Biomedical subjects

Abdulmaged M Traish

Publications and source records attributed to Abdulmaged M Traish.

At least 19 recordsLinked to original sources

PubMed2006

Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat.

BACKGROUND: Tamoxifen, a selective estrogen receptor modulator with both estrogenic and anti-estrogenic activity, is widely used as adjuvant therapy in breast cancer patients. Treatment with tamoxifen is associated with sexual side effects, such as increased vaginal dryness and pain/discomfort during sexual activity. There have been limited investigations of the effect of tamoxifen on estrogen-dependent peripheral genital arousal responses. The objective of this study was to investigate the effects of tamoxifen on vaginal physiology in the rat. METHODS: Female Sprague-Dawley rats were subjected to sham surgery or bilateral ovariectomy. After 2 weeks, sham-operated rats were implanted with subcutaneous osmotic infusion pumps containing vehicle (control) or tamoxifen (150 microg/day). Ovariectomized rats were similarly infused with vehicle. After an additional 2 weeks, vaginal blood flow responses to pelvic nerve stimulation were measured by laser Doppler flowmetry and vaginal tissue was collected for histological and biochemical assay. RESULTS: Tamoxifen treatment did not change plasma estradiol concentrations relative to control animals, while ovariectomized rats exhibited a 60% decrease in plasma estradiol. Tamoxifen treatment caused a significant decrease in mean uterine weight, but did not alter mean vaginal weight. Vaginal blood flow was significantly decreased in tamoxifen-infused rats compared to controls. Similar to ovariectomized animals, estrogen receptor binding was increased and arginase enzyme activity was decreased in tamoxifen-infused rats. However, different from control and ovariectomized animals, the vaginal epithelium in tamoxifen-infused rats appeared highly mucified. Periodic acid-Schiff staining confirmed a greater production of carbohydrate-rich compounds (e.g. mucin, glycogen) by the vaginal epithelium of tamoxifen-infused rats. CONCLUSION: The observations suggest that tamoxifen exerts both anti-estrogenic and pro-estrogenic effects in the vagina. These physiological alterations may eventually lead to vaginal atrophy and compromise sexual function.

Journal Article↗

PubMed2006

Streptozotocin-induced diabetes in the rat is associated with changes in vaginal hemodynamics, morphology and biochemical markers.

BACKGROUND: Diabetes is associated with declining sexual function in women. However, the effects of diabetes on genital tissue structure, innervation and function remains poorly characterized. In control and streptozotocin-treated female rats, we investigated the effects of diabetes on vaginal blood flow, tissue morphology, and expression of arginase I, endothelial nitric oxide synthase (eNOS) and cGMP-dependent protein kinase (PKG), key enzymes that regulate smooth muscle relaxation. We further related these changes with estrogen receptor alpha (ERalpha) and androgen receptor (AR) expression. RESULTS: In addition to significantly elevated blood glucose levels, diabetic rats had decreased mean body weight, lower levels of plasma estradiol, and higher plasma testosterone concentration, compared to age-matched controls. Eight weeks after administration of buffer (control) or 65 mg/kg of streptozotocin (diabetic), the vaginal blood flow response to pelvic nerve stimulation was significantly reduced in diabetic rats. Histological examination of vaginal tissue from diabetic animals showed reduced epithelial thickness and atrophy of the muscularis layer. Diabetic animals also had reduced vaginal levels of eNOS and arginase I, but elevated levels of PKG, as assessed by Western blot analyses. These alterations were accompanied by a reduction in both ERalpha and AR in nuclear extracts of vaginal tissue from diabetic animals. CONCLUSION: In ovariectomized (estrogen deficient) animals, previous reports from our lab and others have documented changes in blood flow, tissue structure, ERalpha, arginase I and eNOS that parallel those observed in diabetic rats. We hypothesize that diabetes may lead to multiple disruptions in sex steroid hormone synthesis, metabolism and action. These pathological events may cause dramatic changes in tissue structure and key enzymes that regulate cell growth and smooth muscle contractility, ultimately affecting the genital response during sexual arousal.

Animals↗

PubMed2006

Dose-response relationship between testosterone and erectile function: evidence for the existence of a critical threshold.

