[Pharmacological studies on alterations in contractile reactivity in aortas isolated from experimental diabetic rats].

The present study was undertaken to determine how the responses to contractile agents are altered in aortas from rats with streptozotocin-induced diabetes and to explore the possible mechanisms of the altered responses in diabetes. Rats were given an intravenous injection of 45 mg/kg streptozotocin. Eight to 12 weeks after treatment, aortas were isolated and set up for measurement of isometric tension. Diabetic aortas exhibited significantly lesser contractions in response to high K+ than those from age-matched controls. Furthermore, the Ca2+ channel agonist Bay K 8644 was not able to consistently contract diabetic aortas even when they were partially depolarized by an elevation of the extracellular K+ concentration to 15 mM where the agonist produced concentration-dependent contractions in all control aortas. On the other hand, the contractile responses to norepinephrine, 5-hydroxytryptamine, endothelin-1 and U46619 were significantly enhanced in diabetic rat aortas. All of the enhanced responses of diabetic aortas were completely eliminated in the presence of the Ca2+ channel antagonist nifedipine. The contractile responses of aortas from both control and diabetic rats to these agonists were abolished or strongly inhibited by the protein kinase C inhibitor staurosporine, and no significant difference was found in the magnitude of the contractile responses of aortas between control and diabetic rats to the agonists in the presence of staurosporine. In diabetic aortas, the protein kinase C activators phorbol 12, 13-dibutyrate and 12-O-tetradecanoylphorbol 13-acetate elicited a delayed, sharply developing rise in tension following the initial, gradually developing contraction, while these agents produced only the initial, slowly developing contraction in control aortas. As a result, the contractions induced by phorbol esters were greater in diabetic aortas than in controls. The enhanced contractile responses of diabetic aortas to phorbol esters were not observed in Ca(2+)-free medium or in the presence of nifedipine. In Ca(2+)-free medium, the transient contraction induced by caffeine was significantly diminished in diabetic aortas, in contrast to the phasic contraction by norepinephrine which was similarly observed in control and diabetic aortas. These results indicate that the extracellular Ca(2+)-dependent contractions elicited by receptor activation are enhanced in aortas from diabetic rats, and this is presumably related to a greater influx of Ca2+ through transmembrane Ca2+ channels as a consequence of increased protein kinase C-activated processes. On the other hand, the contractions associated with depolarization-evoked activation of Ca2+ channels are diminished in diabetic aortas, possibly due to an alteration in activation of the channels by membrane depolarization, and Ca(2+)-induced Ca2+ release from intracellular stores appears to be impaired in diabetes.