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Try out PMC Labs and tell us what you think. Learn More. Epimedium species aka horny goat weed have been utilized for the treatment of erectile dysfunction in Traditional Chinese Medicine for many years. Icariin ICA is the active moiety of Epimedium species.

To evaluate the penile hemodynamic and tissue effects of ICA in cavernous nerve injured free horny. We also studied the in vitro effects of ICA on cultured pelvic ganglia. Rats were subjected to cavernous nerve injury and subsequently treated for 4 weeks with daily gavage feedings of a placebo solution of normal saline and Dimethyl sulfoxide DMSO vs.

Functional testing with cavernous nerve stimulation and real-time assessment of intracavernous pressure ICP was performed at 4 weeks. After functional testing, penile tissue was procured for immunohistochemistry and molecular studies. In separate experiments, pelvic ganglia were excised from healthy rats and cultured in the presence of ICA, sildenafil, or placebo culture media. We also assayed tissue expression of neuronal nitric oxide synthase nNOSeNOS: endothelial nitric oxide synthase eNOScalponin, and apoptosis via immunohistochemistry and Western blot. Differential length of neurite outgrowth was assessed in cultured pelvic free horny.

Immunohistochemistry and Western blot were revealing of ificantly greater positivity for nNOS and calponin in penile tissues of all rats treated with ICA. ICA led to ificantly greater neurite length in cultured specimens of pelvic ganglia. ICA may have neurotrophic effects in addition to known phosphodiesterase type 5 inhibiting effects. The various species of the plant genus Epimedium have been utilized in Traditional Chinese Medicine TCM for centuries to treat a variety of human illnesses.

Recent investigations into the properties of these plants have suggested that the most metabolically active extract of Epimedium is icariin ICAa flavonol glycoside obtained from the aerial part of the plant [ 1 ]. ICA has been demonstrated to exert inhibitory activity against phosphodiesterase type 5 PDE5 in vitro [ 23 ]. Modification of native ICA by addition of two hydroxyethyl ethers moieties enhances the PDE5 inhibitory activity fold, near the level that is observed with sildenafil [ 3 ].

In addition to an erectogenic role, it has been suggested that ICA has testosterone-mimetic properties [ 4 ]. These effects lend credence to the use of ICA for the management of sexual problems. ICA has been demonstrated to enhance eNOS expression and NO production in human endothelial cells as well as decrease caspase-3 expression and cellular apoptosis in response to hydrogen peroxide [ 56 ].

ICA has also been demonstrated to increase the intracavernous pressure ICP response triggered by cavernous nerve stimulation in rats; these effects were abolished by inhibitors of nitric oxide synthase and guanylate cyclase [ 7 ]. Furthermore, ICA has been used successfully to ameliorate both castration-related and arteriogenic impairment of erectile function and decline in penile neuron nNOS content in a rodent model [ 89 free horny.

To our knowledge, the utility of icariin for potentiation of erection in an animal model of radical pelvic surgery has not been explored. This is of particular interest given recent evidence suggesting that the commonly utilized regimen of routine dose therapy with commercially available PDE5 inhibitors may not lead to better erectile function outcomes after prostatectomy [ 10 ]. In this study we administered ICA as a daily supplement or a single dose in healthy week-old rats that had undergone cavernous nerve crush injury.

At study conclusion, subjects underwent functional testing of erectile hemodynamics during cavernous nerve stimulation as well as histological and molecular assessment of penile tissues. We also explored the neurotrophic effects of ICA in an in vitro rat major pelvic ganglion culture system. ICA was procured by three-fold ethanol extraction of the aerial part of Epimedii herba specifically, E. The product was dried with a vacuum.

The dried extract was suspended in water and partitioned successively with n-hexane, CHCl3, and n-butyl alcohol. The n-butyl alcohol fraction was subjected to silica gel column chromatography to isolate ICA, which was further purified by repeated recrystallization with methanol. Free horny final product was Fifty-eight healthy week-old male Sprague Dawley rats Harlan Laboratories, Indianapolis, Indiana, USA were obtained and housed two per cage in standard rodent cages.

Live animals were handled in accordance with our institution's policy on animal husbandry; approval for all procedures on live animals was obtained from our Institutional Animal Care and Use Committee. Cavernous nerve exposure with or without injury was performed as ly described [ 12 ]. Briefly, animals were anesthetized with isoflurane by inhalation. A laparotomy was performed and the cavernous nerves identified in the periprostatic space in all rats.

