sildenafil-citrate and Hypertension

PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.

Topics: Cardiovascular Diseases; Erectile Dysfunction; Humans; Hypertension; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil

Congenital diaphragmatic hernia (CDH) is a birth defect characterized by failed closure of the diaphragm, allowing abdominal viscera to herniate into the thoracic cavity and subsequently impair pulmonary and vascular development. Despite improving standardized postnatal management, there remains a population of severe CDH for whom postnatal care falls short. In these severe cases, antenatal surgical intervention (fetoscopic endoluminal tracheal occlusion [FETO]) may improve survival; however, FETO increases the risk of preterm delivery, is not widely offered, and still fails in half of cases. Antenatal medical therapies that stimulate antenatal pulmonary development are therefore interesting alternatives. By presenting the animal research underpinning novel antenatal medical therapies for CDH, and considering the applications of these therapies to clinical practice, this review will explore the future of antenatal CDH management with a focus on the phosphodiesterase-5 inhibitor sildenafil.

Topics: Adrenal Cortex Hormones; Animals; Female; Fetoscopy; Hernias, Diaphragmatic, Congenital; Humans; Hypertension; Infant, Newborn; Lung; Phosphodiesterase 5 Inhibitors; Pregnancy; Prenatal Care; Randomized Controlled Trials as Topic; Sildenafil Citrate

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.

Topics: Carbolines; Diastole; Drug Resistance; Heart Failure, Diastolic; Humans; Hypertension; Medical Illustration; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Tadalafil; Treatment Outcome; Ventricular Dysfunction, Left

Erectile dysfunction (ED) is a very common multidimensional disorder affecting men worldwide. Physical illness, reaction to life stresses, or an unhappy couple relationship influence clinical outcome. Phosphodiesterase type 5 (PDE5) inhibitors are recognized as efficacious and well tolerated, and are the first-line treatment for ED. Sildenafil, tadalafil, and vardenafil are the most widely used and studied PDE5 inhibitors. Data acquired during a routine diagnostic workup for ED should be taken into account when choosing the best PDE5 inhibitor for the individual patient, creating an individualized treatment plan, and going beyond "experience-based" subjective opinion and unfounded ideas and prejudice regarding currently available drugs.. As the process of matching a given patient's profile to any selected PDE5 inhibitor often relies more on physician's personal convictions than on solid evidence, the aim of this review is to identify the main clinical, demographic, and relational factors influencing the choice of the PDE5 inhibitor to be used for the treatment of ED.. A systematic literature search and current treatment guidelines were evaluated in a systematic manner.. The main clinical, cultural, and demographical factors to be considered for the treatment of ED have been identified.. Main factors influencing the choice of the treatment for ED have been described. A short list of items that may help in choosing the right PDE5 inhibitor for the treatment of different patients in daily clinical practice has been prepared.. The simple algorithms prepared should be a useful tool to be used in daily practice, which may help in choosing the right treatment for each subject affected by ED.

Topics: Algorithms; Carbolines; Cardiovascular Diseases; Diabetes Mellitus; Humans; Hypertension; Imidazoles; Impotence, Vasculogenic; Male; Men's Health; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrimidines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

Erectile dysfunction (ED) is a well-known entity with determined risk factors, which generally has a negative impact on quality of life. Obstructive sleep-disordered breathing (SDB), often referred to as obstructive sleep apnea, stands among the possible risk factors for ED.. Literature review suggests that SDB induces a spectrum of abnormalities in neural, hormonal, and vascular regulation that may contribute to the development of ED. While more studies are required to imply SDB as a risk factor for ED, several case series and expert opinion have contributed evidence for a causal relationship.. In clinical practice, men presenting with symptoms of sexual dysfunction often have concomitant sleep disorders requiring treatment. There is now evidence to suggest that treating SDB may be an effective treatment for ED. It is the authors' opinion that patients with erectile dysfunction would benefit from a sleep evaluation.

Topics: Aged; Cardiovascular Diseases; Continuous Positive Airway Pressure; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Obesity; Phosphodiesterase Inhibitors; Piperazines; Prevalence; Pulmonary Disease, Chronic Obstructive; Purines; Quality of Life; Risk Factors; Sildenafil Citrate; Sleep Apnea, Obstructive; Sulfones

Phosphodiesterase (PDE) 5 inhibitors reduce cyclic guanylate monophosphate breakdown, promoting vascular relaxation in the corpora cavernosa and penile erection during sexual stimulation. Sildenafil, vardenafil, and tadalafil were approved as effective treatments for male erectile dysfunction. Because PDE5 is present in artery and vein smooth muscle cells throughout the body, PDE5 inhibitors have mild systemic vasodilatory effects and thus the potential to impact the vascular system. The US Food and Drug Administration has approved PDE5 inhibitors for treating pulmonary hypertension. Moreover, their systemic vasodilating properties theoretically make these drugs suitable for treating hypertension. Studies indicate that PDE5 inhibition may be an option for reducing blood pressure in hypertensive patients. Additional benefits may be related to improved arterial stiffness and endothelial dysfunction, two early vascular abnormalities characterizing essential hypertension. More investigation is needed on PDE5 inhibitors as antihypertensive drugs, especially with slow-release formulations or compounds with long half-life. Studies on safety during long-term administration, interactions with antihypertensive and nonantihypertensive drugs, and effect on target organ damage are needed.

