LH release in response to GnRH injected at 1400 h was measured in young (3-4 months), middle-aged (10-11 months), and old (19-20 months) female rats. Data were compared when animals were grouped by chronological age or according to their vaginal smear pattern 3-4 weeks before treatment, i.e. regular 4-day cycles, constant vaginal cornification (CVC), or persistently leukocytic smears (PL). Compared to young, regularly cycling females (injected on vaginal estrus or diestrus II), the amount of LH released by all age groups with CVC or PL smears was significantly diminished. However, regardless of age, the amount of LH released by CVC females was similar for each dose of GnRH. Similarly, there was no difference in the amount of LH released by the young, middle-aged, and old PL females at each dose of GnRH. Finally, the amount of LH released by the CVC females was uniformly higher than the amount of LH released by age-matched PL females. In contrast, comparison of LH release after GnRH injection in young and middle-aged rats with regular 4-day vaginal cycles showed that the middle-aged rats released significantly less LH on proestrus. These data suggest that changes in the ability of the pituitary to release LH in the older noncycling female rat occurs as a consequence of the altered endocrine status in the animal and not as a result of the chronological age per se. Changes in the ability of the pituitary of the middle-aged, regularly cycling female rat to release LH in response to GnRH may contribute to the age-related disruption of regular ovarian cycling.

We have compared the potencies of chemically heterogeneous classes of Ca2+ ion channel inhibitors as antagonists of GnRH-stimulated LH release from the rat pituitary. Verapamil and its more potent derivative methoxyverapamil (D600) are effective inhibitors. The 1,4-dihydropyridines, however, had no antagonistic efficacy, and diltiazem had slight inhibitory action, but only when preincubated with cells before GnRH addition. The observation that the potency series of antagonists was identical (verapanoids greater than diltiazem greater than 1,4-dihydropyridines) whether GnRH or veratridine was used to stimulate the release mechanism is consistent with the premise that the same Ca2+ channel is regulated by the receptor and by agents that evoke gonadotropin release by cell depolarization. This potency series is virtually opposite that observed for muscle tissue. Accordingly, these data suggest that the receptor-regulated Ca2+ ion channel of the pituitary gonadotrope is distinct from that described in muscle.