L-arginine/nitric oxide amplifies the magnitude and duration of the luteinizing hormone surge induced by estrogen: involvement of neuropeptide Y.

Although estrogen can induce LH hypersecretion in ovariectomized (ovx) rats, the magnitude and duration of the LH surge are invariably far less than those of the preovulatory LH surge in cycling rats. Recently, the crucial roles of hypothalamic nitric oxide (NO) and neuropeptide Y (NPY) in the induction of LHRH and the LH surge have been recognized. In this study, we have tested the hypothesis that low grade stimulatory feedback effects of 17 beta-estradiol (E2) on LH secretion in ovx rats is due to a deficit in NO signaling. As the NO substrate, L-arginine (L-Arg), can enhance NO-dependent physiological responses, the effects of L-Arg on the LH surge in E2-primed ovx rats was studied. Ovx rats bearing permanent cannulas in the lateral cerebroventricle received 15-mm long SILASTIC capsules filled with E2 (300 micrograms/ml oil, s.c.) at 1000 h. Two days later, saline (SAL) or L-Arg (0.1 or 1 nmol in 5 microliters SAL) or D-Arg (1.0 nmol) was injected intracerebroventricularly every hour from 1100-1400. Blood samples were collected at 1100 h and at hourly intervals from 1400-1800 h via intraatrial cannulae implanted the day before. Whereas an expected moderate LH surge occurred in SAL-injected control rats, L-Arg, but not D-Arg, greatly augmented the magnitude and duration of the LH surge, with peak values attaining the range normally seen on proestrus. Furthermore, L-Arg (1 or 10.0 mM) and the NO donor, sodium nitroprusside (1 or 10.0 mM), stimulated the basal and K(+)-induced in vitro release of LHRH and NPY from the hypothalami of ovarian steroid-primed ovx rats. As NPY is stimulatory to LHRH release, we next tested the possibility that L-Arg/NO may initially stimulate NPY release in the hypothalamus, which, in turn, elicits LHRH discharge. E2-treated ovx rats receiving intracerebroventricular L-Arg were injected with antisense or missense oligodeoxynucleotides (oligos) to NPY-messenger RNA. Antisense, not missense, NPY oligos blocked the L-Arg-induced potentiation of the LH surge. These results revealed for the first time the neurochemical cause underlying the E2 feedback action and show that a deficiency in either L-Arg itself or L-Arg-based NO signaling is responsible for the low grade LH surge in ovx rats treated with estrogen alone. Additionally, the L-Arg-dependent potentiation of the LH surge may involve increased signaling in the NO and NPYergic systems, resulting in optimal LHRH hypersecretion from the hypothalamus.