Topics: Antihypertensive Agents; Blood Pressure; Carbolines; Endothelium; Humans; Hypertension; Imidazoles; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

Erectile dysfunction occurs extensively among patients with arterial hypertension. We investigated the safety of sildenafil for patients with and without antihypertensive medication. Our study included data from 35 double-blind, placebo-controlled, and randomized investigations, with a total of 8115 patients. The term of therapy was between 6 weeks and 6 months, for both the sildenafil group (5-200 mg, n=4819) as well as the placebo group (n=3296). We studied the adverse events in the men who received 1 or more hypertensives (n=2388), and in those who took no antihypertensive medication (n=5727). Our findings disclosed equal frequency of adverse events in both groups, without influence by the number of different antihypertensives administered. The occurrence of AEs associated with blood pressure was slight, and was comparable between the individual groups. These results support the conclusion that sildenafil is also well tolerated by patients taking one or more antihypertensives. Patients being treated with alpha blockers should be stable on this therapy in order to minimize the possibility of orthostatic hypotension. An initial dose of 25 mg should furthermore be considered for these patients.

Topics: Antihypertensive Agents; Drug Interactions; Erectile Dysfunction; Humans; Hypertension; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The treatment of pediatric pulmonary arterial hypertension (PAH) is challenging due to the serious nature of the disease, its rapid progression, and the limited treatment options available. While oral calcium channel antagonists and continuous intravenous epoprostenol have been used successfully for over a decade, novel treatment options - including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors - may change the course of this disease for many children in the future.Prostacyclin analogs offer the benefit over continuous intravenous epoprostenol of an alternative delivery system. However, the efficacy of these medications compared with intravenous epoprostenol and the risk/benefits of each analog need to be weighed in future trials, which need to include larger numbers of pediatric patients to optimize therapy and outcome for individual children with PAH.For patients who do not have an acute response to vasodilator testing or have failed treatment with oral calcium channel antagonists, endothelin receptor antagonists may offer a viable treatment option. Furthermore, in the future, the addition of endothelin receptor antagonists to long-term therapy with calcium channel antagonists or to epoprostenol or a prostacyclin analog may increase the overall efficacy of treatment of PAH. Large multi-institutional randomized trials to determine whether sildenafil is effective and safe for the long-term treatment of PAH in children are in progress.A comprehensive review of these newer agents with an emphasis on the pathobiology/pathophysiology of PAH provides insight into the future management of pediatric PAH patients.

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Erectile dysfunction occurs commonly in untreated and treated hypertensive patients, impairing adherence to treatment and quality of life. Furthermore, it is a marker for enhanced risk for cardiovascular disease. Phosphodiesterase type 5 (PDE5) inhibitors, sildenafil, vardenafil, and tadalafil, provide effective treatment of erectile dysfunction. They reduce blood pressure in healthy patients: sildenafil 100 mg, -3.7/-3.6 mm Hg; vardenafil 20 mg, -7.5/-8 mm Hg; and tadalafil 20 mg, -1.6/-0.8 mm Hg. Greater declines in blood pressure with a PDE5 inhibitor may be observed in treated and untreated hypertensive patients. The additive effect of PDE5 inhibitors with one or multiple antihypertensive drugs is modest. alpha(1)-Blockers, except tamsulosin, may result in larger declines in blood pressure and cause orthostatic hypotension. Thus, caution should be exercised by using the lowest doses of proportional, variant(1)-blockers and PDE5 inhibitors in combination. Nitrates in combination with PDE5 inhibitors cause a profound decline in blood pressure and are contraindicated.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antihypertensive Agents; Blood Pressure; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erectile Dysfunction; Humans; Hypertension; Hypotension; Imidazoles; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vascular Resistance

Three different phosphodiesterase 5 (PDE5) inhibitors are currently available for the treatment of erectile dysfunction: sildenafil, vardenafil and tadalafil. The differences between these 3 are limited: tadalafil has a long duration of action, while vardenafil has a rapid onset of action after intake. Various studies have suggested that there is an improvement in the partners' sex lives when men use a PDE5 inhibitor for erectile dysfunction. The introduction of PDE5 inhibitors has renewed the interest in PDE inhibitors in general, for example in the treatment of pulmonary hypertension. In the near future PDE inhibitors may be used for various disorders as chronic obstructive pulmonary disease, benign prostatic hyperplasia, hypertension and coronary heart disease.

