Enhanced 5-HT2 receptor mediated contractions in diabetic rat aorta: participation of Ca2+ channels associated with protein kinase C activity.
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.
Hattori
Y
Y
Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
Kawasaki
H
H
Kanno
M
M
Fukao
M
M
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006868:Hydrolysis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D019311:Staurosporine
D000470:Alkaloids; D015220:Calcium Channels; D010716:Phosphatidylinositols; D011985:Receptors, Serotonin; D012701:Serotonin; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D019311:Staurosporine; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine