The cystathionine-γ-lyase inhibitor DL-propargylglycine augments the ability of L-cysteine ethyl ester to overcome the adverse effects of morphine on breathing.

Abstract

L-cysteine ethyl ester (L-CYSee) overcomes adverse effects elicited by systemic injection of morphine on ventilatory parameters and arterial blood-gas chemistry in rats. L-CYSee or L-cysteine, resulting from the de-esterification of L-CYSee, may enter enzymatic cascades that produce the ventilatory stimulant, hydrogen sulfide (H₂S). DL-propargylglycine (DL-PROP) is an inhibitor of cystathionine-γ-lyase (CSE)-mediated conversion of L-cysteine to H₂S and has been widely used in vivo. Here, we examined whether L-CYSee (2 injections x 500 μmmol/kg, IV)-induced reversal of the changes in ventilation elicited by morphine (10 mg/kg, IV) in freely-moving male Sprague Dawley rats was altered by prior administration of DL-PROP (25 mg/kg, IV). The major findings were (1) the effects of morphine on ventilatory parameters were not affected by subsequent injection of DL-PROP, (2) injection of L-CYSee elicited a prompt reversal of the adverse effects of morphine that was more pronounced in DL-PROP-treated than vehicle-treated rats, and (3) the actions of the second injection of L-CYSee were dramatically augmented in DL-PROP-treated rats. In addition, the changes in many of the ventilatory parameters during a subsequent hypoxic-hypercapnic (HH) gas challenge were augmented substantially by DL-PROP. This study demonstrates that (1) inhibition of CSE with DL-PROP does not affect the ventilatory actions of morphine, (2) reversal effects of L-CYSee were augmented by blockade of CSE, and (3) blockade of CSE augments the ventilatory responses to HH gas challenge in morphine-treated rats. These unexpected findings suggest that the CSE-dependent production of H₂S from L-CYSee countermands L-CYSee reversal of morphine-induced respiratory depression in rats.