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PubMed2003

Genetic mapping and characterization of the bleeding disorder in the fawn-hooded hypertensive rat.

Release of platelet dense granule contents occurs in response to vascular injury, playing an important role in platelet aggregation and primary hemostasis. Abnormalities of the platelet dense granules results in a bleeding disorder of variable severity termed "storage pool defect" (SPD). We have examined the fawn-hooded hypertensive (FHH) rat as a model of SPD in order to genetically map the locus (Bd) responsible for prolonged bleeding. Platelet function assays of the FHH rat confirmed the presence of a platelet dense granule SPD. However electron microscopy and lysosomal enzyme assays indicated differences between the FHH rat and other rodent models of SPD. Genetic mapping through the use of congenic FHH rats localized the Bd locus to an approximately 1 cM region on rat chromosome 1. Through the use of comparative mapping between species and analysis of the initial draft of the rat genome assembly, six known and thirty-four putative genes were identified in the Bd locus. None of these genes have been previously implicated in platelet function. Therefore positional cloning of the gene responsible for the bleeding disorder in the FHH rat will lead to new insights in platelet physiology, with implications for diagnosis and management of hemostatic and thrombotic disorders.

Animals↗
PubMed1996

Lessons for neurotoxicology from selected model compounds: SGOMSEC joint report.

The ability to identify potential neurotoxicants depends upon the characteristics of our test instruments. The neurotoxic properties of lead, methylmercury, polychlorinated biphenyls, and organic solvents would all have been detected at some dose level by tests in current use, provided that the doses were high enough and administered at an appropriate time such as during gestation. The adequacy of animal studies, particularly rodent studies, to predict intake levels at which human health can be protected is disappointing, however. It is unlikely that the use of advanced behavioral methodology would alleviate the apparent lack of sensitivity of the rodent model for many agents.

Animals↗
PubMed2006

Galanin as a modulator of anxiety and depression and a therapeutic target for affective disease.

Galanin is a 29 amino-acid (30 in humans) neuropeptide with a close functional relationship with neurotransmitter systems implicated in the pathophysiology and treatment of depression and anxiety disorders. In rodent models of depression-related behavior, treatment with galanin or compounds with agonist actions at galanin receptors has been shown to affect depression-related behaviors and the behavioral and neurochemical effects of antidepressants. Treatment with clinically efficacious antidepressants alters galanin and galanin receptor gene expression in rodents. Rodent anxiety-like behaviors appear to be modulated by galanin in a complex manner, with studies showing either increases, decreases and no effects of galanin treatments and galanin mutations on anxiety-like behavior in various tasks. One concept to emerge from this literature is that galanin recruitment during extreme behavioral and physiological provocations such as stress and opiate withdrawal may serve to attenuate negative emotional states caused by noradrenergic hyperactivation. The specific galanin receptor subtypes mediating the anxiety- and depression-related effects of galanin remains to be determined, with evidence supporting a possible contribution of GalR1, GalR2 and GalR3. While our understanding of the role of galanin as a modulator of emotion remains at an early stage, recent progress in this rapidly evolving field raise possibility of that galanin may represent a target for the development of novel antidepressant and anxiolytic drug treatments.

Animals↗
PubMed1999

Desazadesmethyldesferrithiocin analogues as orally effective iron chelators.

Further structure-activity studies of desferrithiocin analogues are carried out. (S)-Desazadesmethyldesferrithiocin, 2-(2-hydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid, serves as the principal framework in the current paper. Desazadesmethyldesferrithiocin can be structurally altered with facility, and data are already available on its iron-clearing properties and toxicity parameters. Four different kinds of structural modifications of this framework are undertaken: introduction of hydroxy, carboxy, or methoxy groups on the aromatic ring; alteration of the thiazoline ring; increasing the distance between the ligand donor atoms; and benz-fusion of the aromatic rings. The structural modifications described are shown to have a tremendous impact on both the iron clearance and toxicity profiles of the desazadesmethyldesferrithiocin molecule. All of the compounds are assessed in a bile-duct-cannulated rodent model to determine iron clearance efficiency. Ligands which demonstrate an efficiency of greater than 2% are carried forward to the iron-overloaded primate for iron-clearing measurements. Ligands with efficiencies greater than 3% in the primate are then evaluated in a formal toxicity study in rodents. On the basis of the results of the present work, 2-(2, 4-dihydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid is a promising candidate for clinical evaluation.

