Inhibition of hydrogen sulfide restores normal breathing stability and improves autonomic control during experimental heart failure

摘要

Cardiovascular autonomic imbalance and breathing instability are major contributors to the progression of heart failure (CHF). Potentiation of the carotid body (CB) chemoreflex has been shown to contribute to these effects. Hydrogen sulfide (H_2S) recently has been proposed to mediate CB hypoxic chemoreception. We hypothesized that H_2S synthesis inhibition should decrease CB chemoreflex activation and improve breathing stability and autonomic function in CHF rats. Using the irreversible inhibitor of cystathione gamma-lyase DL-propargylglycine (PAG), we tested the effects of H_2S inhibition on resting breathing patterns, the hypoxic and hypercapnic ventilatory responses, and the hypoxic sensitivity of CB chemoreceptor afferents in rats with CHF. In addition, heart rate variability (HRV) and systolic blood pressure variability (SBPV) were calculated as an index of autonomic function. CHF rats, compared with sham rats, exhibited increased breath interval variability and number of apneas, enhanced CB afferent discharge and ventilatory responses to hypoxia, decreased HRV, and increased low-frequency SBPV. Remarkably, PAG treatment reduced the apnea index by 90%, reduced breath interval variability by 40-60%, and reversed the enhanced hypoxic CB afferent and chemoreflex responses observed in CHF rats. Furthermore, PAG treatment partially reversed the alterations in HRV and SBPV in CHF rats. Our results show that PAG treatment restores breathing stability and cardiac autonomic function and reduces the enhanced ventilatory and CB chemosensory responses to hypoxia in CHF rats. These results support the idea that PAG treatment could potentially represent a novel pathway to control sympathetic outflow and breathing instability in CHF.