Role of hydrogen sulfide in ventilatory responses to hypercapnia in the medullary raphe of adult rats

New FindingsWhat is the central question of this study? There is evidence that H 2 S plays a role in the control of breathing: what are its actions on the ventilatory and thermoregulatory responses to hypercapnia via effects in the medullary raphe, a brainstem region that participates in the ventilatory adjustments to hypercapnia?What is the main finding and its importance? Hypercapnia increased the endogenous production of H 2 S in the medullary raphe. Inhibition of endogenous H 2 S attenuated the ventilatory response to hypercapnia in unanaesthetized rats, suggesting its excitatory action via the cystathionine β‐synthase–H 2 S pathway in the medullary raphe.Abstract Hydrogen sulfide (H 2 S) has been recently recognized as a gasotransmitter alongside carbon monoxide (CO) and nitric oxide (NO). H 2 S seems to modulate the ventilatory and thermoregulatory responses to hypoxia and hypercapnia. However, the action of the H 2 S in the medullary raphe (MR) on the ventilatory responses to hypercapnia remains to be elucidated. The present study aimed to assess the role of H 2 S in the MR (a brainstem region that contains CO 2 ‐sensitive cells and participates in the ventilatory adjustments to hypercapnia) in the ventilatory responses to hypercapnia in adult unanaesthetized Wistar rats. To do so, aminooxyacetic acid (AOA; a cystathionine β‐synthase (CBS) enzyme inhibitor), propargylglycine (PAG; a cystathionine γ‐lyase enzyme inhibitor) and sodium sulfide (Na 2 S; an H 2 S donor) were microinjected into the MR. Respiratory frequency ( f R ), tidal volume ( V T ), ventilation ( V ̇ E ), oxygen consumption ( V ̇ O 2 ) and body temperature ( T b ) were measured under normocapnic (room air) and hypercapnic (7% CO 2 ) conditions. H 2 S concentration within the MR was determined. Microinjection of the drugs did not affect f R , V T andV ̇ E during normocapnia when compared to the control group. However, the microinjection of AOA, but not PAG, attenuated f R andV ̇ E during hypercapnia in comparison to the vehicle group, but had no effects on T b . In addition, we observed an increase in the endogenous production of H 2 S in the MR during hypercapnia. Our findings indicate that endogenously produced H 2 S in the MR plays an excitatory role in the ventilatory response to hypercapnia, acting through the CBS–H 2 S pathway.