5HT2Aand5HT2BReceptors Contribute to Serotonin-Induced Vascular Dysfunction in Diabetes

Although5HT2Areceptors 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 (5HT1B,5HT2A, and5HT2B) in aorta from nondiabetic (ND) compared to type 2 diabetic mice (DB, BKS.Cg-Dock7m+/+Leprdb/J). 5HT,5HT2A(TCB2 and BRL54443), and5HT2B(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 a5HT1Breceptor agonist. MDL11939, a5HT2Areceptor antagonist, and LY272015, a5HT2Breceptor antagonist, reduced contractions of arteries from DB to 5HT more than ND. Expression of5HT1B,5HT2A, and5HT2Breceptor subtypes was similar in ND and DB. Inhibition of rho kinase decreased contractions to 5HT and5HT2Aand5HT2Breceptor 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.

The Neuroendocrine Challenge Paradigm in Headache Research

The neuroendocrine challenge paradigm provides a “window” on central neurotransmitter function in vivo. This strategy is based on the premise that the sensitivity of certain central receptors can be inferred from the magnitude of the hormonal response to specific pharmacologic probes. For example, the serotonin (5HT) receptor agonist m-chlorophenylpiperazine (m-CPP) stimulates the release of cortisol and prolactin and induces migraine-like headaches. We have previously reported that the headache and cortisol responses to m-CPP are highly correlated, which may implicate a disturbance in central serotonergic neurotransmission in the pathogenesis of migraine. As pharmacologic probes with greater specificity for 5HT receptor subtypes become available, we may be able to elucidate these mechanisms with greater precision. The neuroendocrine challenge methodology is also applicable to the study of other neurotransmitter systems and other headache disorders.