Histaminergic H₃-Heteroreceptors as a Potential Mediator of Betahistine-Induced Increase in Cochlear Blood Flow

Abstract

Objective: Betahistine is a histamine-like drug that is considered beneficial in Ménière's disease by increasing cochlear blood flow. Acting as an agonist at the histamine H1-receptor and as an inverse agonist at the H3-receptor, these receptors as well as the adrenergic α2-receptor were investigated for betahistine effects on cochlear blood flow. Materials and Methods: A total of 54 Dunkin-Hartley guinea pigs were randomly assigned to one of nine groups treated with a selection of H1-, H3- or α2-selective agonists and antagonists together with betahistine. Cochlear blood flow and mean arterial pressure were recorded for 3 min before and 15 min after infusion. Results: Blockage of the H3- or α2-receptors caused a suppression of betahistine-mediated typical changes in cochlear blood flow or blood pressure. Activation of H3-receptors caused a drop in cochlear blood flow and blood pressure. H1-receptors showed no involvement in betahistine-mediated changes of cochlear blood flow. Conclusion: Betahistine most likely affects cochlear blood flow through histaminergic H3-heteroreceptors.

Fingolimod (FTY-720) is Capable of Reversing Tumor Necrosis Factor Induced Decreases in Cochlear Blood Flow

“…We demonstrated that topical application of FTY-720 is able to reverse the effects of TNF on cochlear blood flow: application of FTY-720 caused a significant increase in cochlear blood flow. The fact that the cochlear blood flow had also decreased somewhat in the group that had received a placebo twice could be explained by increased clotting in the capillaries caused by the surgical manipulation, a phenomenon that has previously been reported in this animal model (20). Even though this could be a potential confounder in the animal model used in this study, this also raises the threshold levels to obtain significant results, assuming that FTY-720 would increase cochlear blood flow compared with previous values.…”

“…The technique applied in this experiment has been previously described (19)(20)(21). After induction of anesthesia, a cervical venous catheter was surgically implemented.…”

Betahistine Treatment in a Cat Model of Vestibular Pathology: Pharmacokinetic and Pharmacodynamic Approaches

“…Functionally, the acute effect might be related to an action on the vascular tree as seen in experimental models by the betahistine-induced increase in cochlear and vestibular blood flow ( 28 ). This mechanism of action has been attributed to a direct action on the histamine H3 heteroreceptors located in the cochlear vascular network ( 30 ), and it is supposed to be responsible for the reduction in the number of vertigo attacks in Menière's disease patients. Ihler et al ( 28 ) showed that betahistine exerts a dose dependent effect on cochlear stria vascularis blood flow in guinea pig in vivo .…”

“…Blockade of the histamine H 3 autoreceptors releases histamine that could rebalance the VN cells activity on both sides by actions at the post-synaptic histamine H 1 ( 51 ) or H 2 ( 52 – 54 ) receptors. In addition to this specific mechanism of action, betahistine could improve the microcirculation of the inner ear as well as homeostasis of endolymphatic fluid by acting on H3 and H1 receptors ( 30 , 31 , 55 ).…”

Efficacy and safety of betahistine treatment in patients with Meniere’s disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial)

“…Betahistine is a strong H3 antagonist and a weak H1 agonist26 with three sites of action. Firstly, it increases dose-dependent cochlear blood flow,27 mainly via the H3 receptor as an inverse agonist 28. Because betahistine has a strong first pass effect and is metabolised in the liver into three metabolites, not only betahistine but also its major metabolite aminoethylpyridine increases cochlear blood flow 29.…”