Androgens play an important role in erectile function. However, the dose-response relationship between plasma testosterone levels and penile erection remains unclear. Intact (sham operated) or bilaterally orchiectomized, mature male Sprague-Dawley rats were used. Two weeks after surgery, rats were infused continuously with either vehicle (polyethyleneglycol) or varying doses of testosterone (44, 88, 220, or 440 mug/day) for 14 days using subcutaneous osmotic infusion pumps (study 1). In a separate study, 4 weeks after surgery, rats were infused with a lower range of testosterone doses (11, 22, or 44 mug/day) for 14 days (study 2). In the first study, intact rats had a mean plasma testosterone concentration of 0.56 +/- 0.12 ng/mL ( approximately 1.9 nM), as determined by standard radioimmunoassay. In the second study, a more sensitive enzyme-linked immunoassay was used to measure the lower testosterone levels. Using this assay, intact rats had a mean plasma testosterone concentration of 2.02 +/- 0.59 ng/mL. Intracavernosal pressure measurements indicated that orchiectomy resulted in a significant reduction in erectile function, when compared to intact animals, whereas testosterone infusion restored erectile function to varying degrees. Erectile function was maintained by a wide range of systemic testosterone levels as low as 10%-12% of normal physiological plasma concentrations. Below these concentrations, erectile function was significantly and positively correlated with testosterone plasma levels in a dose-dependent manner. Interestingly, prostate tissue mass was positively correlated to plasma testosterone levels across all concentrations examined. Protein expression of neural nitric oxide synthase (nNOS) and phosphodiesterase type 5 (PDE 5) was reduced in penile tissue from orchiectomized animals and increased in testosterone-infused animals, as assessed by Western blot analyses. We suggest that testosterone at levels approaching one-tenth normal physiological plasma concentration may represent a threshold value, below which erectile function declines in a dose-dependent fashion. However, different androgen-dependent tissues may exhibit varying sensitivities to circulating testosterone with regard to growth and function.

Animals↗

PubMed2006

Identification of G2/M targets for the MAP kinase pathway by functional proteomics.

Although the importance of the extracellular signal-regulated kinase (ERK) pathway in regulating the transition from G1 to S has been extensively studied, its role during the G2/M transition is less well understood. Previous reports have shown that inhibition of the ERK pathway in mammalian cells delays entry as well as progression through mitosis, suggesting the existence of molecular targets of this pathway in M phase. In this report we employed 2-DE and MS to survey proteins and PTMs in the presence versus absence of MKK1/2 inhibitor. Targets of the ERK pathway in G2/M were identified as elongation factor 2 (EF2) and nuclear matrix protein, 55 kDa (Nmt55). Phosphorylation of each protein increased under conditions of ERK pathway inhibition, suggesting indirect control of these targets; regulation of EF2 was ascribed to phosphorylation and inactivation of upstream EF2 kinase, whereas regulation of Nmt55 was ascribed to a delay in normal mitotic phosphorylation and dephosphorylation. 2-DE Western blots probed using anti-phospho-Thr-Pro antibody demonstrated that the effect of ERK inhibition is not to delay the onset of phosphorylation controlled by cdc2 and other mitotic kinases, but rather to regulate a small subset of targets in M phase in a nonoverlapping manner with cdc2.

Amino Acid Sequence↗

PubMed2006

Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence.

Androgens are deemed critical for penile-tissue development, growth, and maintenance of erectile function, however, their role in erection, especially in humans, remains controversial. In this review, we summarize information from clinical and animal model studies to provide a comprehensive and rational argument for the role of androgens, or lack thereof, on penile erection ability in humans. The goal of this review is to present the clinical and preclinical evidence available in the literature with regard to testosterone and erectile physiology and engage the reader in this discussion. Ultimately, each reader will have to form his or her own conclusions based on the existing evidence. In humans, androgen-deficiency manifestations are noted in clinical situations such as: (i) inadequate development of the penis; and (ii) loss of erectile function in prostate cancer and benign prostatic hyperplasia patients managed with medical or surgical castration or antiandrogen therapy. Androgen treatment causes: (i) improvement in sexual function in hypogonadal patients treated with androgen supplementation; (ii) improvement in nocturnal penile tumescence in hypogonadal patients treated with androgens; (iii) improvement in erectile function with androgen supplementation in patients who did not respond to phosphodiesterase type 5 inhibitor therapy initially; and (iv) improvement in the well-being, mood, energy, and sexual function in aging men who have testosterone deficiency treated with androgen therapy. In contrast to animals, especially rodents in which the adrenal cortex does not synthesize androgens, the human adrenal is a source of peripherally circulating androgen precursors, thus, complete androgen insufficiency may not be observed in men at a younger age. Furthermore, in light of the concept that a threshold of androgen levels exists in animals and humans below which sexual function is diminished, further contributes to the complexity of understanding androgens role in erections, especially in humans. Nevertheless, based on the preclinical and clinical data available in the literature, to date, we infer that androgens play a critical role in maintaining erectile physiology in humans.

