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

Abstract

Aims: 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.

Main methods: We studied body temperature (T_b) 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.

Key findings: In rats, NH₄Cl decreased T_b 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 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 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 T_b difference of 1.0°C between the genotypes (p = 0.008). Pretreatment of rats with a TRPA1 antagonist (A967079) also attenuated the NH₄Cl-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 NH₄Cl-induced hypothermia in rats and mice, but other mechanisms are also involved. Our results warrant for regular T_b control and careful consideration of NH₄Cl treatment in patients with TRPA1 and TRPV1 channel dysfunctions.

Keywords: Hypothermia; NH(4)Cl; TRPA1; TRPV1; Thermophysiology; Thermoregulation.