Administration, Oral↗
PubMed1996

Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease.

Huntington disease is a dominantly inherited, untreatable neurological disorder featuring a progressive loss of striatal output neurons that results in dyskinesia, cognitive decline, and, ultimately, death. Neurotrophic factors have recently been shown to be protective in several animal models of neurodegenerative disease, raising the possibility that such substances might also sustain the survival of compromised striatal output neurons. We determined whether intracerebral administration of brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3, or ciliary neurotrophic factor could protect striatal output neurons in a rodent model of Huntington disease. Whereas treatment with brain-derived neurotrophic factor, nerve growth factor, or neurotrophin-3 provided no protection of striatal output neurons from death induced by intrastriatal injection of quinolinic acid, an N-methyl-D-aspartate glutamate receptor agonist, treatment with ciliary neurotrophic factor afforded marked protection against this neurodegenerative insult.

Animals↗
PubMed2003

A model to study differences between primary and secondary degeneration of retinal ganglion cells in rats by partial optic nerve transection.

PURPOSE: To use a rat model of optic nerve injury to differentiate primary and secondary retinal ganglion cell (RGC) injury. METHODS: Under general anesthesia, a modified diamond knife was used to transect the superior one third of the orbital optic nerve in albino Wistar rats. The number of surviving RGC was quantified by counting both the number of cells retrogradely filled with fluorescent gold dye injected into the superior colliculus 1 week before nerve injury and the number of axons in optic nerve cross sections. RGCs were counted in 56 rats, with 24 regions examined in each retinal wholemount. Rats were studied at 4 days, 8 days, 4 weeks, and 9 weeks after transection. The interocular difference in RGCs was also compared in five control rats that underwent no surgery and in five rats who underwent a unilateral sham operation. It was confirmed histologically that only the upper optic nerve had been directly injured. RESULTS: At 4 and 8 days after injury, superior RGCs showed a mean difference from their fellow eyes of -30.3% and -62.8%, respectively (P = 0.02 and 0.001, t-test, n = 8 rats/group), whereas sham-operation eyes had no significant loss (mean difference between eyes = 1.7%, P = 0.74, t-test). At 8 days, inferior RGCs were unchanged from control, fellow eyes (mean interocular difference = -4.8%, P = 0.16, t-test). Nine weeks after transection, inferior RGC had 34.5% fewer RGCs than their fellow eyes, compared with 41.2% fewer RGCs in the superior zones of the injured eyes compared with fellow eyes. Detailed, serial section studies of the topography of RGC axons in the optic nerve showed an orderly arrangement of fibers that were segregated in relation to the position of their cell bodies in the retina. CONCLUSIONS: A model of partial optic nerve transection in rats showed rapid loss of directly injured RGCs in the superior retina and delayed, but significant secondary loss of RGCs in the inferior retina, whose axons were not severed. The findings confirm similar results in monkey eyes and provide a rodent model in which pharmacologic interventions against secondary degeneration can be tested.

Animals↗
PubMed2001

Visualization of GFP-expressing tumors and metastasis in vivo.

We have developed mouse models of metastatic cancer with genetically fluorescent tumors that can be imaged in fresh tissue, in situ, as well as externally. To achieve this capability, we have transduced the green fluorescent protein (GFP) gene, cloned from the bioluminescent jellyfish Aequorea victoria, into a series of human and rodent cancer cell lines that were selected in vitro to stably express GFP in vivo after transplantation to metastatic rodent models. Techniques were also developed for transduction of tumors by GFP in vivo. With this fluorescent tool, we detected and visualized for the first time tumors and metastasis in fresh viable tissue or in situ in host organs down to the single-cell level. GFP tumors on the colon, prostate, breast, brain, liver, lymph nodes, lung, pancreas, bone, and other organs can also be visualized externally, transcutaneously by quantitative whole-body fluorescence optical imaging. Real-time tumor and metastatic growth and angiogenesis and inhibition by representative drugs can be imaged and quantified for rapid antitumor, antimetastatic, and antiangiogenesis drug screening. The GFP-transfected tumor cells enabled a fundamental advance in the visualization of tumor growth and metastasis in real time in vivo.

