Related Experiment Videos
Enhanced 5-HT2 receptor mediated contractions in diabetic rat aorta: participation of Ca2+ channels associated with
Y Hattori1, H Kawasaki, M Kanno
1Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
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.
Insights
Diabetic rat aortas show enhanced contractile responses to serotonin (5-HT) due to increased calcium influx via 5-HT2 receptors. However, intracellular calcium release mechanisms are impaired, suggesting complex vascular reactivity changes in diabetes.
Area of Science:
- Vascular Physiology
- Endocrinology
- Pharmacology
Background:
- Diabetes mellitus is associated with significant alterations in vascular function.
- Serotonin (5-HT) plays a crucial role in regulating vascular tone.
- Understanding 5-HT's role in diabetic vasculopathy is vital for therapeutic development.
Purpose of the Study:
- To investigate the impact of streptozotocin-induced diabetes on aortic contractile responses to 5-HT.
- To elucidate the underlying mechanisms of altered vascular reactivity to 5-HT in diabetes.
Main Methods:
- Comparative analysis of aortic contractile responses in diabetic and control rats.
- Assessment of 5-HT2 receptor-mediated contractions and intracellular signaling pathways.
- Measurement of calcium (Ca2+) uptake and inositol phosphate accumulation.
Main Results:
- Diabetic aortas exhibited enhanced contractile responses to 5-HT and phorbol-12,13-dibutyrate (PDBu), mediated by extracellular Ca2+ influx through nifedipine-sensitive channels.
- Contractions induced by high potassium (K+) were diminished in diabetic aortas.
- 5-HT-induced intracellular Ca2+ release was attenuated in diabetic aortas, linked to impaired phosphoinositide signaling.
Conclusions:
- Enhanced extracellular Ca2+ influx via 5-HT2 receptors contributes to augmented vascular contraction in diabetic aortas.
- Impaired intracellular Ca2+ release mechanisms, possibly due to altered phosphoinositide metabolism, affect vascular responses in diabetes.
- These findings highlight the complex, receptor-specific changes in vascular smooth muscle contractility during diabetes.