Abstract
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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Aorta / drug effects
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Aorta / metabolism*
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Aorta / physiopathology
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Diabetes Mellitus, Type 2 / complications*
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / physiopathology
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Diabetic Angiopathies / genetics
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Diabetic Angiopathies / metabolism*
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Diabetic Angiopathies / physiopathology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Protein Kinase Inhibitors / pharmacology
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Receptor, Serotonin, 5-HT2A / deficiency
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Receptor, Serotonin, 5-HT2A / drug effects
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Receptor, Serotonin, 5-HT2A / genetics
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Receptor, Serotonin, 5-HT2A / metabolism*
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Receptor, Serotonin, 5-HT2B / deficiency
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Receptor, Serotonin, 5-HT2B / drug effects
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Receptor, Serotonin, 5-HT2B / genetics
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Receptor, Serotonin, 5-HT2B / metabolism*
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Serotonin / metabolism*
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Serotonin 5-HT2 Receptor Agonists / pharmacology
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Serotonin 5-HT2 Receptor Antagonists / pharmacology
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Signal Transduction
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Vasoconstriction* / drug effects
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Vasoconstrictor Agents / pharmacology
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rho-Associated Kinases / antagonists & inhibitors
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rho-Associated Kinases / metabolism
Substances
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Protein Kinase Inhibitors
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Receptor, Serotonin, 5-HT2A
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Receptor, Serotonin, 5-HT2B
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Serotonin 5-HT2 Receptor Agonists
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Serotonin 5-HT2 Receptor Antagonists
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Vasoconstrictor Agents
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Serotonin
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rho-Associated Kinases