Topics: Carbolines; Coronary Disease; Erectile Dysfunction; Humans; Hypertension; Imidazoles; Male; Phosphodiesterase Inhibitors; Piperazines; Prostatic Hyperplasia; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

Cardiovascular (CV) risk factors are associated with an increased risk of erectile dysfunction (ED). In men with diabetes mellitus (DM), pooled from clinical trials of sildenafil treatment for ED, this retrospective analysis determined efficacy and safety, overall and in subgroups with additional CV risk (i.e., hypertension, dyslipidemia, and smoking).. From the manufacturer's database of worldwide research, 12-week data from men with DM were pooled from randomized, double-blind, placebo-controlled trials of flexible-dose sildenafil (25, 50, or 100 mg, PRN) for ED.. Question 3 (achieving an erection), question 4 (maintaining an erection), and the Erectile Function domain of the International Index of Erectile Function; percentage of successful intercourse attempts according to patient event logs; and response to a global efficacy question (GEQ). Differences between groups were determined using logistic regression (percentage of responders according to GEQ) and analysis of covariance (all other outcomes).. Inclusion criteria were met by 11 trials and by 974 men with DM and ED who were randomized to placebo (n = 482) and sildenafil (n = 492) within the selected trials. For all outcomes, overall and regardless of additional CV risk, the benefit was greater for sildenafil versus placebo (p < or = 0.0001), including 3-fold more men responding that sildenafil treatment improved their erections (62% vs. 18%) and a more than doubling of the mean +/- standard error percentage of successful sexual intercourse attempts (52.6 +/- 5.0 vs. 22.4 +/- 5.1). Adverse events were mild to moderate and included (sildenafil vs. placebo) headache (5% vs. 2%), flushing (7% vs. 2%), and dyspepsia (4% vs. 0%), which is consistent with the profile in the general population of men treated with sildenafil for ED.. This retrospective analysis of pooled data showed that sildenafil was well tolerated and improved erectile function and intercourse success in men with ED and DM, regardless of additional CV risk factors.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Coitus; Diabetes Complications; Dyslipidemias; Erectile Dysfunction; Humans; Hypertension; Logistic Models; Male; Middle Aged; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Sildenafil Citrate; Smoking; Sulfones; Surveys and Questionnaires; Treatment Outcome

Risk factors for erectile dysfunction (ED) (hypertension, diabetes, smoking, lipid abnormality) are also risk factors for coronary artery disease. However, most cardiologists do not routinely ask about ED and patients often are reluctant or embarrassed to discuss it. We determined how common ED was in a group of patients with chronic stable coronary artery disease.. We administered the validated Sexual Health Inventory for Men (SHIM) 5-item questionnaire, based on the International Index of Erectile Function questionnaire, to 76 men with chronic stable coronary artery disease during routine outpatient cardiology visits. Most of these men had not previously discussed ED with their cardiologist.. The mean patient age was 64 years (range 40 to 82). The questionnaire took about 5 minutes to complete. Of the patients 47% were on beta blockers, 92% statins, 28% diuretics. SHIM score was 21 or less in 53 men (70%), which is indicative of ED. Of the patients 75% had some difficulty achieving erections (question 2) and 67% had some difficulty maintaining an erection after penetration (question 3). The questionnaire reflected successful sildenafil treatment in 4 patients (SHIM scores 23 to 25). If these 4 men are included as having had ED then 57 of 76 (75%) had ED or recent history of ED.. ED is extremely common in men with chronic coronary artery disease (affecting approximately 75%) yet most cardiologists do not ask about it. The SHIM is a useful, quick and inexpensive tool for discussion and diagnosis of ED in this population. Although it is well established that cardiovascular risk factors are associated with erectile dysfunction, once it is present there is mixed information on whether treating the risk factors will treat the ED. Problems appear to be that lifestyle modification in midlife may simply be too late to effect a change, and some antihypertensive and lipid lowering drugs may actually exacerbate ED. Oral therapy for ED, namely the PDE5 inhibitors, is effective and safe in most cardiac and hypertensive patients. Organic nitrates such as nitroglycerin remain a contraindication to the concomitant use of these drugs. Guidelines for treatment of ED in the cardiac patient issued by the American College of Cardiology/American Heart Association and Princeton Guidelines may be useful in the approach to the cardiac patient with ED.

Topics: Comorbidity; Coronary Disease; Diabetic Angiopathies; Erectile Dysfunction; Heart Diseases; Humans; Hypertension; Imidazoles; Life Style; Male; Penile Erection; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Smoking; Sulfones; Triazines; Vardenafil Dihydrochloride

Topics: Algorithms; Cardiovascular System; Coronary Disease; Erectile Dysfunction; Heart Diseases; Humans; Hypertension; Male; Piperazines; Purines; Referral and Consultation; Risk Assessment; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Coronary Artery Disease; Humans; Hypertension; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Sildenafil is an inhibitor of phosphodiesterase 5, which has important vasodilatory properties. Though sildenafil provokes a decrease in systemic arterial pressure, its safety has been confirmed in large series of patients on several kinds of anti-hypertensive therapy. Likewise, post-marketing surveys, in the US or United Kingdom, have recorded a number of cardio-vascular deaths following sildenafil administration which was lower than expected, provided the contra-indication with the concomitant use of nitrates is observed. In patients with known or suspected coronary artery disease, sildenafil does not modify the tolerance or results of echocardiographic exercise testing. However, sildenafil does increase coronary flow reserve, both in narrowed or normal coronary arteries, with no sign of a "steal" phenomenon. Because of its capacity to retard the degradation of cGMP, by the inhibition of phosphodiesterase 5, the effect of sildenafil in primary pulmonary hypertension has been evaluated in several studies: acutely, sildenafil decreases pulmonary artery pressure, either alone or in combination with inhaled iloprost or NO. On the same line, sildenafil decreases hypoxia-induced pulmonary hypertension in normal volunteers. These findings, together with reports of long-term improvement in symptoms and levels of pulmonary artery pressure in patients with primary pulmonary hypertension, will warrant further trials to document its potential role in this otherwise severe disease.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Computer Graphics; Contraindications; Coronary Artery Disease; Coronary Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Interactions; Humans; Hypertension; Hypertension, Pulmonary; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Hypertension is an important risk factor for erectile dysfunction (ED). Consequently, there is a high coincidence between hypertension and ED. Oral sildenafil (Viagra) is an effective treatment for ED in patients with treated or untreated hypertension. The most common adverse events of sildenafil (headache, flushing, hypotension) result from its moderate vasodilating properties. The concomitant use of sildenafil and organic nitrates is contraindicated because it may lead to a potentiation of the decreases in blood pressure and thus cause life-threatening hypotension. In contrast, the concomitant use of sildenafil and different classes of antihypertensive agents (beta-blockers, alpha-blockers, diuretics, ACE inhibitors, calcium antagonists) may lead to additive but not to potentiating blood pressure decreases. Thus, this combination is unlikely to cause clinically significant hypotension or an increased incidence of adverse events. Sildenafil is an effective and well-tolerated treatment for ED in patients taking concomitant antihypertensive medication, including those on multidrug regimens.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Drug Interactions; Drug Therapy, Combination; Erectile Dysfunction; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Placebos; Posture; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Time Factors

