Ammonium chloride-induced hypothermia is attenuated by transient receptor potential channel vanilloid-1, but augmented by ankyrin-1 in rodents.

Aims: Systemic administration of ammonium chloride (NH ₄ Cl), an acidifying agent used in human patients and experimental conditions, causes hypothermia in mice, however, the mechanisms of the thermoregulatory response to NH ₄ Cl and whether it develops in other species remained unknown.
Main Methods: We studied body temperature (T _b ) changes in rats and mice induced by intraperitoneal administration of NH ₄ Cl after blockade of transient receptor potential vanilloid-1 (TRPV1) or ankyrin-1 (TRPA1) channels.
Key Findings: In rats, NH ₄ Cl decreased T _b by 0.4-0.8°C (p < 0.05). The NH ₄ Cl-induced hypothermia also developed in Trpv1 knockout (Trpv1 ^-/- ) and wild-type (Trpv1 ^+/+ ) mice, however, the T _b drop was exaggerated in Trpv1 ^-/- mice compared to Trpv1 ^+/+ controls with maximal decreases of 4.0 vs. 2.1°C, respectively (p < 0.05). Pharmacological blockade of TRPV1 channels with AMG 517 augmented the hypothermic response to NH ₄ Cl in genetically unmodified mice and rats (p < 0.05 for both). In contrast, when NH ₄ Cl was infused to mice genetically lacking the TRPA1 channel, the hypothermic response was significantly attenuated compared to wild-type controls with maximal mean T _b difference of 1.0°C between the genotypes (p = 0.008). Pretreatment of rats with a TRPA1 antagonist (A967079) also attenuated the NH ₄ Cl-induced T _b drop with a maximal difference of 0.7°C between the pretreatment groups (p = 0.003).
Significance: TRPV1 channels limit, whereas TRPA1 channels exaggerate the development of NH ₄ Cl-induced hypothermia in rats and mice, but other mechanisms are also involved. Our results warrant for regular T _b control and careful consideration of NH ₄ Cl treatment in patients with TRPA1 and TRPV1 channel dysfunctions.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)