Enhanced 5-HT2 receptor mediated contractions in diabetic rat aorta: participation of Ca2+ channels associated with protein kinase C activity.

Abstract

The aim of this study was to determine how the contractile responses to 5-hydroxytryptamine (5-HT) are altered in aortas from rats with streptozotocin-induced diabetes and to explore the possible mechanisms of the altered vascular reactivity to 5-HT in diabetes. In the presence of extracellular Ca2+ (2.5 mM), the contractile responses to stimulation of 5-HT2 receptors with 5-HT were greater in aortas from diabetic rats as compared with those from age-matched controls. Similarly, phorbol-12,13-dibutyrate (PDBu) (> or = 30 nM) induced significantly greater contractions in diabetic aortas. The enhanced contractile responses of diabetic aortas to 5-HT and PDBu were abolished in the presence of 1 microM nifedipine. Pretreatment with 20 nM staurosporine caused a complete inhibition of the contractile responses to 5-HT in both control and diabetic aortas. In contrast to those to 5-HT and PDBu, the contractile responses to high K+ (40 mM) were markedly diminished in diabetic aortas. The nifedipine-sensitive uptake of 45Ca2+ induced by 5-HT was significantly greater in diabetic aortas than in controls, whereas that induced by high K+ was significantly less in diabetics. The phasic contractions produced by 5-HT in Ca(2+)-free medium were significantly attenuated in diabetic aortas, but those produced by norepinephrine were unchanged. Accumulation of [3H]inositol monophosphate (IP1) in aortic strips prelabeled with myo-[3H]inositol was increased to a similar extent by 5-HT and norepinephrine in control rats, but the 5-HT-induced increase in [3H]IP1 accumulation was significantly less than the norepinephrine-induced one in diabetics. These findings indicate that the extracellular Ca(2+)-dependent contractions mediated by 5-HT2 receptors 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 contraction induced by release of Ca2+ from intracellular stores in response to 5-HT is diminished in these tissues, possibly due to the impaired phosphoinositide response.