Current Pharmaceutical Design - Volume 9, Issue 5, 2003

Nitric oxide (NO) is a major paracrine mediator and important regulatory agent in various female reproductive processes, such as ovulation, implantation, pregnancy maintenance, labor and delivery. Ovulation: Circulating NOproducts are increased during follicle development and decreased right after ovulation. INOS-inhibition results in a 50%reduction of ovulation, an effect completely reversed by an NO. Endometrium / Implantation: NO also regulates endometrial functions such as endometrial receptivity, implantation and menstruation. NO-donors may be useful for promoting fertility, while NO-inhibitors might be used for contraception. Uterine contractility: Throughout gestation myometrial NO-production is upregulated thus contributing to achieve uterine quiescence. Close to term, NO-production decreases promoting effective contractions resulting in labor. Clinical trials have demonstrated that NO-donors are effective tocolytics. Cervical ripening: In contrast to the myometrium, NO-production in the cervix is low during gestation and becomes upregulated once pregnancy advances to term. NO-donors are effective and safe cervical ripening agents. This finding from animal studies has been confirmed by several clinical trials. Vasoreactivity: In blood vessels, NO is a potent vasodilator and platelet-aggregation-inhibitor. Lack of NO during gestation was related to the development of pregnancy-induced hypertension and preeclampsia. In conclusion, NO-donors and NOS-inhibitors may provide novel, effective, safe, and inexpensive drugs to regulate and steer various functions in female reproductive life. The benefits reach from contraception to preventing possibly lethal pregnancy complications such as preeclampsia. Introducing NOdonors as tocolytics and cervical ripening agents may contribute to a reduction of fetal and maternal perinatal morbidity and mortality.

Nitric oxide (NO) plays a crucial role in reproduction at every level in the organism. In the brain, it activates the release of luteinizing hormone-releasing hormone (LHRH). The axons of the LHRH neurons project to the mating centers in the brain stem and by efferent pathways, evoke the lordosis reflex in female rats. In males, there is activation of NOergic terminals that release NO in the corpora cavernosa penis to induce erection by generation of cyclic guanosine monophosphate (cGMP). NO also activates the release of LHRH which reaches the pituitary and activates the release of gonadotropins by activating neural NO synthase (NOS) in the pituitary gland. Follicle stimulating hormone (FSH)RH selectively releases FSH also by activating NOS. Leptin releases LHRH by activating NOS to release FSH and LH with the same potency as LHRH. These actions are mediated by specific receptors on the gonadotropes for LHRH, FSHRH and leptin. The responsiveness of the pituitary is controlled by gonadal steroids. In the gonad, NO plays an important role inducing ovulation and in causing luteolysis, whereas in the reproductive tract, it relaxes uterine muscle via cGMP and constricts it by prostaglandins.

As a group, nitric oxide synthase (NOS) isoforms are localized to a wide variety of tissues. Understanding the role of NOS in reproductive physiology was facilitated by the introduction of genetically engineered mice. Specifically, “knock-out” mice with targeted disruptions in neuronal NOS, endothelial NOS and inducible NOS have been made. These models have been useful in addressing the of role of nitric oxide in areas of reproductive biology that include:hypothalamic-pituitary-ovarian axis, mating behavior, maternal blood pressure regulation and fetal development. Despite several promising observations using “knock-out” mouse models, one must exercise caution in interpreting data from individual experiments. Very often the need to draw on two mouse strains to generate the founder NOS deficient line, purity of the strain used for observing phenotypes (presence or absence of backcrossing to achieve a pure strain), and the strain used for comparison purposes (control strains are often not identical in their genetic make-up to the deficient line) make wide spread applicability of results open to criticism.

Nitric oxide synthases, the enzymes that generate NO gas, may be involved in reproduction and development of multicellular organisms at many levels and thus provide important targets for design of drugs to intervene in reproductive processes. This review focuses on the role of nitric oxide in key events of reproduction including gamete activation, fertilization, early cell divisions and implantation. A general trend highlighted by the studies reviewed is that NO plays a biphasic role in reproduction. That is, a narrow range of NO concentrations, usually low, will stimulate or enhance these early events in reproduction, but either a lack of NO or too much NO has negative consequences. One of the shortcomings of the field currently is the lack of molecular detail concerning the mechanism of NO action. This has been due in part to lack of technology for effective detection of NO and its molecular targets. A few targets of NO have been indirectly implicated and advances in this area of research will provide substrates for development of drugs to control reproductive function. Work from both invertebrate and vertebrate model systems is presented and implications for control of reproductive physiology discussed. Ubiquity of NO signaling in animals may mean that effective control of reproduction must target mediators of NO action and not NOS enzymes themselves.

This paper reviews new models of nitric-oxide (NO) - related regulation of transepithelial and transendothelial permeability in normal tissues, with emphasis on physiological relevance of the data. Novel data obtained in cultured human epithelial and endothelial cells indicate that NO can originate from different intracellular sources, and can be selectively regulated and employed to activate various intracellular mechanisms that will affect the permeability via different mechanisms. These models may be important for understanding NO regulation of permeability in vivo.

Low and controlled concentrations of nitric oxide play an important role in sperm physiology. Nitric oxide is produced by spermatozoa and acts as an intracellular signaling molecule in the processes of capacitation and acrosome reaction. It has been documented that during capacitation, nitric oxide interacts with the cAMP-protein kinase A pathway and also is involved in tyrosine nitration of sperm proteins. On the other hand, during the acrosome reaction, two different pathways have been postulated for nitric oxide to exert its effects. During the progesterone-induced acrosome reaction, nitric oxide stimulates a heme-containing enzyme, named cyclooxygenase with a subsequent increase in prostaglandin E2. Furthermore, the acrosome reaction inducing effect of NO-releasing compounds occurs via an increase in cGMP levels and protein kinase G activation. Taken together, these data support a role for nitric oxide in sperm function.This review focuses on providing new evidence for the physiological role of nitric oxide (NO) on sperm function. We will first present a brief description on nitric oxide chemistry and on the events leading to sperm fertilizing ability followed by the observations obtained on the participation of NO on fertilization.