Androgens↗

PubMed2006

Differential regulation of the expression of estrogen, progesterone, and androgen receptors by sex steroid hormones in the vagina: immunohistochemical studies.

OBJECTIVE: Significant structural changes occur in the rat vagina in response to sex steroid hormone deprivation and replacement. However, the mechanism by which these changes occur is not clearly understood and our current hypothesis is that these effects are mediated, at least in part, by the expression of sex steroid hormone receptors. The goal of this study was to assess changes in steroid hormone receptor expression and distribution in response to sex steroid hormone deprivation and administration. METHODS: Female rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or hormone combinations. Using immunohistochemistry, hormone receptor distribution was assessed in all layers of the vaginal wall. RESULTS: After ovariectomy, estrogen receptor alpha (ERalpha) was up-regulated and progesterone receptor (PR) was down-regulated. Estradiol replacement restored these ovariectomy-induced changes, and this effect was dose-dependent. Androgen receptor (AR) expression was unaffected by ovariectomy or estradiol replacement. However, testosterone treatment resulted in increased AR density in the muscularis. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone. CONCLUSION: Estradiol down-regulated ERalpha and up-regulated PR expression in the vagina, suggesting this may be a mechanism to prevent continued proliferation of the epithelium by surges of estradiol during the estrous cycle.

Animals↗

PubMed2005

Differential effects of estradiol, progesterone, and testosterone on vaginal structural integrity.

Ovarian steroids are known to be important in maintaining vaginal tissue, and evidence is mounting that imbalances in the hormonal milieu contribute to vaginal pathophysiology. To date, limited data are available on the effects of hormone deprivation and replacement on vaginal tissue morphology and vaginal innervation. The goal of this study was to assess the dynamic changes in vaginal tissue structure in response to sex steroid hormone deprivation and administration. Female Sprague-Dawley rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or a combination of estradiol plus testosterone or progesterone. Histological techniques, including stereological analysis and immunohistochemistry for localization of neuronal markers, were used. Ovariectomy produced a significant decrease in epithelial height that was restored with estradiol replacement. Interestingly, a subphysiological dose of estradiol resulted in hyperplasia of the vaginal epithelium and nonvascular smooth muscle. Neither testosterone nor progesterone had a significant effect on epithelial height or muscularis thickness. However, testosterone treatment resulted in a significant increase in small adrenergic nerve fibers. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone. This study demonstrates that estradiol and testosterone have differential effects on vaginal tissue parameters and that ovarian hormones are critical for the maintenance of genital tissue structure. Present observations also suggest that combined replacement regimens may be required for an optimal physiological response.

Animals↗

PubMed2005

The multifunctional nuclear protein p54nrb is multiphosphorylated in mitosis and interacts with the mitotic regulator Pin1.

The human protein p54nrb and its mouse homolog NonO have been implicated in a variety of nuclear processes including transcription, pre-mRNA processing, nuclear retention of edited RNA and DNA relaxation. We have identified p54nrb as an antigen of the phosphodependent monoclonal antibodies CC-3 and MPM-2 and shown that this protein is phosphorylated on multiple sites during mitosis. The use of the cyclin-dependent protein kinase inhibitor roscovitine and immunodepletion studies with an anti-cyclin B1 antibody established that Cdk1 was responsible for the phosphorylation of the carboxy-terminal extremity of p54nrb whereas a different kinase appeared to be involved in the generation of CC-3 epitope(s) in the amino-terminal moiety of the protein. Like many CC-3 and MPM-2 antigens, we show that p54nrb is a target of the peptidylprolyl isomerase Pin1, suggesting that it may be regulated by phosphorylation-dependent conformational changes as many other nuclear proteins upon entry into mitosis. In addition, site-directed mutagenesis indicated that the interaction of Pin1 with p54nrb was mediated by three threonine residues located in the proline-rich carboxy-terminal extremity of the protein. Our results also showed that Pin1 binding was favored when at least two of the three threonine residues were phosphorylated, suggesting a regulation mechanism based on multisite phosphorylation.

