Functional evidence that S-nitroso-L-cysteine may be a candidate carotid body neurotransmitter

The primary objective of the present study is to provide further evidence that the endogenous S-nitrosothiol, S-nitroso-L-cysteine (L-CSNO), plays an essential role in signaling the hypoxic ventilatory response (HVR) in rodents. Key findings were that (1) injection of L-CSNO (50 nmol/kg, IV) caused a pronounced increase in frequency of breathing (Freq), tidal volume (TV) and minute ventilation (MV) in naïve C57BL/6 mice, whereas injection of D-CSNO (50 nmol/kg, IV) elicited minimal responses; (2) L-CSNO elicited minor responses in (a) C57BL/6 mice with bilateral carotid sinus nerve transection (CSNX), (b) C57BL/6 mice treated neonatally with capsaicin (CAP) to eliminate small-diameter C-fibers, and (c) C57BL/6 mice receiving continuous infusion of L-CSNO receptor antagonists, S-methyl-L-cysteine and S-ethyl-L-cysteine (L-SMC + L-SEC, both at 5 μmol/kg/min, IV); and (3) injection of S-nitroso-L-glutathione (L-GSNO, 50 nmol/kg, IV) elicited pronounced ventilatory responses that were not inhibited by L-SMC + L-SEC. Subsequent exposure of naïve C57BL/6 mice to a hypoxic gas challenge (HXC; 10% O₂, 90% N₂) elicited pronounced increases in Freq, TV and MV that were subject to roll-off. These HXC responses were markedly reduced in CSNX, CAP, and L-SMC + L-SEC-infused C57BL/6 mice. Subsequent exposure of all C57BL/6 mice (naïve, CSNX, CAP, and L-SMC + L-SEC) to a hypercapnic gas challenge (5% CO₂, 21% O₂, 74% N₂) elicited similar robust increases in Freq, TV and MV. Taken together, these findings provide evidence that an endogenous factor with pharmacodynamic properties similar to those of L-CSNO, rather than L-GSNO, mediates the HVR in male C57BL/6 mice.