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Viagra action mechanism


The Mechanism Of Action Of Viagra Cialis Viagra Online Canada - Order Cheap Tadalafil (Generic Cialis) Online, It is the only drug which is not only fast acting (works in 30 minutes) Tadalafil(Cialis) 20mg Cost Without Rx. Viagra - Clinical Pharmacology Mechanism of Action. The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle. Viagra And Mechanism Of Action Online Pharmacy from Canada, Buy generic medications. Buy Cialis|Viagra|Levitra Online! % Satisfaction Guaranteed! Generic Cialis online from authorised, on-line pharmacy in the U.S., Canada, and worldwide.
Apr 23,  · Objectives. Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, is increasingly used for pulmonary hypertension in pregnancy. Sildenafil is also emerging as a potential candidate for the treatment of intra-uterine growth retardation and for premature labor. Mechanism Of Action For Viagra. Buy Cheap Pills with genericcialistadalafil.online Cheap Viagra for $99 per Pills. Canadian pharmacy, for viagra action mechanism of. In addition Viagra Action Mechanism to periodontal and implant services, we offer a complete line of general dentistry services including fillings, cosmetic services, root canals, crowns, bridges, dentures and extractions. Our office is one of the very few where you can have an implant placed and restored by the same dentist.


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Asunaprevir The metabolism of Sildenafil can be increased when combined with Asunaprevir. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections, viagra action mechanism. Oxamniquine The metabolism of Sildenafil can be decreased when combined with Oxamniquine. Viagra action mechanism Оценка становится доступна после аренды видео-. В данный момент эта функция недоступна. Повторите попытку позже. Sildenafil, sold as the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. Its effectiveness for treating sexual dysfunction in women has not been demonstrated. Common side effects include headaches and heartburn, as well as flushed skin. Caution is advised in those who have cardiovascular disease. Rare but serious side effects include prolonged erections, which can lead to damage to the penis, and sudden-onset hearing loss. Viagra mechanism - Do not doubt and make your choice in favor of convenient and advantageous shopping for remedies Shop for the needed preparation offered at different doses, types and costs Boost your health with effective and safe drugs presented here.

Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 PDE5 , which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum.

Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Studies in vitro have shown that sildenafil is selective for PDE5. PDE3 is involved in control of cardiac contractility. Sildenafil is only about fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [ see Clinical Pharmacology In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle.

The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro , an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.

Effects of Viagra on Erectile Response: Most studies assessed the efficacy of Viagra approximately 60 minutes post dose. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours. Effects of Viagra on Blood Pressure: The decrease in sitting blood pressure was most notable approximately 1—2 hours after dosing, and was not different than placebo at 8 hours.

Similar effects on blood pressure were noted with 25 mg, 50 mg and mg of Viagra, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications 4. In the following patients: Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications 4.

Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of Viagra with doxazosin, an alpha-adrenergic blocking agent.

In the first study, a single oral dose of Viagra mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia BPH. Following at least 14 consecutive daily doses of doxazosin, Viagra mg or matching placebo was administered simultaneously with doxazosin.

Following a review of the data from these first 4 subjects details provided below , the Viagra dose was reduced to 25 mg. Thereafter, 17 subjects were treated with Viagra 25 mg or matching placebo in combination with doxazosin 4 mg 15 subjects or doxazosin 8 mg 2 subjects. The mean subject age was The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg Viagra or matching placebo are shown in Figure 2.

Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1. No severe adverse events potentially related to blood pressure effects were reported in this group. Of the four subjects who received Viagra mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient postural hypotension that began 35 minutes after dosing with Viagra with symptoms lasting for 8 hours , and mild adverse events potentially related to blood pressure effects were reported in two others dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing.

There were no reports of syncope among these patients. For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension.

In the second study, a single oral dose of Viagra 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, Viagra 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg 17 subjects or with doxazosin 8 mg 3 subjects. The mean subject age in this study was Twenty subjects received Viagra 50 mg, but only 19 subjects received matching placebo.

One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with Viagra 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study. The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg Viagra or matching placebo are shown in Figure 3.

Blood pressure was measured after administration of Viagra at the same times as those specified for the first doxazosin study. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of Viagra 50 mg and resolving after approximately 7. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.

In the third study, a single oral dose of Viagra mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of Viagra 50 mg simultaneously, after at least 14 consecutive days of doxazosin.

If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study using Viagra 50 mg , including no significant hemodynamic adverse events, were allowed to skip dose period 1.

Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, Viagra mg or matching placebo was administered simultaneously with doxazosin 4 mg 14 subjects or doxazosin 8 mg 6 subjects in standard crossover fashion.

Twenty-five subjects were screened. Two were discontinued after study period 1: Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study using Viagra 50 mg. The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with mg Viagra or matching placebo are shown in Figure 4.

Blood pressure was measured after administration of Viagra at the same times as those specified for the previous doxazosin studies. All three were taking Viagra mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both Viagra 50 mg and mg.

There were no episodes of syncope reported in this study. When Viagra mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Viagra 50 mg did not potentiate the hypotensive effect of alcohol 0. The maximum observed decrease in systolic blood pressure was The maximum observed decrease in diastolic blood pressure was There were no reports of postural dizziness or orthostatic hypotension.

The maximum recommended dose of mg sildenafil was not evaluated in this study [ see Drug Interactions 7. Effects of Viagra on Cardiac Parameters: Single oral doses of sildenafil up to mg produced no clinically relevant changes in the ECGs of normal male volunteers.

Studies have produced relevant data on the effects of Viagra on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by four intravenous infusions.

Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients. In a double-blind study, patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or Viagra mg 1 hour prior to exercise testing.

The primary endpoint was time to limiting angina in the evaluable cohort. The mean times adjusted for baseline to onset of limiting angina were These results demonstrated that the effect of Viagra on the primary endpoint was statistically non-inferior to placebo. Effects of Viagra on Vision: At single oral doses of mg and mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina.

An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of Viagra on visual acuity, intraocular pressure, or pupillometry. Effects of Viagra on Sperm: There was no effect on sperm motility or morphology after single mg oral doses of Viagra in healthy volunteers. The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism mainly CYP3A4 and is converted to an active metabolite with properties similar to the parent, sildenafil.

Both sildenafil and the metabolite have terminal half lives of about 4 hours. Mean sildenafil plasma concentrations measured after the administration of a single oral dose of mg to healthy male volunteers is depicted below:. Viagra is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to minutes median 60 minutes of oral dosing in the fasted state.

The mean steady state volume of distribution Vss for sildenafil is L, indicating distribution into the tissues. Protein binding is independent of total drug concentrations. Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.

The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function Child-Pugh Class C have not been studied [ see Dosage and Administration 2. A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration 2.

Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. The concomitant use of erythromycin or strong CYP3A4 inhibitors e. Viagra had no effect on saquinavir pharmacokinetics.

A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors such as ketoconazole, erythromycin, or cimetidine [ see Dosage and Administration 2.

This is consistent with ritonavir's marked effects on a broad range of P substrates. Viagra had no effect on ritonavir pharmacokinetics [ see Dosage and Administration 2. Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels. In a study of healthy male volunteers, co-administration of sildenafil at steady state 80 mg t.

Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil.

In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin mg daily for 3 days on the systemic exposure of sildenafil or its major circulating metabolite. Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors such as tolbutamide, warfarin , CYP2D6 inhibitors such as selective serotonin reuptake inhibitors, tricyclic antidepressants , thiazide and related diuretics, ACE inhibitors, and calcium channel blockers.

These effects on the metabolite are not expected to be of clinical consequence. No significant interactions were shown with tolbutamide mg or warfarin 40 mg , both of which are metabolized by CYP2C9. In a study of healthy male volunteers, sildenafil mg did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.

Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction 80 mg t. Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure AUCs for unbound sildenafil and its major metabolite of and times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose MRHD of mg.

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. In clinical studies, Viagra was assessed for its effect on the ability of men with erectile dysfunction ED to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity.

Viagra was evaluated primarily at doses of 25 mg, 50 mg and mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs fixed dose, titration, parallel, crossover. Viagra was administered to more than 3, patients aged 19 to 87 years, with ED of various etiologies organic, psychogenic, mixed with a mean duration of 5 years.

Viagra demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo. Efficacy Endpoints in Controlled Clinical Studies. The effectiveness of Viagra was evaluated in most studies using several assessment instruments.

The primary measure in the principal studies was a sexual function questionnaire the International Index of Erectile Function - IIEF administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment.

Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about 1 the ability to achieve erections sufficient for sexual intercourse and 2 the maintenance of erections after penetration.

The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were 0 no attempted intercourse, 1 never or almost never, 2 a few times, 3 sometimes, 4 most times, and 5 almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary.

In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered. Efficacy Results from Controlled Clinical Studies. The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and mg doses than at 25 mg.

The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received mg, showed similar results. Figure 6 shows that regardless of the baseline levels of function, subsequent function in patients treated with Viagra was better than that seen in patients treated with placebo.