3T3 Cells↗
PubMed1994

Surrogate endpoint biomarker assays in phase II chemoprevention clinical trials.

Surrogate endpoint biomarker (SEB) assays carried out in rodent models have benefitted from large amounts of available colonic tissue, abundant well-aligned colonic crypts, and population groups with fairly uniform biological characteristics. In contrast, SEB assays in human colon studies have often been carried out on small groups of subjects, without the advantages inherent in rodent studies. Some factors that contribute to variations in human colon SEB assays include differences in genetic background, the extent and duration of previous colonic diseases, degree of previous chronic irritation to the colonic mucosa, the initial levels of nutrients ingested prior to the study, administration of large volumes of fluid prior to SEB measurement which induce hypermetabolic and then quiescent changes in the mucosa, failure to use strict morphologic criteria in counting colonic crypts, and availability of only a small number of crypts for analysis. Measurements of adenoma recurrence over short durations are limited by factors that include a large potential miss-rate of small adenomas, a window of observation with short duration which limits the stage of adenoma observed, and the consequent inability to measure mechanisms that a chemopreventive intervention is affecting in a different stage of adenoma development.

Animals↗
PubMedDate not supplied

Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic aging.

Over the course of normal aging, all female mammals with regular cycles display an irreversible arrest of cyclicity at mid-life. Males, in contrast, exhibit gametogenesis until death. Although it is widely accepted that exposure to estradiol throughout life contributes to reproductive aging, a unified hypothesis of the role of estradiol in reproductive senescence has yet to emerge. Recent evidence derived from a rodent model of chronic estradiol-mediated accelerated reproductive senescence now suggests such a hypothesis. It has been shown that chronic estradiol exposure results in the destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus while leaving other neuronal populations spared. This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals. Furthermore, we have shown that this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies. The increment in mu opioid receptors presumably renders the opioid target cells supersensitive to either residual beta-endorphin or other endogenous mu ligands, such as met-enkephalin, thus resulting in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH. Indeed, prevention of the neuroendocrine effects of estradiol by antioxidant treatment also prevents the cascade of neuroendocrine aberrations resulting in anovulatory acyclicity. The loss of beta-endorphin neurons along with the paradoxical opioid supersensitivity which ensues, provides a unifying framework in which to interpret the diverse features that characterize the reproductively senescent female.

Aging↗
PubMed1986

Animal extrapolation and the challenge of human heterogeneity.

The capacity of animal models to predict the responses of humans to carcinogenic agents in light of the occurrence of human heterogeneity is assessed in this paper. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. At the same time, it is believed that the conventional rodent models, which are usually highly inbred and reared in standard ways, display a very homogeneous response to toxic agents, including carcinogens. The question then becomes, To which narrow band of the broad spectrum of human responses can specific animal models likely be extrapolated? First, the occurrence of human heterogeneity is examined with respect to a broad range of biological characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, glutathione S-transferase activity, beta-glucuronidase activity, debrisoquine hydroxylation, and DNA adduct formation), with particular emphasis on those which affect responses to carcinogens. Second, the occurrence of heterogeneity for selected animal models for these characteristics is assessed and the outcomes are related to the spectrum of human responses noted above.

Acetylation↗
PubMed2006

Altered distributions of nucleocytoplasmic transport-related proteins in the spinal cord of a mouse model of amyotrophic lateral sclerosis.