Topics: Cardiovascular Diseases; Depressive Disorder; Diabetes Complications; Erectile Dysfunction; Humans; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Prostatic Diseases; Purines; Sildenafil Citrate; Smoking; Sulfones

Topics: Adult; Aged; Contraindications; Coronary Disease; Drug Interactions; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Hypertension is another predictor of erectile dysfunction (ED). This is further evidence supporting a link between the pathogenesis of atherosclerotic disease and ED. In one study (TOMHS) involving hypertensive patients, the incidence of ED was 14.4%. The drugs used to treat hypertension may cause ED. However, there is little trial-based evidence to indicate which drugs are more likely to cause this side effect. In general, thiazide diuretics and beta-blockers seem to cause ED more often. In contrast, the alpha-blocker, doxazosin, has not been associated with an increased incidence of ED as a side effect. Doxazosin also improves urinary flow in patients with benign prostatic hyperplasia (BPH). This condition is common in elderly men as is hypertension and ED. Therefore, doxazosin may present a special advantage among this group of patients. This alpha-blocker would also be a good choice in patients with impaired glucose tolerance/diabetes because it improves insulin sensitivity. Moreover, ED and hypertension are more prevalent among diabetics. On a more speculative note, doxazosin may potentiate the therapeutic impact of specific treatments for ED.

Topics: Antihypertensive Agents; Diabetes Complications; Doxazosin; Erectile Dysfunction; Humans; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Arterial hypertension is associated with structural and functional alterations of the vessel walls. Because vascular endothelium plays a central role in the control of vascular tone, endothelial dysfunction can also cause certain types of erectile dysfunction. Erectile dysfunction is also a common side effect of certain drugs, including many antihypertensive agents. Physicians should be aware of potential sexual side effects of such drugs and take appropriate steps to alleviate persistent problems. Most important, physicians need to ask patients about sexual function and discuss the possibility of erectile dysfunction caused by antihypertensive therapy. Erectile dysfunction can be effectively treated in most patients, and many treatment options are available. Sildenafil therapy has revolutionized the management of this disorder, but this agent should be used with caution in certain patients taking nitrates.

Topics: Antihypertensive Agents; Contraindications; Erectile Dysfunction; Humans; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sexual Behavior; Sildenafil Citrate; Sulfones

Topics: Depressive Disorder; Diabetes Complications; Erectile Dysfunction; Humans; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones

Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by pulmonary hypertension (PH). A pulmonary vascular contribution could be considered as a substantial therapeutic target in HFpEF and PH and combined pre- and postcapillary PH (Cpc-PH).. We enrolled 50 patients with HFpEF and Cpc-PH who were determined by echocardiography to have pulmonary artery systolic pressure (PASP) > 40 mmHg, pulmonary vascular resistance > 3 Wood units, and/or transpulmonary gradient > 15 mmHg.. The patients were assigned to the phosphodiesterase 5 (PDE5) inhibitor sildenafil group (25 mg TID for 3 months followed by 50 mg TID for 3 months; n = 30) or the control group (n = 20). In the sildenafil group after 6 months, the 6-min walk distance increased by 50 m (95% CI, 36 to 64 m); substantial improvement in NYHA functional class and exercise capacity during diastolic stress test were revealed; decreases in early mitral inflow to mitral annulus relaxation velocities ratio by 2.4 (95% CI, - 3.3 to - 1.4) and PASP by 17.0 mmHg (95% CI, 20.4 to 13.5) were observed; right ventricular systolic function (M-mode tricuspid annular plane systolic excursion) increased by 0.42 cm (95% CI, 0.32 to 0.52 cm; P < 0.01 for all). No changes occurred in the control group.. In a subset of patients with HFpEF and Cpc-PH assessed by echocardiography, PDE5 inhibition was associated with an improvement in exercise capacity, pulmonary haemodynamic parameters, and right ventricular function. The role of sildenafil needs to be considered in randomized trials in selected patients with HFpEF with invasively confirmed Cpc-PH.. Russian National Information System of Research, Development and Technology Data of Civilian Usage (NIS, https://rosrid.ru), registration number 01201257849 . Registered 20 April 2012. This manuscript adheres to the CONSORT guidelines.