Animals↗

PubMed2005

Clinical biologic pathophysiologies of women's sexual dysfunction.

INTRODUCTION: Data concerning the biologic pathophysiology of desire, arousal, and orgasm in women are limited. AIM: To gain knowledge of biologic pathophysiology of female sexual function. METHODS. To provide state-of-the-art knowledge concerning female sexual dysfunction, representing the opinions of seven experts from five countries developed in a consensus process over a 2-year period. MAIN OUTCOME MEASURE: An International Consultation in alliance with key urological and sexual medicine societies convened over 200 multidisciplinary specialists from 60 countries into 17 consultation committees. The aims, goals and intentions of each committee were defined. Expert opinion was based on grading of evidence-based medical literature, extensive internal committee dialogue, open presentation, and debate. RESULTS: Three critical physiologic requirements, including intact sex steroids, autonomic/somatic nerves, and arterial inflow/perfusion pressure to women's genital organs play fundamental roles in maintaining women's sexual function. Despite this, there are nominal data supporting a direct pathophysiologic involvement of abnormal sex steroid values, and/or damage/injury to neurologic and/or blood flow integrity in women with problems in sexual desire, arousal, and/or orgasm. This summary details the available literature concerning hormonal, neurologic, and vascular organic pathophysiologies of women's sexual dysfunctions. CONCLUSIONS: Additional research on clinical pathophysiologies in women's sexual dysfunction is needed. This chapter encompasses data presented at the 2nd International Consultation on Sexual Medicine in Paris, France, June 28-July 1, 2003.

Antidepressive Agents↗

PubMed2004

Binding characteristics of [3H]delta(5)-androstene-3beta,17beta-diol to a nuclear protein in the rabbit vagina.

In this study, we investigated the binding characteristics of [3H]Delta(5)-androstene-3beta,17beta-diol to rabbit vaginal cytosolic and nuclear extracts and in freshly excised intact tissue strips. [3H]delta(5)-Androstene-3beta,17beta-diol bound to a protein(s) in the vaginal nuclear extract with high affinity (K(d)=3-5 nM) and limited capacity (50-100 fmol/mg protein). No specific binding was detected in the cytoplasmic extracts. Competitive binding studies showed that binding of [3H]delta(5)-androstene-3beta,17beta-diol was effectively displaced with unlabeled delta(5)-androstene-3beta,17beta-diol but not with dehydroepiandrosterone, testosterone, dihydrotestosterone, triamcinolone acetonide, or progesterone. However, estradiol at high concentrations partially displaced bound [3H]delta(5)-androstene-3beta,17beta-diol. Incubation of freshly excised vaginal tissue strips with [3H]delta(5)-androstene-3beta,17beta-diol in the absence or presence of excess unlabeled delta(5)-androstene-3beta,17beta-diol for 1h at 37 degrees C resulted in specific binding to a soluble macromolecule in the nuclear KCl extracts. In addition, quantitative measurement of estrogen receptor, androgen receptor and delta(5)-androstene-3beta,17beta-diol binding protein was performed by equilibrium ligand binding assays using extracts of distal vaginal tissue from intact animals or ovariectomized animals treated for 2 weeks with vehicle, estradiol, testosterone, or estradiol plus testosterone. These changes in steroid hormone levels resulted in opposing trends between the estrogen receptor and delta(5)-androstene-3beta,17beta-diol binding protein, suggesting that delta(5)-androstene-3beta,17beta-diol binding protein is regulated differently by the hormonal milieu than the estrogen receptor. These data suggest that rabbit vaginal tissue expresses a novel binding protein which specifically binds delta(5)-androstene-3beta,17beta-diol and is distinct from the androgen and estrogen receptors.