Recent investigations have indicated that the nucleocytoplasmic transport system is essential for maintaining cell viability and cellular functions and that its dysfunction could lead to certain disorders. To investigate the involvement of this system in the pathomechanisms of amyotrophic lateral sclerosis (ALS), we examined the immunohistochemical localization of proteins associated with nucleocytoplasmic transport in the lumbar spinal cord in a mutant SOD1 (G93A) transgenic mouse model of ALS. This model is widely used for ALS research, and the mutant mice are known to exhibit neuronal loss and Lewy body-like hyaline inclusions (LBHIs) in the anterior horns, similar to the pathology seen in familial ALS patients associated with an SOD1 mutation and in several other transgenic rodent models. Using antibodies against the importin beta family of proteins, the major carrier proteins of nucleocytoplasmic transport, and those against their adapter protein, importin alpha, we found that the immunoreactivities were decreased within the nuclei and increased within the cytoplasm of a subset of the surviving anterior horn cells of the transgenic mice. In addition, LBHIs were invariably reactive toward these antibodies. Furthermore, the immunoreactivities for histone H1 and beta-catenin, representative cargo proteins transported by importin beta-dependent and beta-independent nucleocytoplasmic transport pathways, respectively, showed distributions similar to those for importin beta family and importin alpha proteins. The altered distributions of these proteins were not associated with caspase-3 expression, suggesting that the findings are unlikely to be a manifestation of apoptotic processes. Chronological quantitative analysis of importin beta-immunostained sections from the transgenic mice revealed a statistically significant progressive decrease in the proportion of the anterior horn cells exhibiting a more intense reactivity for these proteins in the nucleus than in the cytoplasm. To the contrary, we found that the anterior horn cells with the immunoreactivity in their cytoplasm, being more pronounced than that in their nucleus, were significantly increased in number along with the disease progression. This is the first report investigating nucleocytoplasmic transport in the ALS model mouse, and our present results imply that its dysfunction could be involved in the pathomechanisms underlying ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Systemic and local interferon gamma gene delivery to the lungs for treatment of allergen-induced airway hyperresponsiveness in mice.

Allergen-induced airway hyperresponsiveness, an animal model of asthma in humans, may respond to immunotherapy with Th1 cytokines. For example, local administration of recombinant IL-12 or IFN-gamma, or intratracheal delivery of the genes for these cytokines, has been shown to reduce the severity of allergen-induced airway hyperresponsiveness (AHR) in rodent models. We reasoned that systemic cytokine gene delivery to the lungs by intravenous injection of lipid-DNA complexes might also be an effective approach to treatment of allergen-induced AHR. Therefore, the effects of either systemic or local pulmonary IFN-gamma gene delivery were evaluated in mice with allergen-induced AHR. The effects of treatment on AHR, airway eosinophilia and cytokine production, and serum IgE concentrations were evaluated in mice that were first sensitized to ovalbumin and then subjected to aerosol ovalbumin challenge. Intravenous IFN-gamma gene delivery significantly inhibited development of AHR and airway eosinophilia and decreased serum IgE levels, compared with control mice or mice treated with noncoding DNA. Intratracheal IFN-gamma gene delivery also significantly inhibited AHR and airway eosinophilia, but did not affect serum IgE levels. Treatment with recombinant IFN-gamma was much less effective than IFN-gamma gene delivery by either route. We conclude that either systemic or local pulmonary delivery of a Th1 cytokine gene such as IFN-gamma may be an effective approach for treatment of allergen-induced asthma.

Allergens↗
PubMed2004

Stroke in the female: role of biological sex and estrogen.

Women are protected from stroke relative to men until the years of menopause. Because stroke is the leading cause of serious, long-term disability in the United States, modeling sex-specific mechanisms and outcomes in animals is vital to research. Important research questions are focused on the effects of hormone replacement therapy, age, reproductive status, and identification of sex-specific risk factors. Available research relevant to stroke in the female has almost exclusively utilized rodent models. Gender-linked stroke outcomes are more detectable in experimental studies than in clinical trials and observational studies. Various estrogens have been extensively studied as neuroprotective agents in women, animals, and a variety of in vitro models of neural injury and degeneration. Most data in animal and cell models are based on 17 beta estradiol and suggest that this steroid is neuroprotective in injury from ischemia/reperfusion. However, current evidence for the clinical benefits of hormone replacement therapy is unclear. Future research in this area will need to expand into stroke models utilizing higher order, gyrencephalic animals such as nonhuman primates if we are to improve extrapolation to the human scenario and to direct and enhance the design of ongoing and future clinical studies and trials.

Animals↗
PubMed2006

Prevention and repair of circulatory shock and cerebral ischemia/injury by various agents in experimental heatstroke.