At the same time, on-treatment function was better in treated patients who were less impaired at baseline. The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies patients of 12 to 24 weeks duration is shown in Figure 7.

These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 a few times on principal IIEF questions. The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period.

In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about patients, analyses of patient diaries showed no effect of Viagra on rates of attempted intercourse about 2 per week , but there was clear treatment-related improvement in sexual function: During 3 to 6 months of double-blind treatment or longer-term 1 year , open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness.

Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured again using a 5-point scale in the IIEF. Viagra improved these aspects of sexual function: As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to mg or down to 25 mg of Viagra; all patients, however, were receiving 50 mg or mg at the end of the study.

There were highly statistically significant improvements on the two principal IIEF questions frequency of successful penetration during sexual activity and maintenance of erections after penetration on Viagra compared to placebo. The changes from baseline in scoring on the two end point questions frequency of successful penetration during sexual activity and maintenance of erections after penetration were highly statistically significantly in favor of Viagra.

A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. Viagra sildenafil citrate is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil and debossed on the obverse and reverse sides as follows:.

Physicians should discuss with patients the contraindication of Viagra with use of guanylate cyclase stimulators such as riociguat [ see Contraindications 4. Physicians should advise patients of the potential for Viagra to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. Concomitant administration of Viagra and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when Viagra is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating Viagra treatment and Viagra should be initiated at the lowest dose [ see Warnings and Precautions 5.

Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms e. Physicians should advise patients to stop use of all PDE5 inhibitors, including Viagra, and seek medical attention in the event of a sudden loss of vision in one or both eyes.

Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy NAION , a cause of decreased vision including possible permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a "crowded" optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including Viagra, for this uncommon condition [ see Warnings and Precautions 5.

It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [ see Warnings and Precautions 5. Physicians should warn patients that prolonged erections greater than 4 hours and priapism painful erections greater than 6 hours in duration have been reported infrequently since market approval of Viagra. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result [ see Warnings and Precautions 5.

Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus HIV , may be considered [ see Warnings and Precautions 5.

What is the most important information I should know about Viagra? Viagra can cause your blood pressure to drop suddenly to an unsafe level if it is taken with certain other medicines. Do not take Viagra if you take any other medicines called "nitrates.

The presence of phosphodiesterase-5 in the feto-placental circulation was determined by western blotting and immunohistochemical staining. In a subsequent series of pharmacologic studies, the effects of sildenafil citrate in pre-constricted chorionic plate arterial rings were determined.

Additional studies examined the role of cGMP and nitric oxide in mediating the effects of sildenafil. Phosphodiesterase-5 mRNA and protein was demonstrated in human chorionic plate arteries. Immunohistochemistry demonstrated phosphodiesterase-5 within the arterial muscle layer. Sildenafil citrate produced dose dependent vasodilatation at concentrations at and greater than 10 nM.

In contrast, sildenafil citrate significantly enhanced the vasodilation produced by the NO donor sodium nitroprusside. Phosphodiesterase-5 is present in the feto-placental circulation. Sildenafil citrate vasodilates the feto-placental circulation via a cGMP dependent mechanism involving increased responsiveness to NO. Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, has demonstrated considerable promise as a pulmonary vasodilator [ 1 - 4 ]. Sildenafil has been proposed as a potentially useful therapy for pulmonary hypertension in pregnancy, a disease characterized by poor maternal and fetal outcome [ 5 , 6 ].

Several case reports of its use in pregnant patients with pulmonary hypertension have been published to date [ 7 , 8 ]. The effects of sildenafil citrate on the pulmonary vasculature and on pulmonary artery pressure are increasingly well understood.

Sildenafil is also emerging as a potential candidate for the treatment of intra-uterine growth retardation and for premature labor [ 11 ]. Sildenafil has also been proposed as a potential therapeutic strategy to maintain placental function in pre-eclampsia [ 12 ]. While placental transfer of sildenafil citrate has not been quantified, due to its chemical characteristics it is likely to easily cross the placenta into the fetus. Should sildenafil citrate possess vasodilatory effects in the feto-placental circulation, this would significantly enhance its therapeutic potential in the setting of placental insufficiency.

Of interest, sildenafil citrate has recently been demonstrated not to alter the contractile response to vasoconstrictors or to endothelial dependent vasodilators[ 13 ]. However, the direct effects of sildenafil citrate in the feto-placental circulation have not been determined. The purposes of these studies were to determine whether the phosphodiesterase-5 enzyme was present in the feto-placental circulation, and then to characterize the effects and mechanisms of action of sildenafil citrate in this circulation.