Topics: Aged; Arterial Pressure; Exercise Tolerance; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pilot Projects; Pulmonary Artery; Recovery of Function; Russia; Sildenafil Citrate; Stroke Volume; Time Factors; Treatment Outcome; Vasodilator Agents; Ventricular Function, Right

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Atrial Natriuretic Factor; Biphenyl Compounds; Blood Pressure; Cyclic GMP; Double-Blind Method; Drug Combinations; Drug Interactions; Humans; Hypertension; Male; Middle Aged; Sildenafil Citrate; Tetrazoles; Valsartan

The authors previously demonstrated that acute administration of sildenafil-a phosphodiesterase 5 (PDE5) inhibitor-improves hemodynamic parameters in patients with resistant hypertensive (RH), but its effect on ambulatory blood pressure monitoring (ABPM) is unknown. This interventional, nonrandomized, single-blinded, placebo-controlled, crossover trial included 26 patients with RH. A dose of sildenafil (187.5mg) was given, and after a washout period of 14 days the patients received a single oral dose of placebo and the protocol was repeated. The patients underwent 24-hour ABPM recordings the day before and immediately after the protocols. The reduction of systolic (-8.8±1.4 vs 1.3±1.2 mm Hg, P=.02), diastolic (-5.3±3.3 vs 1.8±1.1 mm Hg, P=.03), and mean (-7.9±3.6 vs 0.8±0.9 mm Hg, P=.01) 24-hour BP were found after the use of sildenafil compared with placebo. Improvement in daytime BP levels was also observed (systolic -6.0±4.7 vs 4.4±1.5 mm Hg [P=.02] and mean -4.8±3.9 vs 3.5±1.4 mm Hg [P=.02] for sildenafil vs placebo, respectively). Considering its antihypertensive effect, sildenafil may represent a therapeutic option for RH treatment.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged; Sildenafil Citrate; Treatment Outcome

Neuronal NO synthase (nNOS) regulates blood flow in resistance vasculature at rest and during mental stress. To investigate whether nNOS signaling is dysfunctional in essential hypertension, forearm blood flow responses to mental stress were examined in 88 subjects: 48 with essential hypertension (42±14 years; blood pressure, 141±17/85±15 mm Hg; mean±SD) and 40 normotensive controls (38±14 years; 117±13/74±9 mm Hg). A subsample of 34 subjects (17 hypertensive) participated in a single blind 2-phase crossover study, in which placebo or sildenafil 50 mg PO was administered before an intrabrachial artery infusion of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC, 0.05, 0.1, and 0.2 μmol/min) at rest and during mental stress. In a further subsample (n=21) with an impaired blood flow response to mental stress, responses were measured in the presence and absence of the α-adrenergic antagonist phentolamine. The blood flow response to mental stress was impaired in hypertensive compared with normotensive subjects (37±7% versus 70±8% increase over baseline; P<0.001). SMTC blunted responses to mental stress in normotensive but not in hypertensive subjects (reduction of 40±11% versus 3.0±14%, respectively, P=0.01, between groups). Sildenafil reduced the blood flow response to stress in normotensive subjects from 89±14% to 43±14% (P<0.03) but had no significant effect in hypertensive subjects. Phentolamine augmented impaired blood flow responses to mental stress from 39±8% to 67±13% (P<0.02). Essential hypertension is associated with impaired mental stress-induced nNOS-mediated vasodilator responses; this may relate to increased sympathetic outflow in hypertension. nNOS dysfunction may impair vascular homeostasis in essential hypertension and contribute to stress-induced cardiovascular events.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Endothelium, Vascular; Essential Hypertension; Female; Follow-Up Studies; Humans; Hypertension; Male; Nitric Oxide Synthase Type I; Phentolamine; Piperazines; Purines; Regional Blood Flow; Sildenafil Citrate; Single-Blind Method; Stress, Psychological; Sulfonamides; Treatment Outcome; Vasodilation; Vasodilator Agents

Sildenafil, a selective phosphodiesterase-type-5 (PDE-5) inhibitor, produces vasodilation that improves erectile dysfunction and pulmonary hypertension. Sildenafil could also cause baroreflex sympathetic activation that would enhance vascular tone and oppose direct vasodilation. We tested the hypothesis that sildenafil administration increases sympathetically mediated vascular tone in healthy middle-aged men.. We randomized 9 healthy, middle-aged, male volunteers (mean age 45±2 years) in a double-blind, crossover fashion to receive a single oral dose of sildenafil 100mg or placebo on 2 separate study days. Hemodynamics and forearm blood flow responses were measured at baseline, at 30 and 45 minutes after study drug administration, and then during intra-arterial infusions of vasoactive drugs. After sildenafil and placebo administration, intrabrachial medications were infused to test forearm alpha receptor sensitivity (norepinephrine), cyclic-AMP-mediated vasodilation (isoproterenol), and sympathetically mediated vascular tone (phentolamine) (adenosine was a control vasodilator). Blood samples were taken before and 60 minutes after study drug administration and at the end of the intrabrachial infusions for measurement of plasma norepinephrine concentrations.. Forearm vascular responses to norepinephrine, isoproterenol, and adenosine were not different after placebo and sildenafil administration. Percentage reduction in forearm vascular resistance during phentolamine was significantly lower after sildenafil than placebo (-73% ± 3% vs -63% ± 3%; P = 0.0002). Sildenafil significantly increased plasma norepinephrine compared with placebo 60 minutes after study drug administration and at the end of the study session (P = 0.02).. Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic-mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the significant hypotension observed in patients taking alpha-blockers with sildenafil.

