Tetrodotoxin augmentation of secretagogue-induced luteinizing hormone secretion

Gonadotrophs are known to possess voltage-sensitive Na channels. We used two experimental systems, proestrous rat anterior pituitary tissue superfusion and 17 beta-estradiol-treated rat anterior pituitary cells in primary culture, to examine the effect of Na channel inhibition on LH secretion. We found that a blocker of voltage-sensitive Na channels, tetrodotoxin (TTX), significantly augments LHRH- and elevated extracellular [K+]-induced LH secretion 20-90%. The augmentation of LHRH-induced secretion was demonstrable for both experimental systems and was independent of the time of TTX exposure. These results differ from previous studies in which TTX was without effect or was found to inhibit LH secretion. These discrepancies may be explained, in part, by the demonstration that TTX augmentation requires relatively low TTX concentrations (10(-6)-10(-8) M) and is not demonstrable at higher concentrations, requires submaximal LHRH concentrations (10(-10)-10(-9) M), and requires exposure of cultured cells to 17 beta-estradiol. The site of TTX action could be either directly on gonadotroph voltage-sensitive Na channels or indirect via modulation of Na channels of a paracrine modulator of gonadotroph function. The mechanism by which TTX Na channel blockade augments secretagogue-induced LH secretion is unknown; however, the data are interpreted as favoring direct action of TTX on the gonadotroph, with Na channel blockade affecting a site or sites common to both LHRH and elevated extracellular [K+]. Whether the inhibition of Na channels is one of the several effects of LHRH-receptor interaction remains to be determined.