Following approval by the Galway University Hospitals Clinical Research Ethical Committee, and written informed patient consent, term placentae were obtained following both vaginal and elective cesarean delivery under regional anesthesia from patients following normal pregnancy.

None of the patients from whom the samples were taken received general anesthesia for delivery. Exclusion criteria included intra-uterine growth retardation, pre-eclampsia, and patients with pregnancy induced hypertension, hepatitis and HIV. In all studies, umbilical arteries and their branches were identified as they spread out onto the chorionic plate of the placenta. Samples of the second-generation second-order chorionic plate arteries were taken within minutes of delivery and placed directly into ice-cold pyrogen-free physiologic saline solution RNA was then isolated as previously described [ 14 ].

Detection primers used were:. Samples were sonicated, and centrifuged at g for 5 minutes to remove insoluble proteins. Sections were permeabilized with 0.

The coverslip was later removed and the section stained with haematoxylin and eosin to demonstrate ring structure. All studies, conducted in four separate series of experiments, followed a randomized, controlled, paired design. Schematic representation of the ex vivo incubation model system used in the isolated vessel experiments. Following a 60 minute equilibration period, an optimal pre-tension of 2. Priming contractions were induced by exposing the rings three times to 80 mM KCl solution iso-osmotically substituted for NaCl , and pre-tension re-established at the end of each five minute exposure by rinsing with physiologic saline solution.

The paired preparations were then randomized to group allocation. Series 1 examined the direct effects of sildenafil citrate on pre-constricted chorionic plate arterial rings. Once a stable plateau contractile response was obtained, the rings were allowed to remain at plateau for 30 minutes.

Two rings from each placenta were then randomly assigned to receive sildenafil citrate or vehicle. A cumulative concentration response curve for sildenafil citrate 10 to 10 -3 M or vehicle was then constructed. The effects of sildenafil citrate were measured by calculating the mean amplitude of selected areas for the final 5 minutes of each 15 minute interval. Series 2 examined the potential for direct inhibition of cGMP to attenuate sildenafil citrate induced vasorelaxation.

Following equilibration for 20 minutes, a cumulative concentration response curve for sildenafil citrate 10 -7 to 10 -3 M or vehicle was constructed. This resulted in a four group design: Series 3 examined the potential for direct inhibition of the cGMP-dependent protein kinase to attenuate sildenafil citrate induced vasorelaxation. A cumulative concentration response curve for sildenafil citrate 10 -7 to 10 -3 M or vehicle was then constructed. Series 4 examined the role of nitric oxide NO in mediating the relaxant effect of sildenafil citrate.

The vasorelaxant effect of sildenafil citrate may be mediated via the generation of NO or via an increase in sensitivity to NO. Series 4A determined the potential for sildenafil citrate to produce vasorelaxation via NO generation. Series 4B examined the potential for sildenafil citrate to produce relaxation via an increase in sensitivity to NO.

One ring from each placenta was randomly assigned to undergo pre-incubation with vehicle, sildenafil citrate 10 -8 M , and sildenafil citrate 10 -6 M respectively, in a three group design.

Following pre-constriction with U, sildenafil citrate 10 -8 M and 10 -6 M or vehicle was then added to each bath and allowed to equilibrate for 20 minutes. A cumulative concentration response curve for sodium nitroprusside, an NO donor, in half log increments from 10 -9 to 10 -8 M was then constructed. At the end of each experimental protocol, pre-tension was re-established by rinsing with physiologic saline solution.

A recovery time of 30 minutes was then allowed. The contractile response to 80 mM KCl was then reassessed in order to assess performance over the course of the experiment. Between group analyses were restricted to comparisons relevant to our a priori hypotheses, and were made using student's t testing with corrections for multiple comparisons.

Chorionic plate arterial rings were obtained from placentae from 55 women median age, 26 years [range, 18—42 years]; median parity, 1 [range, 0—4] following uncomplicated full term median gestation 40 wks [range 38 — 41] gestation, for these studies. Demonstration of PDE-5 protein in chorionic plate arterial rings. The Phosphodiesterase-5 protein is present in chorionic plate arterial rings as demonstrated by Western blot.

Fluorescent microscopy of paraffin embedded slices of chorionic plate arterial rings demonstrated specific binding of PDE-5 primary antibodies within the cytoplasm of cells in the muscle layer within the arterial ring section. Immunohistochemical demonstration of the localization of PDE-5 protein in chorionic plate arterial rings.