Topics: Blood Flow Velocity; Brachial Artery; Cross-Over Studies; Double-Blind Method; Follow-Up Studies; Forearm; Humans; Hypertension; Infusions, Intra-Arterial; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Reference Values; Sildenafil Citrate; Sulfones; Sympathetic Nervous System; Vasodilation

Failure to control blood pressure (BP) despite the use of three or more drugs characterizes resistant hypertension (RHTN). Impaired endothelial function is associated with this condition and phosphodiesterase-5 inhibitors (PDE5i)-inhibiting cGMP breakdown-reduce BP in RHTN patients. We hypothesized that acute administration of PDE5i could ameliorate hemodynamic, endothelial parameters and left ventricular diastolic function (LVDF) in RHTN patients. Also, an exploratory analysis was performed to assess the influence of the T-786C endothelial NO synthase polymorphism on those responses.. Subjects (n = 26) underwent a 6-month clinical screening for RHTN diagnosis. Increasing doses of oral sildenafil were given at 30 min intervals (37.5, 50 and 100 mg) while continuous non-invasive hemodynamic measures were assessed. LVDF, flow mediated dilation (FMD), nitrite and cGMP levels were also determined.. Mean arterial pressure and total peripheral resistance decreased in all patients (84.17 ± 21.04 to 75 ± 17.21 mmHg; 1149 ± 459.7 to 1037 ± 340 dyn.s/cm(-5), respectively). Likewise, sildenafil improved diastolic dysfunction parameters (Left atrial volume: 25 ± 5.8 to 20 ± 4.4; IVRT: 104 ± 19.33 to 88 ± 15.22; E/e' septal: 9.7 ± 3.8 to 7.9 ± 2.9; E/e' lateral: 7.7 ± 3.4 to 6.4 ± 3.2). No statistical changes were found in FMD, nitrite and cGMP with PDE5i.. Our data suggest PDE5i acutely improves diastolic function and hemodynamic profile in RHTN subjects, despite unchanging endothelial dysfunction.

Topics: Aged; Arterial Pressure; Cross-Over Studies; Cyclic GMP; Drug Resistance; Female; Genotype; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Nitric Oxide Synthase Type III; Nitrites; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Single-Blind Method; Sulfones; Ventricular Function, Left

Established hypertension is associated with abnormal exercise hemodynamics and reduced exercise capacity through mechanisms that may include contributions from arterial stiffness and endothelial vasomotor dysfunction. Phosphodiesterase type 5 (PDE5) inhibitors prolong nitric oxide-mediated cyclic guanosine monophosphate (cGMP) signaling in vascular smooth muscle, and have beneficial effects on exercise tolerance in pulmonary hypertension and heart failure. Recent studies suggest they may also be useful antihypertensive agents. We hypothesized they would reduce arterial stiffness and increase exercise capacity in hypertensive men.. In a 3-way, randomized, placebo-controlled study, 15 untreated hypertensive and 15 matched normotensive male subjects received 50mg sildenafil (PDE5 inhibitor), 25mg hydralazine (control, cGMP-independent vasodilator) or placebo, 3 times daily for 1 week, and the effects on exercise blood pressure (during modest and maximal exercise), peak oxygen uptake, and arterial stiffness were investigated.. Peak oxygen uptake was significantly lower in hypertensive than normotensive subjects (analysis of variance [ANOVA] P < 0.0001), but not affected by sildenafil in either group. However, while pulse wave velocity, as a measure of arterial stiffness, increased after exercise in hypertensive men following placebo, sildenafil reversed these changes, significantly reducing pulse wave velocity compared with both placebo and hydralazine (ANOVA P = 0.0001).. PDE5 inhibition with sildenafil did not improve exercise capacity in hypertensive men. Nevertheless, our findings suggest that sildenafil may reduce arterial stiffness in the recovery period after exercise.

Topics: Adult; Blood Pressure; Exercise; Exercise Tolerance; Humans; Hydralazine; Hypertension; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Pulse Wave Analysis; Purines; Sildenafil Citrate; Sulfones; Vascular Stiffness

