Altered Ventilation in Rats With Established Severe Monocrotaline‐Induced Pulmonary Hypertension: The Role of the Dorsal Hypothalamus

Pulmonary hypertension (PH) is a progressive condition characterized by muscularization of precapillary arteries, chronic inflammation, and a loss of the distal pulmonary circulation. These changes can be mimicked in rats by monocrotaline (MCT) administration. The impact of MCT-induced pulmonary damage on ventilatory control is poorly understood. In this study, we investigated whether the severity of PH induced by MCT in rats is linked to ventilatory changes. We examined ventilatory variables in awake (plethysmographic) and anesthetized (tracheal) rats, stratified by disease severity (Fulton's index). Two subgroups were identified: mild (Fulton's index < 0.49) and severe (Fulton's index > 0.53) PH. Resting ventilation was significantly increased in severe but not mild PH rats compared to controls, in both awake and anesthetized states. However, the responses to a carotid chemoreflex were similar between all groups. The variability of ventilatory variables was elevated in both groups of PH rats compared to controls, with a more pronounced increase in animals severely affected. Disease severity was also associated with increased adrenal gland weight, reduced brain-derived neurotrophic factor (BDNF) levels, and prolonged grooming, suggesting a heightened arousal state in severe PH rats. Interestingly, these alterations were reversed by inhibition of the dorsomedial hypothalamus area, a key structure in stress defense responses, and the blockade of the parabrachial complex, which projects onto the central ventral respiratory group. These findings suggest that PH-induced changes, whether due to vascular remodeling and/or right ventricular dysfunction, are associated with severity-dependent ventilatory alterations, possibly mediated via stress-related neural activation.