Androstane-3,17-diol↗

PubMed2004

Role of arginase in the male and female sexual arousal response.

The NO-cGMP pathway plays a key role in the male and female genital sexual arousal response. Nitric oxide synthase (NOS) utilizes L-arginine and oxygen as substrates to produce nitric oxide (NO) and citrulline. Arginase is a metalloenzyme that catalyzes the hydrolysis of L-arginine to produce L-ornithine and urea. It is proposed that arginase competes for L-arginine and reduces NOS activity in genital tissues, thus modulating sexual function. Using 2 transition state analogue inhibitors of arginase, 2(S)-Amino-6-boronohexanoic acid (ABH) and S-(2-boronoethyl)-L-cysteine (BEC), we have characterized arginase activity in penile and vaginal tissue. Neither of these inhibitors has activity against NOS. Thus, ABH and BEC are useful compounds for examining the role of arginase in genital tissue physiology, without directly influencing NOS activity. We present data to suggest that arginase may regulate NO production by competing for endogenous pools of L-arginine. In this fashion, arginase is an indirect regulator of penile and vaginal blood flow and specific arginase inhibitors may improve genital blood flow during sexual arousal. As evidenced by the upregulation of arginase in specific disease states, its distribution in the vagina, and its modulation by sex steroid hormones, this enzyme may also participate in numerous other physiological and pathophysiological processes, such as tissue growth, fibrosis, and immune function.

Animals↗

PubMed2004

An in vivo rat model to investigate female vaginal arousal response.

PURPOSE: We established a rat model to investigate the female vaginal arousal response and the role of the nitric oxide (NO) pathway on vaginal blood flow in vivo. MATERIALS AND METHODS: Vaginal blood flow changes induced by pelvic nerve stimulation (PNS) in female Sprague-Dawley rats were determined by laser Doppler flowmetry. Frequency response data were determined in each animal. In addition, changes in vaginal blood flow were measured after intravenous administration of the NO synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester) or the phosphodiesterase type 5 inhibitor sildenafil in response to PNS at submaximal frequency. Changes in blood flow were evaluated by comparing the area under the curve of each response. RESULTS: Reproducible frequency dependent increases in vaginal blood flow were observed in response to PNS. Administration of L-NAME (a NO synthase inhibitor) resulted in significant attenuation (25.6% to 18.2% vs control at 30 minutes, p <0.00001) of the PNS induced increase in vaginal blood flow. In contrast, sildenafil administration significantly increased PNS induced vaginal blood flow (166.9% +/- 25.8% vs control at 30 minutes, p <0.00001). CONCLUSIONS: Our data suggest that the rat is a useful and reliable animal model for investigating the vaginal arousal response. In addition, we used this model to demonstrate the important role of the NO-cyclic guanosine monophosphate pathway in vaginal arousal.

Animals↗

PubMed2004

Modulation of rat vaginal blood flow and estrogen receptor by estradiol.

PURPOSE: The effects of subphysiological and physiological levels of estradiol on vaginal blood flow and estrogen receptor were investigated. MATERIALS AND METHODS: Intact or ovariectomized female Sprague-Dawley rats were used. Two weeks after surgery rats were infused with vehicle (polyethyleneglycol), or estradiol at subphysiological (5 microg daily) or physiological (15 microg daily) concentrations for 14 days using osmotic pumps. Changes in vaginal blood flow elicited by pelvic nerve stimulation were assessed by laser Doppler flowmetry. Total levels of functional estrogen receptor were determined by radioligand binding and Western blot analyses were used to assess estrogen receptor (ER) alpha protein. RESULTS: Mean plasma estradiol concentration +/- SEM decreased by 63% in the vehicle group (intact 36.5 +/- 10.3 pg/ml). The subphysiological and physiological estradiol groups had plasma levels that were 55% and 83% of the intact group, respectively. Uterine and vaginal wet weight, and vaginal blood flow were significantly decreased in the vehicle group and normalized by physiological levels of estradiol. However, vaginal blood flow was significantly greater in the subphysiological estradiol group compared to intact animals. Specific binding of [H]estradiol in vaginal tissue extracts from intact rats was 0.51 fmol/mg protein and it was increased 30-fold in the vehicle group. ER binding in vaginal tissue in the physiological estradiol group decreased to levels that were comparable to those in intact animals, whereas estrogen receptor binding remained elevated in the subphysiological estradiol group. These changes were paralleled by ERalpha protein levels. CONCLUSIONS: Estradiol is crucial for maintaining optimal vaginal blood flow in the rat. Lower levels of plasma estradiol trigger compensatory ERalpha up-regulation.