The goal of this study was to examine the effects of coadministration of sildenafil and inhaled nitric oxide (iNO) in patients with out-of-proportion pulmonary hypertension who underwent cardiac valve replacement surgery.. Twenty consecutive cardiac surgery patients with out-of-proportion pulmonary hypertension were randomly assigned postoperatively into 2 groups: group A received 10 ppm of iNO followed by sildenafil (100 mg) orally 30 minutes later, and group B initially received sildenafil (100 mg) orally followed by 10 ppm of iNO 60 minutes later. Hemodynamic and gas exchange data were obtained at baseline, after administration of either iNO or sildenafil alone, and at 90 minutes from baseline. In group A, iNO resulted in a significant reduction in mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance index (PVRI) (by 9.6% and 20.8%, respectively). In group B, sildenafil administration also resulted in a significant decrease in mean arterial pressure, MPAP, pulmonary artery occlusive pressure, PVRI, and systemic vascular resistance index but also in the PaO(2)/inspired fraction of oxygen ratio (by 18.7%, 22.0%, 15.7%, 31.6%, 21.3%, and 14%, respectively). In both groups, the coadministration of the 2 drugs resulted in a significant further reduction of mean arterial pressure, MPAP, pulmonary artery occlusive pressure, systemic vascular resistance index, and PVRI, whereas cardiac index and mixed venous oxygen saturation remained unchanged. The hypoxemia after sildenafil administration in group B improved after the coadministration of iNO, and thus PaO(2)/inspired fraction of oxygen returned to values near baseline.. In this study, the postoperative coadministration of iNO and oral sildenafil in patients with out-of-proportion pulmonary hypertension undergoing cardiac surgery is safe and results in an additive favorable effect on pulmonary arterial pressure and pulmonary vascular resistance, without systemic hypotension and ventilation/perfusion mismatch.

Topics: Administration, Inhalation; Administration, Oral; Aged; Blood Pressure; Cardiac Surgical Procedures; Drug Therapy, Combination; Female; Heart Valve Diseases; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Piperazines; Postoperative Period; Prospective Studies; Pulmonary Gas Exchange; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

NO donor drugs (eg, isosorbide mononitrate; ISMN) and phosphodiesterase 5 inhibitors (eg, sildenafil) have antihypertensive properties, and the combination can markedly reduce blood pressure (BP). The objective of this "proof-of-concept" study was to investigate the effect on BP of a combination of single oral doses of sildenafil (50 mg) and ISMN (10 mg) in patients with treatment-resistant hypertension. Six subjects with treatment-resistant hypertension were included, and their usual antihypertensive medication was continued during the study. Sildenafil alone, ISMN alone, and the combination all reduced brachial and central aortic BPs compared with placebo. The combination of sildenafil and ISMN produced the largest fall in BP (maximum brachial BP reduction of 26/18 mm Hg compared with placebo), without producing significant adverse effects. ISMN, alone and in combination with sildenafil, also reduced arterial wave reflection and central BP. In summary, in patients with treatment-resistant hypertension maintained on their usual antihypertensive treatment, sildenafil given alone and ISMN given alone both acutely reduced BP. There was additional BP reduction when these drugs were given in combination. In this therapeutically challenging group of patients, the combination of an NO donor drug and a phosphodiesterase 5 inhibitor may represent an effective treatment. Longer studies in larger numbers of patients are now justified.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Isosorbide Dinitrate; Male; Middle Aged; Nitric Oxide Donors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Erectile dysfunction (ED) has been associated with several comorbidities and can cause significant loss of quality of life and self-esteem.. In men with ED, to use the validated Self-Esteem and Relationship (SEAR) questionnaire to evaluate changes in self-esteem associated with sildenafil treatment of ED and to assess changes dependent on concomitant comorbid conditions.. This was a 14-week, international, randomized, parallel-group, double-blind, flexible-dose (25, 50, or 100 mg), placebo-controlled study of sildenafil in men aged >or=18 years with a clinical diagnosis of ED (score

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Depressive Disorder; Double-Blind Method; Erectile Dysfunction; Expressed Emotion; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Prostatic Hyperplasia; Purines; Quality of Life; Self Concept; Sildenafil Citrate; Sulfones; Surveys and Questionnaires; Young Adult

Established hypertension is characterized by increased peripheral vascular resistance and endothelial dysfunction, features that may underlie the reduced exercise-induced vasodilatation seen in hypertensive patients. Sildenafil citrate is a phosphodiesterase type 5 (PDE5) inhibitor used clinically for the treatment of male erectile dysfunction. Its vasodilating properties are due to the inhibition of cyclic guanosine monophosphate (cGMP) breakdown and prolongation of the signalling actions of the nitric oxide (NO)-cGMP pathway in vascular smooth muscle cells. Sildenafil has beneficial effects on endothelial function and exercise tolerance in congestive heart failure and pulmonary hypertension, and we hypothesized that it would improve exercise-induced vasodilatation in hypertensive patients.. Ten hypertensive patients and ten matched normotensive subjects were studied in a three-way, randomized, single-blind and placebo-controlled study. On each study day, forearm blood flow (FBF) responses to handgrip exercise were assessed before and after intra-arterial (brachial) infusion of sildenafil, verapamil (a control, cGMP-independent vasodilator), and saline (placebo). Preinfusion exercise-induced vasodilatation was significantly reduced in hypertensive patients compared to normotensive controls. Sildenafil and verapamil infusions both caused a similar increase in baseline FBF. However, while verapamil did not affect the vasodilator response to handgrip exercise in either group, sildenafil substantially enhanced this response in hypertensive patients, but not in normotensive subjects.. Our data suggest that sildenafil, through an increase in cGMP levels in the vasculature, substantially and selectively improves the vasodilator response to handgrip exercise in hypertensive patients. These findings represent an essential first step in support of further studies exploring the potentially beneficial effects of PDE5 inhibition on impaired exercise capacity in hypertension.