Subsequent images, enlarged from the section of the wall of this ring indicated by the rectangle, demonstrate nuclear staining with DAPI Panel B , staining with PDE-5 primary and phycoerythrin labeled secondary Sigma antibodies Panel C , and the superimposition of panels B and C to demonstrate the cytoplasmic location of PDE-5 Panel D.

Stable and comparable gas tensions were maintained throughout all experiments, and comparable baseline levels of contractile responses were observed in all series. Post-intervention responses to potassium chloride were not different between the groups in any series.

Mean relaxation increased from 1. Cumulative concentration-response curve for sildenafil citrate from 10 M to 10 -3 M compared to control vehicle at a submaximal U induced contraction. Cumulative concentration-response curve for sildenafil citrate from 10 -7 M to 10 -3 M compared to vehicle at a submaximal U induced contraction, in the presence and absence of methylene blue. There was minimal vasodilation in the rings exposed to control conditions or methylene blue alone.

These findings indicate a role for cGMP in mediating the vasodilation produced by sildenafil citrate. Series 3 examined the potential for direct inhibition of the cGMP-dependent protein kinase to attenuate sildenafil citrate induced Vasorelaxation. These findings indicate that the cGMP dependent effect of sildenafil citrate in producing vasodilation in the feto-placental circulation is mediated via the cGMP-dependent protein kinase.

Cumulative concentration-response curve for sildenafil citrate from 10 -7 M to 10 -3 M compared to vehicle at a submaximal U induced contraction, in the presence and absence of L-NAME. Histogram of concentration dependent relaxation for sodium nitroprusside in the presence of increasing concentrations of sildenafil citrate. SNP dose dependently dilated pre-constricted rings, with a maximal relaxation of Our results demonstrate the presence of phosphodiesterase-5 in the human feto-placental circulation and further demonstrate that sildenafil citrate is a vasodilator in this circulation.

The vasodilatory effects of sildenafil citrate are mediated by via cGMP pathway, and involve an increase in vascular sensitivity to NO. These results are of clear significance given the growing role for sildenafil citrate for the treatment of pulmonary hypertension in pregnancy. In addition, these findings provide support for the hypothesis that sildenafil citrate may have a role in augmenting feto-placental blood flow in the setting of placental vascular insufficiency and pre-eclampsia [ 12 ].

Sildenafil citrate is increasingly used in the pregnant patient for the treatment of pulmonary hypertension in pregnancy, a disease associated with poor maternal [ 5 ] and fetal outcome [ 18 ].

Its safety and efficacy in this setting, combined with its lack of teratogenic or fetotoxic effects even at very high dosages in animal studies, mean that its use for the treatment of pulmonary hypertension in pregnancy is likely to increase [ 11 ]. Sildenafil citrate also causes relaxation of the human myometrium [ 19 , 20 ], and reduces intra-uterine pressures during preterm labor in rodents [ 21 ] and may therefore have a role as a tocolytic agent in the setting of premature labor.

In addition, sildenafil citrate increases uteroplacental blood flow, and may have a role in the treatment of intra-uterine growth retardation. Sildenafil citrate improves the endothelial function of myometrial vessels from women whose pregnancies are complicated by intrauterine growth restriction [ 22 ]. Sildenafil enhanced fetal tolerability to induced intrapartum asphyxia, and increased fetal weight in guinea pigs [ 23 ].

Sildenafil increases rodent fetal size in the setting of hypoxia, induced by exposure of pregnant rats to environmental hypoxia, although this was not seen in the non-hypoxic setting [ 24 ]. The effects of sildenafil in the feto-placental circulation have not been characterized. In the uterine circulation, sildenafil citrate causes uterine artery vasodilation in non-pregnant females [ 25 ], and produces vasodilation in small myometrial arteries in women whose pregnancies are complicated by fetal growth retardation [ 22 ].

Should sildenafil citrate possess a similar vasodilatory effect in the feto-placental circulation, this would significantly enhance its therapeutic potential in the setting of placental insufficiency.

Know the medicines you take. There are a number of aspects of this study that indicate the need for caution prior to extrapolation to the clinical scenario. These results are of clear significance given the growing role for sildenafil citrate for the treatment of pulmonary hypertension in pregnancy and may indicate a potential role for sildenafil citrate in augmenting feto-placental blood flow in the setting of placental vascular insufficiency. Physicians should advise patients of the potential for Viagra to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. This analysis was performed retrospectively, viagra action mechanism, and was not powered to detect any pre-specified difference in adverse reactions. Viagra action mechanism
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