The current report summarized animal models of heatstroke experimentation that advance our current knowledge of therapeutic effects on cerebrovascular dysfunction, hypercoagulable state and/or systemic inflammation with various agents in the setting of heatstroke. This was a narrative review of selected published primary basic literature from MEDLINE for 1973-2006. It was found that rodents shared with humans almost the same heatstroke reactions such as hyperpyrexia, hypotension, hyperventilation, pulmonary edema, hepatic and renal failure, hypercoagulable state, metabolic acidosis, systemic inflammation, and cerebral ischemia, injury and dysfunction. Therefore, the rodent model would allow testing of new therapeutic strategies for heatstroke. It was found that brain cooling produced by infusion of cold (4 degrees C) normal saline via the jugular vein or whole body cooling improved survival during heatstroke by reducing cerebrovascular dysfunction, multiple organ failure, systemic inflammation and hypercoagulable state. However, even under the absence of brain or whole body cooling, these heatstroke reactions still could be reversed by treating with the following agents: (1) free radical scavengers; (2) human recombinant protein C: (3) platonin; (4) hyperbaric oxygen; (5) hydroxyethyl starch, hypertonic solution, or human albumin; (6) glucocorticoids; (7) interleukin-1 receptor antagonists; (8) L-arginine; (9) estrogen; and (10) human umbilical cord blood cells or CD +34 cells. Before initiation of heat stress, prior manipulations with one of the following measures were found to be able to protect against heatstroke syndromes: (1) systemic delivery of inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin-1A receptor antagonists, dopaminergic or serotoninergic nerve depletor or receptor antagonists, or glutamate receptor antagonists; or (2) heat shock protein 72 preconditioning.

Animals↗
PubMed2004

Salivary gland involvement in graft-versus-host disease: the underlying mechanism and implicated treatment.

Patients with graft-versus-host disease suffer from xerostomia, oral infections and mucosal pathologies. The continuous increase in the number of patients treated with bone marrow transplants worldwide, combined with improved survival statistics result in a concomitant increase in the number of GVHD patients. The pathogenesis of GVHD is based on donor graft T lymphocytes that recognize antigenic disparities between donor and recipient, and on the disregulation of a broad panel of cytokines. Consequently, various tissues and organs, including the mucosa of the oral and gastrointestinal tract, are damaged via cytotoxicity caused by infiltrating T cells. Since the salivary glands are a known major target of GVHD and their secretions significantly contribute to preserving mucosal integrity, this mucosal insult is further enhanced by the reduced quantity and altered quality of saliva. GVHD occurs in 40-70% of patients treated by bone marrow and peripheral blood stem cell transplantation. Limited studies suggest that a large percentage of GVHD patients are affected and that the induced salivary dysfunction occurs rapidly following transplantation, affecting both major and minor salivary glands and reflecting the severity of the disease. Moreover, profound sialochemical alterations may be diagnostic of GVHD. An additional reason for the vast amount of research is that GVHD, as an autoimmune-like disease, seems to be an appropriate model for studying a much more prevalent, well-known and studied autoimmune disease involving salivary glands, namely, Sjögren's syndrome. The present review describes the GVHD-related sialometric and sialochemical data available in the literature for both major and minor salivary glands in both human and rodent models, and discusses a possible mechanism.

Animals↗
PubMed2006

A single dose of liposome-encapsulated hydromorphone provides extended analgesia in a rat model of neuropathic pain.

Opioids have been shown to relieve thermal hyperalgesia associated with neuropathic pain. We used a novel technique to produce liposome-encapsulated hydromorphone (LEH), which we then tested in a chronic constriction injury (CCI) thermal hyperalgesia model of neuropathic pain. Rats were divided into sham-operated and CCI groups. Treatments consisted of LEH or standard hydromorphone, administered at surgery or 3 d after surgery, when thermal hyperalgesia had developed in the CCI rats. We measured thermal withdrawal latencies on days 0, 3, and 5. CCI rats given liposome-encapsulated vehicle or standard hydromorphone at surgery developed full thermal hyperalgesia. CCI rats given LEH at surgery exhibited no significant change compared with baseline values in thermal withdrawal latency, indicating that this preparation prevented hyperalgesia after a single injection. CCI rats given LEH on day 3 (that is, after they had developed hyperalgesia) showed reversal of hyperalgesia that persisted to day 5, whereas CCI rats given standard hydromorphone on day 3 showed only brief (approximately 90 min) reversal of hyperalgesia. Preemptive injection of LEH prevented hyperalgesia in this model for as long as 5 d. In addition, hyperalgesia was alleviated for at least 2 d after injection of a single dose of LEH. These results suggest that liposome-encapsulation of hydromorphone offers a convenient and effective means to provide relief from neuropathic pain in this rodent model.

