IMPAIRED OVULATION IN MICE WITH TARGETED DELETION OF THE NEURONAL ISOFORM OF NITRIC-OXIDE SYNTHASE

Background: Nitric oxide (NO) plays an important role in numerous repr oductive processes. To date, most studies have assessed the role of NO by using nonspecific pharmacological inhibitors of the precursor to N O, nitric oxide synthase (NOS). These pharmacological NOS inhibitors s uppress all isoforms of NOS: thus, the precise contribution of each is oform to female reproductive physiology is unknown. The purpose of thi s study was to determine the specific role of neuronal NOS (nNOS) in t he regulation of ovulation in female mice lacking the gene that encode s for nNOS (nNOS-/-). Materials and Methods: Ovulation was assessed in wild-type (WT) and nNOS-/- female mice by examining the number of ova rian rupture sites and number of oocytes recovered from the oviducts f ollowing mating or exposure to exogenous gonadotropins (i.e., 5 IU pre gnant mares serum gonadotropin [PMSG] and 5 IU human chorionic gonadot ropin [hCG]). Ovulatory efficiency was determined as the number of ovu lated oocytes per number of ovarian rupture sites. To examine whether ovulatory deficits in nNOS-/- mice were due to alterations in central mechanisms, plasma luteinizing hormone (LH) concentrations were assess ed in WT and nNOS-/- mice that were challenged with 25 ng of gonadotro pin-releasing hormone (GnRH). To determine whether ovulatory deficits in nNOS-/- mice were due to local ovulation processes, nerves innervat ing the reproductive tract of WT and nNOS-/- females were examined for the presence of nNOS protein. Results: There were substantial fertili ty deficits in nNOS-/- female mice; the nNOS-/- mice had fewer oocytes in their oviducts following spontaneous and gonadotropin-stimulated o vulation. Pituitary responsiveness to exogenous GnRH challenge was int act in nNOS-/- mice. Dense nNOS protein staining was observed in nerve s innervating the reproductive tracts of WT mice. Conclusions: The rep roductive deficits in nNOS-/- females are most likely due to alteratio ns in the transfer of oocytes from the ovaries to the oviducts during ovulation. These results suggest that defects in neuronally derived NO production may contribute to female infertility.