Peripheral Thermoregulatory Compensation During Acute Heat Exposure in Heat-Vulnerable Adults: Physiological Responses Consistent with Non-Adrenergic, Non-Cholinergic Pathway Involvement

<title>Abstract</title> <p> Background Maintenance of thermal homeostasis during heat exposure depends on coordinated autonomic, vascular, and sudomotor responses. Although adrenergic and cholinergic pathways are recognized as principal regulators of heat dissipation, accumulating evidence suggests that non-adrenergic, non-cholinergic (NANC) mediators, including prostaglandins and histamine, may also contribute to peripheral thermoregulatory control. However, their physiological contribution during acute heat stress in heat-vulnerable adults remains poorly characterized. Objective To investigate whether pharmacological modulation of prostaglandin- and histamine-associated pathways alters peripheral thermoregulatory responses during controlled heat exposure. Methods Six heat-vulnerable adults (24–41 years) completed a repeated-measures crossover study under three experimental conditions: control, cyclooxygenase inhibition using ibuprofen (400 mg), and H1-receptor antagonism using cetirizine (10 mg). Participants underwent standardized heat exposure (35°C; 50–60% relative humidity) combined with moderate treadmill exercise. Core temperature, mean skin temperature, heart rate, and sweat rate were measured throughout baseline, exercise, and recovery. Data were analyzed using repeated-measures ANOVA with Bonferroni-adjusted comparisons and partial eta squared (η²p). Results Heat exposure significantly increased skin temperature and sweat rate (both <italic>P</italic>  &lt; 0.01). Ibuprofen was associated with the greatest attenuation of sweating and the largest increase in core temperature, whereas cetirizine produced moderate impairment of peripheral heat dissipation. Large physiological effect sizes were observed for sweat rate (η²p = 0.88) and skin temperature (η²p = 0.70). These findings indicate preserved core temperature through enhanced peripheral thermoeffector activation despite pharmacological modulation. Conclusions This pilot study provides preliminary physiological evidence that prostaglandin- and histamine-associated pathways contribute to peripheral thermoregulatory compensation during acute heat exposure. Although direct NANC activity was not measured, the observed physiological responses are consistent with a contributory role of these pathways in human heat dissipation and support further mechanistic investigations integrating molecular biomarkers with physiological measurements. </p>