Analgesics, Opioid↗
PubMed2006

Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy.

OBJECTIVES: We evaluated the therapeutic potential of a recombinant 61-residue neuregulin-1 (beta2a isoform) receptor-active peptide (rhNRG-1) in multiple animal models of heart disease. BACKGROUND: Activation of the erbB family of receptor tyrosine kinases by rhNRG-1 could provide a treatment option for heart failure, because neuregulin-stimulated erbB2/erbB4 heterodimerization is not only critical for myocardium formation in early heart development but prevents severe dysfunction of the adult heart and premature death. Disabled erbB-signaling is also implicated in the transition from compensatory hypertrophy to failure, whereas erbB receptor-activation promotes myocardial cell growth and survival and protects against anthracycline-induced cardiomyopathy. METHODS: rhNRG-1 was administered IV to animal models of ischemic, dilated, and viral cardiomyopathy, and cardiac function and survival were evaluated. RESULTS: Short-term intravenous administration of rhNRG-1 to normal dogs and rats did not alter hemodynamics or cardiac contractility. In contrast, rhNRG-1 improved cardiac performance, attenuated pathological changes, and prolonged survival in rodent models of ischemic, dilated, and viral cardiomyopathy, with the survival benefits in the ischemic model being additive to those of angiotensin-converting enzyme inhibitor therapy. In addition, despite continued pacing, rhNRG-1 produced global improvements in cardiac function in a canine model of pacing-induced heart failure. CONCLUSIONS: These beneficial effects make rhNRG-1 promising as a broad-spectrum therapeutic for the treatment of heart failure due to a variety of common cardiac diseases.

Animals↗
PubMed2000

Impact of uremia on female reproductive cyclicity, ovulation, and luteinizing hormone in the rat.

BACKGROUND: Impaired reproductive function accompanies chronic renal insufficiency (uremia) in both the human and experimental animal. Clinical hypogonadism occurs in both genders. The present studies were designed to investigate possible anti-ovulatory effects of uremia in the female rat, a species that produces multiple ova during the normal estrous cycle. METHODS: Renal insufficiency (uremia) was induced by 5/6 nephrectomy. Two control groups comprised sham-operated animals fed ad libitum (sham) or pair-wise with the uremic animals (pair-fed). Estrous cycles were determined by cytology of vaginal lavage. We examined concomitant changes in the preovulatory luteinizing hormone (LH) surge by radioimmunoassay (RIA), immunoradiometric assay (IRMA), and bioassay. Repetitive LH measurements were made from blood samples taken by intra-atrial catheter throughout the afternoon and evening of proestrus. The following morning (estrus), ovaries were collected, and ova were enumerated per oviduct. RESULTS: Experimentally uremic animals manifested a threefold elevation of plasma creatinine and urea nitrogen and concomitantly a more than 50% impoverishment of ova production. Analyses of a large group of animals (N = 83) by RIA revealed uremia-associated attenuation of the preovulatory LH surge. Further measurements of the preovulatory LH surge by independent IRMA and LH bioassay (N = 26) corroborated this attenuation. Additional experiments indicated that these hormonal changes, but not changes in ovulation, might further reflect modulation of LH release by the anesthesia used in the preparative nephrectomy and catheterization surgeries. When normalized to body weight, the ovaries of uremic rats were found to weigh more than those of either the sham or pair-fed animals. CONCLUSIONS: The present experiments take advantage of an experimental uremic model to document a consistent decrease in the number of ova released during estrus in the uremic animal. Possible disruption of hypothalamic-pituitary-ovarian regulation is further highlighted by attenuation in the preovulatory LH surge. These results provide a basis for further studies of neuroendocrine pathophysiology in a rodent model of uremia-associated ovulatory disruption.

Amenorrhea↗