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

• Published in: Life sciences (1973) Vol. 346; p. 122633
• Main Authors: Rumbus, Zoltan, Fekete, Kata, Kelava, Leonardo, Gardos, Bibor, Klonfar, Krisztian, Keringer, Patrik, Pinter, Erika, Pakai, Eszter, Garami, Andras
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-06-2024
• Subjects: Hypothermia; NH4Cl; Thermophysiology; Thermoregulation; TRPA1; TRPV1; Thermoregulation; TRPV1; Thermophysiology; TRPA1; Hypothermia; NH4Cl; NHCl
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2024.122633

Systemic administration of ammonium chloride (NH4Cl), an acidifying agent used in human patients and experimental conditions, causes hypothermia in mice, however, the mechanisms of the thermoregulatory response to NH4Cl and whether it develops in other species remained unknown.
We studied body temperature (Tb) changes in rats and mice induced by intraperitoneal administration of NH4Cl after blockade of transient receptor potential vanilloid-1 (TRPV1) or ankyrin-1 (TRPA1) channels.
In rats, NH4Cl decreased Tb by 0.4–0.8°C (p < 0.05). The NH4Cl-induced hypothermia also developed in Trpv1 knockout (Trpv1−/−) and wild-type (Trpv1+/+) mice, however, the Tb 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 NH4Cl in genetically unmodified mice and rats (p < 0.05 for both). In contrast, when NH4Cl was infused to mice genetically lacking the TRPA1 channel, the hypothermic response was significantly attenuated compared to wild-type controls with maximal mean Tb difference of 1.0°C between the genotypes (p = 0.008). Pretreatment of rats with a TRPA1 antagonist (A967079) also attenuated the NH4Cl-induced Tb drop with a maximal difference of 0.7°C between the pretreatment groups (p = 0.003).
TRPV1 channels limit, whereas TRPA1 channels exaggerate the development of NH4Cl-induced hypothermia in rats and mice, but other mechanisms are also involved. Our results warrant for regular Tb control and careful consideration of NH4Cl treatment in patients with TRPA1 and TRPV1 channel dysfunctions.