Animals↗

PubMed2004

Physiology of female sexual function: animal models.

INTRODUCTION: Data concerning the physiology of desire, arousal, and orgasm in women are limited because of ethical constraints. Aim. To gain knowledge of physiology of female sexual function through animal models. METHODS: To provide state-of-the-art knowledge concerning female sexual function in animal models, representing the opinions of seven experts from five countries developed in a consensus process over a 2-year period. MAIN OUTCOME MEASURE: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: Sexual desire may be considered as the presence of desire for, and fantasy about, sexual activity. Desire in animals can be inferred from certain appetitive behaviors that occur during copulation and from certain unconditioned copulatory measures. Proceptive behaviors are dependent in part on estrogen, progesterone, and drugs that bind to D1 dopamine receptors, adrenergic receptors, oxytocin receptors, opioid receptors, or gamma-amino butyric acid receptors. Peripheral arousal states are dependent on regulation of genital smooth muscle tone. Multiple neurotransmitters/mediators are involved including adrenergic, and nonadrenergic, noncholinergic agents such as vasoactive intestinal polypeptide, nitric oxide, neuropeptide Y, calcitonin gene-related peptide, and substance P. Sex steroid hormones, estrogens and androgens, are critical for structure and function of genital tissues including modulation of genital blood flow, lubrication, neurotransmitter function, smooth muscle contractility, mucification, and sex steroid receptor expression in genital tissues. Orgasm may be investigated by urethrogenital (UG) reflex, in which genital stimulation results in rhythmic contractions of striated perineal muscles and contractions of vagina, anus, and uterine smooth muscle. The UG reflex is generated by a multisegmental spinal pattern generator involving the coordination of sympathetic, parasympathetic, and somatic efferents innervating the genital organs. Serotonin and dopamine may modulate UG reflex activity. CONCLUSIONS: More research is needed in animal models in the physiology of female sexual function.

Anal Canal↗

PubMed2003

Human arginase II: crystal structure and physiological role in male and female sexual arousal.

Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. The X-ray crystal structure of a fully active, truncated form of human arginase II complexed with a boronic acid transition state analogue inhibitor has been determined at 2.7 A resolution. This structure is consistent with the hydrolysis of l-arginine through a metal-activated hydroxide mechanism. Given that human arginase II appears to play a role in regulating l-arginine bioavailability to NO synthase in human penile corpus cavernosum smooth muscle, the inhibition of human arginase II is a potential new strategy for the treatment of erectile dysfunction [Kim, N. N., Cox, J. D., Baggio, R. F., Emig, F. A., Mistry, S., Harper, S. L., Speicher, D. W., Morris, S. M., Ash, D. E., Traish, A. M., and Christianson, D. W. (2001) Biochemistry 40, 2678-2688]. Since NO synthase is found in human clitoral corpus cavernosum and vagina, we hypothesized that human arginase II is similarly present in these tissues and functions to regulate l-arginine bioavailability to NO synthase. Accordingly, hemodynamic studies conducted with a boronic acid arginase inhibitor in vivo are summarized, suggesting that the extrahepatic arginase plays a role in both male and female sexual arousal. Therefore, arginase II is a potential target for the treatment of male and female sexual arousal disorders.

Amino Acid Sequence↗

PubMed2003

Selective P2Y2 receptor agonists stimulate vaginal moisture in ovariectomized rabbits.

