mdl-100907 and Diabetic-Angiopathies

Although 5HT(2A) receptors mediate contractions of normal arteries to serotonin (5HT), in some cardiovascular diseases, other receptor subtypes contribute to the marked increase in serotonin contractions. We hypothesized that enhanced contractions of arteries from diabetics to 5HT are mediated by an increased contribution from multiple 5HT receptor subtypes. We compared responses to selective 5HT receptor agonists and expression of 5HT receptor isoforms (5HT(1B), 5HT(2A), and 5HT(2B)) in aorta from nondiabetic (ND) compared to type 2 diabetic mice (DB, BKS.Cg-Dock7(m)+/+Lepr(db)/J). 5HT, 5HT(2A) (TCB2 and BRL54443), and 5HT(2B) (norfenfluramine and BW723C86) receptor agonists produced concentration-dependent contractions of ND arteries that were markedly increased in DB arteries. Neither ND nor DB arteries contracted to a 5HT(1B) receptor agonist. MDL11939, a 5HT(2A) receptor antagonist, and LY272015, a 5HT(2B) receptor antagonist, reduced contractions of arteries from DB to 5HT more than ND. Expression of 5HT(1B), 5HT(2A), and 5HT(2B) receptor subtypes was similar in ND and DB. Inhibition of rho kinase decreased contractions to 5HT and 5HT(2A) and 5HT(2B) receptor agonists in ND and DB. We conclude that in contrast to other cardiovascular diseases, enhanced contraction of arteries from diabetics to 5HT is not due to a change in expression of multiple 5HT receptor subtypes.

Topics: Animals; Aorta; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Kinase Inhibitors; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; rho-Associated Kinases; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction; Vasoconstriction; Vasoconstrictor Agents

We compared the levels of plasma adiponectin, platelet activation markers (P-selectin, CD63, PAC-1, annexin V, and platelet-derived microparticles), and endothelial injury markers (soluble E-selectin and soluble vascular cell adhesion molecule-1) in 53 patients with type 2 diabetes mellitus to investigate potential contributions to diabetic vascular complications. In addition, we administered serotonin antagonist (sarpogrelate hydrochloride) to type 2 diabetes patients who had increased soluble E-selectin levels. The concentrations of platelet activation markers and endothelial injury markers in diabetic patients were significantly higher than those in normal subjects. However, levels of adiponectin were lower in type 2 diabetes patients than in control subjects. A total of 32 patients had high-soluble E-selectin levels (soluble E-selectin >or= 62 ng/ml); a subset of patients that also had significant elevation of platelet activation and endothelial injury markers compared with patients without high soluble E-selectin. In addition, both platelet-P-selectin and platelet-derived microparticle levels negatively correlated with the adiponectin level. Patients with high soluble E-selectin exhibited significant improvement of all markers after sarpogrelate hydrochloride treatment. These findings suggest that there is a link between vascular change in type 2 diabetes and activated platelets, endothelial dysfunction, and an adiponectin abnormality.

Topics: Adiponectin; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Platelet Activation; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Succinates