL ESTERS ELICIT CA2-DEPENDENT DELAYED CONTRACTIONS IN DIABETIC RAT AORTA()

To determine whether diabetes alters vascular effects mediated by acti vation of protein kinase C, the contractions induced by phorbol esters were examined in aortic rings from rats with 8- to 12-week streptozot ocin-induced diabetes and compared with those from age-matched control rats. In diabetic rat aorta, phorbol 12,13-dibutyrate (PDB) (greater than or equal to 30 nM) and 12-O-tetradecanoylphorbol 13-acetate (TPA) (300 nM) elicited a delayed, sharply developing rise in tension follo wing 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 di abetic aorta were completely abolished by pretreatment with 20 nM stau rosporine, and the delayed phase of contraction was not seen in Ca2+-f ree medium or in the presence of 1 mu M nifedipine. The concentration- response curves for the contractions induced by PDB revealed that PDB at concentrations greater than or equal to 30 nM produced significantl y greater responses in diabetic aorta than in control aorta. In contro l aorta, exposure to Ca2+-free medium and pretreatment with I mu M nif edipine 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 aort as. These results suggest that the appearance of the delayed phase of contraction, possibly due to a delayed opening of Ca2+ channels, durin g activation of protein kinase C may be responsible for the enhanced c ontractile responses to phorbol esters in diabetic rat aorta.