High-Dose Furosemide Enhances the Magnetic Resonance Signal of Systemic Gadolinium in the Mammalian Cochlea

Abstract

Hypothesis: Furosemide alters the permeability of the intrastrial fluid–blood barrier. Background: The cochlear sensory cells are protected by the blood-perilymph and intrastrial fluid–blood barriers, which hinder substances, including gadolinium-based contrast agents (GdCAs), to enter the endolymphatic space. High-dose furosemide causes transient shift of hearing thresholds and morphological changes in stria vascularis. Furosemide is also known to enhance drug-induced ototoxicity. Methods: Furosemide (400 mg/kg b.w.) was injected i.v. in Balb/C mice (n = 20). Twenty minutes later, the GdCA gadobutrol, gadopentetic acid, or gadoteric acid was injected i.v. The distribution of GdCA to the perilymphatic and endolymphatic spaces was studied with MRI (9.4 T) for 250 minutes. Results: The perilymphatic and endolymphatic spaces were signal-enhanced in all animals. Gadopentetic acid and gadoteric acid yielded similar signal enhancement in all three scalae, while gadobutrol yielded significantly higher enhancement in scala tympani than scala media (p = 0.043) and scala vestibuli (p = 0.043). The signal enhancement reached a plateau but did not decrease during the time of observation. Conclusion: Treatment with a high dose of furosemide before injection of a GdCA resulted in enhancement of the MRI signal in the endolymphatic space as well as the perilymphatic space, which supports our hypothesis that furosemide alters the permeability of the intrastrial fluid–blood barrier.

MRI With Gadolinium as a Measure of Blood-Labyrinth Barrier Integrity in Patients With Inner Ear Symptoms: A Scoping Review

“…The areas correspond to capillary networks in the inner ear, suggesting entry of GBCA at the blood-labyrinth barrier. Comparison of different GBCA found some variation in signal intensity and uptake kinetics, but intravenous administration of both macrocyclic and linear agents reliably led to enhancement of perilymph ( 20 , 21 ). In mice, all GBCAs led to enhancement of perilymph with increasing intensity over time from 15–105 min ( 20 ).…”

Manipulation of the Endocochlear Potential Reveals Two Distinct Types of Cochlear Nonlinearity

“…Finally, in addition to reducing the EP, furosemide may reduce auditory sensitivity through other mechanisms. Loop diuretics weaken the blood labyrinth barrier by damaging the tight junctions lining the stria vascularis, an effect that has been exploited to enhance the uptake of contrast agents in magnetic resonance imaging studies (58). The ototoxicity of other agents such as cisplatin or aminoglycosides increases when administered simultaneously with loop diruetics such as furosemide, likely because of the increased permeability of the drugs in the perilymphatic spaces of the cochlea (59).…”

The Acute Effects of Furosemide on Na-K-Cl Cotransporter-1, Fetuin-A and Pigment Epithelium-Derived Factor in the Guinea Pig Cochlea

“…Experiments on the permeability of the blood-perilymph barrier in the chinchilla demonstrate that EP loss after furosemide administration is correlated to the concentration of the drug in perilymph (Juhn and Rybak, 1981 ). More recent findings in an MRI study showed a much slower opening of the intrastrial fluid-barrier after the administration of a high dose of furosemide (Videhult Pierre et al, 2020 ) than the expected loss of EP. We, therefore, consider the observation of a more rapid loss of NKCC1 in type II fibrocytes than in marginal cells, to be consistent with previous experiments on inner ear barriers and the differences in the permeability of the barriers might be a mechanism behind the more rapid effect on the type II fibrocytes of furosemide.…”

“…Stimulation of PEDF production was reported to increase the survival of PVM/M in cell culture and stimulate the formation of tight junctions (Zhang et al, 2021 ). It could therefore be part of a counter mechanism to the increased permeability of the intrastrial fluid-blood barrier caused by furosemide (Videhult Pierre et al, 2020 ).…”