Betahistine Exerts a Dose-Dependent Effect on Cochlear Stria Vascularis Blood Flow in Guinea Pigs In Vivo

Abstract

ObjectiveBetahistine is a histamine H1-receptor agonist and H3-receptor antagonist that is administered to treat Menière’s disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation.MethodsThirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9% or NaCl 0.9% alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of betahistine.ResultsWhen betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933–1.546 arb. units) compared to baseline (p<0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. betahistine or NaCl 0.9% had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages.ConclusionsBetahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of the dosage range of betahistine on cochlear microcirculation corresponded well to clinically used single dosages to treat Menière’s disease. Our data suggest that the improved effects of higher doses of betahistine in the treatment of Menière’s disease might be due to a corresponding increase of cochlear blood flow.

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

“…These findings are in line with the literature that suggests that the H 1 -receptor has no effect on betahistine-induced effects on cochlear blood flow [Laurikainen et al, 1993]. However, one more observation should be pointed out here: in previous experiments it has been shown that higher doses of betahistine show a significant yet short-lived drop in mean arterial pressure and cochlear blood flow at the beginning of betahistine infusion [Ihler et al, 2012a]. This initial and brief drop seems to be steeper the high- er the concentration of betahistine [Dziadziola et al, 1999].…”

“…Moreover, betahistine could aid in the central-nervous compensation that takes place after a patient has suffered from an attack [Redon et al, 2011]. Lastly, it has been shown that betahistine is capable of increasing cochlear blood flow in animal models and could therefore aid in the reduction of the endolymphatic hydrops [Dziadziola et al, 1999;Laurikainen et al, 2000;Ihler et al, 2012a]. So far, this has been viewed as the most likely mechanism of action in Ménière's disease [Strupp et al, 2011].…”

Ryanodine-induced vasoconstriction of the gerbil spiral modiolar artery depends on the Ca2+ sensitivity but not on Ca2+ sparks or BK channels

“…Regulation of cochlear blood flow is essential for hearing and is important as a treatment strategy for the restoration of hearing loss in humans [3–8]. Homeostatic regulation of blood flow in the cochlear capillary beds is achieved by the dynamic adjustment of the vascular diameter or “tone” of pre-capillary arteries and arterioles against systemic changes of pressure, nerve and metabolic activity [9–14].…”

Evaluation of the Effect of Betahistine on Noise-Induced Hearing Loss Using Distortion Product Otoacoustic Emission and Scanning Electron Microscopy

“…Betahistine is a strong histaminergic H3 receptor antagonist; this property may account for the increase in CoBF via an increase in histamine release and consequent activation of postsynaptic histaminergic H1 and H2 receptors. Betahistine may also have weak direct effects on these postsynaptic receptors or an effect modulated by other autonomic receptors [3] .…”

“…Betahistine is a strong histaminergic H3 receptor antagonist; this property may account for the increase in CoBF via an increase in histamine release and consequent activation of postsynaptic histaminergic H1 and H2 receptors. Betahistine may also have weak direct effects on these postsynaptic receptors or an effect modulated by other autonomic receptors [3] .In this study, the protective effect of betahistine on noise-induced hearing loss (NIHL) was evaluated for the first time using scanning electron microscopy (SEM) and distortion product otoacoustic emission (DPOAE) data. Preyer's reflexes and normal tympanic membranes were used for these experiments.…”