The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice

Hydrogen sulfide (H2S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H2S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na2S) and slow-releasing (GYY4137) H2S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1−/−) and wild-type (Trpa1+/+) mice. Intracerebroventricular administration of Na2S (0.5–1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na2S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H2S donors was significantly (p < 0.001) attenuated in Trpa1−/− mice compared to their Trpa1+/+ littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H2S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways.

Chronic Anticholinergic Toxicity Discovered in a Pharmacogenomics, Polypharmacy Patient

OBJECTIVE: To report a case of chronic anticholinergic toxicity in a referred, pharmacogenomics (PGx), polypharmacy patient. SUMMARY: The patient is a 67-year-old male who was referred to the polypharmacy service for a PGx consult. This patient has had episodic fever of unknown origin, general cutaneous vasodilation, tremors, jerks, and brain fogginess which have been unexplained. He has seen specialists from infectious disease, rheumatology, endocrinology, and neurology with no contributory condition causing these symptoms, so he was referred for PGx testing and evaluation by the polypharmacy pharmacist. CONCLUSION: This case demonstrates the importance of pharmacist-patient consultations and how a PGx consult may expose polypharmacy medicationrelated problems of greater significance than the PGx indication for the consult. In addition, the case demonstrates positive interprofessional collaboration between pharmacists and physicians to more effectively solve complex medication-related problems that may not be easily diagnosed through objective lab or diagnostic testing.

Effects of Isomaltulose Ingestion on Thermoregulatory Responses during Exercise in a Hot Environment

Isomaltulose is a low glycemic and insulinemic carbohydrate available as a constituent of sports drinks. However, it remains unclear whether thermoregulatory responses (sweating and cutaneous vasodilation) after isomaltulose drink ingestion differ from those of sucrose and water during exercise in a hot environment. Ten young healthy males consumed 10% sucrose, 10% isomaltulose, or water drinks. Thirty-five minutes after ingestion, they cycled for fifteen minutes at 75% peak oxygen uptake in a hot environment (30 °C, 40% relative humidity). Sucrose ingestion induced greater blood glucose concentration and insulin secretion at the pre-exercise state, compared with isomaltulose and/or water trials, with no differences during exercise in blood glucose. Change in plasma volume did not differ between the three trials throughout the experiment, but both sucrose and isomaltulose ingestions similarly increased plasma osmolality, as compared with water (main beverage effect, p = 0.040)—a key response that potentially delays the onset of heat loss responses. However, core temperature thresholds and slopes for heat loss responses were not different between the trials during exercise. These results suggest that ingestion of isomaltulose beverages induces low glycemic and insulinemic states before exercise but does not alter thermoregulatory responses during exercise in a hot environment, compared with sucrose or water.

TRPV4 channel blockade does not modulate skin vasodilation and sweating during hyperthermia or cutaneous post-occlusive reactive and thermal hyperemia

Transient receptor potential vanilloid 4 (TRPV4) channels exist on vascular endothelial cells and eccrine sweat gland secretory cells in human skin. Here, we assessed if TRPV4 channels contribute to cutaneous vasodilation and sweating during whole-body passive heat stress (protocol 1) and to cutaneous vasodilation during post-occlusive reactive hyperemia and local thermal hyperemia (protocol 2). Intradermal microdialysis was employed to locally deliver pharmacological agents to forearm skin sites where cutaneous vascular conductance (CVC) and sweat rate were assessed. In protocol 1 (twelve young adults), CVC and sweat rate were increased by passive whole-body heating resulting in a body core temperature elevation of 1.2±0.1ºC. The elevated CVC and sweat rate assessed at sites treated with TRPV4 channel antagonist (either 200 µM HC-067047 or 125 µM GSK2193874) were not different from the vehicle control site (5 % dimethyl sulfoxide). After whole-body heating, a TRPV4 channel agonist (100 µM GSK1016790A) was administered to each skin site, eliciting elevations in CVC. Relative to control, this response was partly attenuated by both TRPV4 channel antagonists, confirming drug efficacy. In protocol 2 (ten young adults), CVC was increased following a 5-min arterial occlusion and during local heating from 33 to 42ºC. These responses did not differ between the control and the TRPV4 channel antagonist sites (200 µM HC-067047). We show that TRPV4 channels are not required for regulating cutaneous vasodilation or sweating during a whole-body passive heat stress. Further, they are not required for regulating cutaneous vasodilation during post-occlusive reactive hyperemia and local thermal hyperemia.