In all other animals the cavernous nerve was crushed distal to the major pelvic ganglion with a specially deated needle driver for a period of 2 minutes; this procedure was repeated on the contralateral side. After cavernous nerve crush the laparotomy was closed in two layers with absorbable suture. All free horny received an opioid and an nonsteroidal anti-inflammatory drug NSAID by intraperito-neal IP injection in the perioperative period.

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Animals were weighed free horny and dosing was adjusted as appropriate. A repeat laparotomy was performed and the cavernous nerves were identified. The penis was denuded of overlying skin and cannulated with a heparinized gauge needle connected to a real-time continuous pressure transducer. The cavernous nerves were then stimulated with a bipolar steel electrode; stimulation parameters were second continuous trains at 20 Hz, 1.

Real-time response of the erectile tissue was determined by change in ICP. After functional testing, systemic blood pressure was measured via aortic cannulation. Serum samples were obtained at the time of aortic cannulation. Whole blood was aspirated into a collection tube and allowed to clot for 30 minutes. Clotted blood was then centrifuged at 1, rpm for 15 minutes. Serum was decanted from the collection tube and stored at centigrade until use. A segment of the penis from all subject rats was fixed in optimal cutting temperature fixative and subsequently sectioned at 5 microns in a cryostat.

Slides were examined by an observer blinded to treatment group. TUNEL positivity was calculated by counting positive nuclei in four random hpf fields of the corporal bodies. All staining intensity was measured using Image-Pro Plus v 5. Cell lysates containing 20 mcg of protein were electrophoresed in sodium docecyl sulfate polyacrylamide gel electrophoresis and then transferred to a polyvinylidene fluoride membrane Millipore Corp, Bedford, MA, USA. The membrane was stained with Ponceau S to verify the integrity of the transferred proteins and to monitor the unbiased transfer of free horny protein samples.

A separate group of twelve week-old Sprague-Dawley rats underwent isoflurane anesthesia for harvest of the major pelvic ganglia MPG for the purpose of cell culture as ly described [ 13 ]. Each dorsocaudal region of the MPG from which the cavernous nerve originates of subject rats was sectioned into three pieces and plated on a sterile cell culture well in a matrigel medium for a total of 72 specimens.

Control specimens were incubated with phosphate buffered saline. At 48 hours, MPG fragments were examined under the dissecting microscope for neurite outgrowth. The longest neurite from each segment was measured; mean neurite length for each treatment group was calculated. For statistical analysis, one-way anova was performed followed by Bonferroni multiple comparison's test for between-group differences.

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All calculations were performed using Prism version 4. A gavage feeding mishap led to a single fatality in the sham surgery group during the study period. Additionally, a lethal reaction to ketamine anesthesia at the time of functional testing occurred in four rats one each from all the Free horny groups and the positive control group. In these subjects it was impossible to perform functional testing. There was ificantly greater positivity for nNOS fibers in the sham group compared with all others. The level of eNOS positivity in the control group was ificantly lower relative to all other groups.

There was no ificant difference in positivity between ICA-treated and sham rats. Although histochemistry suggested greater eNOS content in ICA-treated rats, this finding free horny not confirmed on Western blot, which showed no ificant differences between groups Figure 3C. There was a trend toward lesser calponin positivity in control animals vs. Western blot confirmed that the penile content of calponin was ificantly higher in all ICA treatment groups relative to control and single-dose ICA animals Figure 3D.

Calponin Immunohistochemistry. There were no ificant differences in caspase-3 expression nor in TUNEL positivity between groups data not shown. Mean serum testosterone levels are presented in Figure 6A. No other differences between groups reached statistical ificance. Serum LH levels are presented in Figure 6B. The standard deviation of the mean was large between groups; there was no ificant difference in LH expression. Gonadotropin and testosterone levels. The mean length of neurites in the various groups is presented in Figure 7B. There was no ificant difference in neurite length between control and sildenafil-treated MPG.

Neurite outgrowth in cell culture under various treatment conditions. A Representative images from cultured major pelvic ganglia in the control top two panelsICA left column and sildenafil right column. ICA has garnered attention as a potential therapeutic agent for a variety of human disease states, including osteoporosis, congestive heart failure, and ischemic brain injury [ 15 — 18 ]. While ICA may have numerous applications in different fields of medicine, it is best free horny for its' putative role in potentiating sexual function by inhibition of PDE5I [ 23 ].

