Cathine and norephedrine, both phenylpropanolamines, accelerate capacitation and then inhibit spontaneous acrosome loss

BACKGROUND: Cathinone, released when Catha edulis leaves (khat) are chewed, has euphoric, stimulatory properties. It is metabolized to the phenylpropanollamines (PPAs) cathine and norephedrine. This study investigated whether PPAs affect mammalian sperm function, using primarily mouse, but also human, spermatozoa. METHODS: Uncapacitated sperm suspensions were treated with cathine, norephedrine, adrenaline and noradrenaline, then assessed using chlortetracycline (CTC) fluorescence. Cathine and adrenaline were also evaluated using in vitro fertilization. Capacitated suspensions were treated with PPAs +/- progesterone and +/- pertussis toxin. Finally, cAMP production was evaluated in uncapacitated and capacitated suspensions. RESULTS: In uncapacitated mouse spermatozoa, cathine, norephedrine, adrenaline and noradrenaline all significantly accelerated capacitation; uncapacitated human spermatozoa responded similarly to cathine. Consistent with these results, cathine- and adrenaline-treated suspensions were significantly more fertile than controls. In capacitated spermatozoa, both PPAs inhibited spontaneous acrosome reactions (ARs) but progesterone could over-ride this inhibition. Pertussis toxin abolished cathine's inhibition of ARs, suggesting G protein involvement. Finally, cathine and adrenaline significantly stimulated cAMP production in uncapacitated suspensions, but significantly inhibited it in capacitated suspensions. CONCLUSIONS: This is the first demonstration that PPAs can directly affect mammalian sperm function, accelerating capacitation and inhibiting spontaneous ARs. These responses correlated with initial stimulation and subsequent inhibition of cAMP production. Adrenaline/noradrenaline elicited similar responses, suggesting the presence of adrenergic receptors. Therefore, regulation of adenylyl cyclase/cAMP in a G proteinmediated fashion by PPAs may possibly involve adrenergic receptors. These results suggest that PPAs, at appropriate doses, might provide a novel approach to enhance natural fertility.