OBJECTIVE: To determine the expression of P2Y(2) receptors in vaginal and cervical tissues and the effects of P2Y(2) receptor agonists INS45973 and INS365 on vaginal moisture. DESIGN: Pilot in vivo and histological study using animal subjects. SETTING: Experimental laboratory research. ANIMAL(S): Female New Zealand White rabbits were used for in vivo studies and female cynomolgus monkey (Macaca fascicularis) was used for in situ hybridization. INTERVENTION(S): Rabbits were kept intact or ovariectomized. Two weeks after ovariectomy, animals received daily vaginal instillation of vehicle or drugs for 16 days. MAIN OUTCOME MEASURE(S): Vaginal moisture was assessed in rabbits on 4 separate days during the treatment period. The P2Y(2) receptor mRNA distribution was assessed by in situ hybridization of monkey vagina and cervix. RESULT(S): Compared to control, vaginal moisture was significantly diminished in ovariectomized animals treated with vehicle. INS365 (8.1%) and INS45973 (0.9%) increased vaginal moisture in ovariectomized animals to levels that were comparable to or significantly higher than control animals, respectively. In situ hybridization studies indicated that P2Y(2) receptor mRNA was localized to endocervical and cervical gland, epithelium, and stratified squamous epithelium of the vagina. CONCLUSION(S): INS45973 and INS365 may interact with P2Y(2) receptors in the cervix and vagina to stimulate vaginal moisture in the estrogen (E)-deprived state. The P2Y(2) receptor agonists provide a potential nonhormonal alternative for treating vaginal dryness in postmenopausal women.

Animals↗

PubMed2003

Cocaine and ephedrine-induced priapism: case reports and investigation of potential adrenergic mechanisms.

OBJECTIVES: To investigate the direct effect of ephedrine and cocaine on neurogenic contraction of penile trabecular smooth muscle. We also provide three case reports of patients who developed priapism secondary to using either cocaine or nonprescription weight loss formulations containing ephedrine. The use/abuse of cocaine has been associated with priapism. In addition, anecdotal evidence suggests that priapism may result from ephedrine use. However, the effects of cocaine and ephedrine on adrenergic regulation of cavernosal tissue and the potential role of sympathetic dysregulation in the development of priapism have not been studied. METHODS: Isolated rabbit penile cavernosal tissue strips in organ bath preparations were subjected to electrical field stimulation (EFS) at varying frequencies (5 to 40 Hz) in the absence or presence of ephedrine (60 microg/mL) or cocaine (10 microM). Tissues were then subjected to EFS every 30 minutes for up to 20 hours. RESULTS: Ephedrine and cocaine initially caused contractions in cavernosal tissue strips that persisted for several hours. EFS-induced contractions became attenuated over time in tissues treated with ephedrine or cocaine. Eventually, the contractile responses to EFS were not distinguishable from the basal tone, although the tissues remained responsive to exogenous phenylephrine. CONCLUSIONS: Functional activation of alpha-adrenergic receptors on trabecular smooth muscle does not appear to be impaired with prolonged cocaine or ephedrine exposure. However, chronic use of cocaine or ephedrine may deplete norepinephrine from sympathetic nerve terminals, leading to priapism.

Adrenergic alpha-Agonists↗

PubMed2003

Reperfusion of ischemic corporal tissue: physiologic and biochemical changes in an animal model of ischemic priapism.

OBJECTIVES: To assess the physiologic and biochemical changes resulting from ischemia and reperfusion. Effective therapy for ischemic priapism reestablishes corporal venous outflow and arterial inflow and results in increased corporal partial pressure of oxygen. Data are limited concerning reperfusion injury of ischemic erectile tissue associated with reactive oxygen species (ROS) and the potential role of ROS scavengers in the clinical therapy of ischemic priapism. METHODS: Anesthetized adult New Zealand white male rabbits (n = 7) were exposed to a low oxygen tension breathing gas to achieve hypoxia within the corpora cavernosa. This resulted in a mean systemic oxygen saturation of 60%. The pelvic nerve was electrically stimulated to induce penile erection, and the base of the erect penis was clamped. After varying durations of ischemia, the clamp was removed to allow reperfusion. We determined the intracavernosal oxygen tension, histologic changes, myeloperoxidase activity, and lipid peroxidation. RESULTS: Corporal partial pressure of oxygen progressively decreased as the duration of priapism increased. A statistically significant increase was noted in myeloperoxidase activity and lipid peroxidation with corporal reperfusion. Polymorphonuclear leukocyte infiltration was documented in the ischemic reperfused tissue. CONCLUSIONS: In the management of ischemic priapism, reperfusion causes erectile tissue injury owing to the presence of ROS. There is a need to investigate the utility of ROS scavengers and antioxidants in the management of ischemic priapism.

Animals↗