In the current study we provide functional evidence that ICA may have beneficial effects on erectile function after cavernous nerve injury. These effects may extend beyond PDE5 inhibition; we detected ificantly higher nNOS expression and smooth muscle content in ICA-treated rats relative to untreated controls.

Furthermore, it is suggested that eNOS was also up-regulated in endothelial cells of the penis after ICA treatment, although the evidence of this is somewhat less robust given the discrepancy between histochemical and Western blotting for eNOS. Interestingly, it was low-dose ICA that produced the most consistently beneficial. Prior work has supported a role for ICA in enhancing erectile function in various animal models of erectile dysfunction ED.

Makarova et al. Liu et al. The expression of nNOS in ICA-treated animals was higher than what was observed in controls, similar to the of our study. In addition to a role in erectile physiology, a prior study suggested that ICA has been shown to correct hypogonadism induced by cyclophosphamide exposure in rats [ 4 ]. Zhang et al. Rodents in the ICA group had higher serum testosterone levels compared with animals not treated with cyclophosphamide and animals treated with cyclophosphamide alone [ 4 ].

These are in contrast to the of Liu et al. Differences in the purity and dosing interval of ICA as well as differences in the assay method may have played a role in these discrepancies. Interestingly, in the one prior study demonstrating changes in serum T with ICA, there were no ificant perturbations in LH and follicle stimulating hormone FSH level in rats in any of free horny treatment arms [ 4 ]; this result is similar to our own.

It is possible that ICA may influence aromatase or 5-alpha reductase activity in vivo and thereby modulate serum T levels without directly impacting LH secretion. While both functional and molecular differences were apparent between our study groups, statistically ificant differences were not observed in several key areas; the lack of ificant difference in functional between the higher-dose ICA groups and control animals is likely secondary to the small of animals and subsequent lack of statistical power. However, it is apparent that even with the small of animals low-dose ICA was effective at producing improved erectile responses.

It may be that the improvement noted was secondary to an acute PDE5 inhibitory effect of the drug on subject rats. Cavernous nerve injury in our rats was associated with an increase albeit an inificant one in serum testosterone relative to uninjured rats. This differs from a recent study that suggested that cavernous nerve injury is associated with centrally mediated hypogonadism in rats [ 14 ]. Variations in measurement method, rat strain, and mechanism of injury transection in the other study compared to crush in ours may have contributed to the observed differences and further research will be required to resolve this discrepancy.

Furthermore, we free horny not detect any ificant differences in apoptosis between sham and cavernous nerve injured animals; this contrasts with prior reports in which cavernous nerve injury increases expression of apoptotic markers [ 21 — 23 ]. However, in a study of the time course of apoptosis after cavernous nerve injury, User et al. We theorize that cavernous nerve injury-mediated apoptosis had returned to near-baseline levels in all groups at the time of functional assay in this study, although we cannot rule out the possibility that a less severe injury was inflicted in our study relative to other similar studies.

Despite several important limitations, our study adds to the mounting evidence that ICA may play an important salubrious role with respect to maintenance of penile erectile function.

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It is particularly intriguing that ICA had neurotrophic properties when cultured with nerve fragments. PDE5 inhibitors are the agents most commonly utilized for penile rehabilitation in humans [ 25 ], and to our knowledge no synthetic PDE5 inhibitor has been demonstrated to have ificant neurotrophic effects, a finding confirmed in the sildenafil arm of our MPG culture experiments. Whether ICA would be a superior alternative to PDE5I remains to be determined; further studies of this interesting compound from nature may enhance our understanding and ability to treat men with ED.

Daily treatment with low-dose, purified ICA improves penile hemodynamic parameters 4 weeks free horny cavernous nerve injury in a rat model of ED. Improved functional outcomes in ICA-treated animals are associated with increased penile nNOS and smooth muscle content. Our findings are of interest not just as a validation of this traditional treatment for erectile problems but also as a new and potentially important means to study and treat nerve injuries in human patients. Alan W. Breyer; Maurice M. Shindel; Tom F. Funding for this study was provided by the California Urological Foundation.

We thank Lora Nunes and Guifang Wang for their assistance with immunohistochemistry. National Center for Biotechnology InformationU. J Free horny Med. Author manuscript; available in PMC Jan Thomas M. Benjamin N. Maurice M.

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