ENHANCED 5-HT2 RECEPTOR-MEDIATED CONTRACTIONS IN DIABETIC RAT AORTA -PARTICIPATION OF CA2-KINASE-C ACTIVITY( CHANNELS ASSOCIATED WITH PROTEIN)

The aim of this study was to determine how the contractile responses t o 5-hydroxytryptamine (5-HT) are altered in aortas from rats with stre ptozotocin-induced diabetes and to explore the possible mechanisms of the altered vascular reactivity to 5-HT in diabetes. In the presence o f extracellular Ca2+ (2.5 mM), the contractile responses to stimulatio n of 5-HT2 receptors with 5-HT were greater in aortas from diabetic ra ts as compared with those from age-matched controls. Similarly, phorbo l-12,13-dibutyrate (PDBu) (greater than or equal to 30 nM) induced sig nificantly greater contractions in diabetic aortas. The enhanced contr actile responses of diabetic aortas to 5-HT and PDBu were abolished in the presence of 1 mu M nifedipine. Pretreatment with 20 nM staurospor ine 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 dimin ished in diabetic aortas. The nifedipine-sensitive uptake of Ca-45(2+) induced by 5-HT was significantly greater in diabetic aortas than in controls, whereas that induced by high K+ was significantly less in di abetics. The phasic contractions produced by 5-HT in Ca2+-free medium were significantly attenuated in diabetic aortas, but those produced b y norepinephrine were unchanged. Accumulation of [H-3]inositol monopho sphate (IP1) in aortic strips prelabeled with myo-[H-3] inositol was i ncreased to a similar extent by 5-HT and norepinephrine in control rat s, but the 5-HT-induced increase in [H-3]IP1 accumulation was signific antly less than the norepinephrine-induced one in diabetics. These fin dings indicate that the extracellular Ca2+-dependent contractions medi ated by 5-HT2 receptors are enhanced in aortas from diabetic rats, and this is presumably related to a greater influx of Ca2+ through transm embrane Ca2+ channels as a consequence of increased protein kinase C a ctivated processes. On the other hand, the contraction induced by rele ase of Ca2+ from intracellular stores in response to 5-HT is diminishe d in these tissues, possibly due to the impaired phosphoinositide resp onse.