Topics: Adult; Aged; Case-Control Studies; Exercise; Female; Forearm; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Single-Blind Method; Sulfones; Vasodilation; Vasodilator Agents; Verapamil

Approximately 50% of patients with autonomic failure (AF) suffer from supine hypertension, even those with very low plasma norepinephrine and renin. Because NO is arguably the most potent metabolic modulator of blood pressure, we hypothesized that impaired NO function contributes to supine hypertension in AF. However, we found that AF patients (n=14) were more sensitive to the pressor effects of the NO synthase inhibitor N(G)-monomethyl-l-arginine, suggesting increased NO function rather than deficiency; a lower dose of N(G)-monomethyl-l-arginine was needed to produce a similar increase in blood pressure in AF patients, as in healthy control subjects in whom AF was induced with the ganglionic blocker trimethaphan (171+/-37 mg versus 512+/-81 mg, respectively; P=0.001). Furthermore, potentiation of the actions of endogenous NO with the phosphodiesterase inhibitor sildenafil (25 mg PO) decreased nighttime supine systolic blood pressure from 182+/-11 to 138+/-4 mm Hg in 8 AF patients with supine hypertension (P=0.012 compared with placebo). Finally, AF patients tolerated a greater degree of upright tilt during infusion of N(G)-monomethyl-l-arginine (56+/-6 degrees versus 41+/-4 degrees with placebo; n=7; P=0.014), an improvement in orthostatic tolerance similar to that obtained with equipressor doses of phenylephrine. In conclusion, AF patients do not have NO deficiency contributing to supine hypertension. Instead, they have increased NO function contributing to their orthostatic hypotension. Potentiation of NO could be used in the treatment of supine hypertension, and its inhibition offers a novel approach to improve orthostatic hypotension.

Topics: Aged; Blood Pressure; Cross-Over Studies; Enzyme Inhibitors; Female; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Piperazines; Purines; Shy-Drager Syndrome; Sildenafil Citrate; Sulfones; Supine Position; Vasodilator Agents

Erectile dysfunction (ED) is common among men taking antihypertensive agents to control blood pressure.. We evaluated the efficacy and safety of sildenafil citrate in men with ED taking antihypertensive agents.. A total of 198 male subjects, aged 20 years and older were enrolled. This study was conducted for 10 weeks as an open-label, multicenter and flexible dose trial with a 2-week screening period and an 8-week treatment phase.. Subjects were asked to complete Event Log Worksheets, as well as the International Index of Erectile Function (IIEF) and the Global Efficacy Assessment Questions (GEAQ) questionnaires during the study period.. The average age among the 167 subjects who completed the study was 55.8 (31.7 to 77.1). The scores for questions 3 and 4 of IIEF improved from 2.3 and 1.8 at baseline to 3.7 and 3.4 at week 4 and 3.8 and 3.4 at week 8, respectively. There were 86.3% of the patients reported improved erectile function at week 8; 88.3% of the patients reported improved ability to achieve sexual intercourse at week 8. There were no significant differences observed in the responses to questions 3 and 4 of IIEF and GEAQ by the number of antihypertensive agents taken. The adverse events were facial flushing (20.1%), headache (11.7%), palpitation (5.0%), rhinitis (2.8%), URI (2.8%), dizziness (2.2%), dyspnea (2.2%), and nausea (1.7%).. Sildenafil citrate is an effective treatment for ED; it is safe and well tolerated by patients with ED taking multiple antihypertensive agents for arterial hypertension.

Topics: Adult; Aged; Analysis of Variance; Antihypertensive Agents; Erectile Dysfunction; Humans; Hypertension; Korea; Male; Middle Aged; Penis; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Surveys and Questionnaires

The nitric oxide/cyclic-guanosine 3',5'-monophosphate signaling cascade plays an essential role in cardiovascular homeostasis but its involvement in the pathophysiology of refractory hypertension is unclear. The acute vasodilatory effect of a single oral dose of a phosphodiesterase-5 inhibitor (sildenafil citrate) on the brachial artery dilatation was evaluated in 25 normal healthy volunteers (NL) and in 25 refractory hypertensive patients (RH). Endothelial and vascular smooth muscle functions were assessed two times. First, the brachial artery response to endothelium-dependent (flow-mediated dilatation [FMD]) and independent (glyceryl trinitrate [GTN]) stimuli was examined. The FMD in NL was 14.2+/-3.2% compared to 10.3+/-3.5% in RH (P<0.001) and the GTN-induced responses were 23.5+/-6.3 in NL compared to 18.4+/-5.7% in RH (P<0.001). Two weeks later, the brachial artery responses to FMD were determined before and after the administration of sildenafil citrate. Sildenafil caused a significant, slow and progressive dilatation of the brachial artery until 45 min after administration (4.7+/-3.0%, 6.7+/-3.0% and 9.4+/-3.9% after 15', 30' and 45', respectively, in RH and 3.7+/-1.9%, 7.4+/-2.7% and 10.1+/-3.0%, respectively, in NL). A second FMD stimulus, applied 45 min after ingesting 50mg of sildenafil resulted in an additional significant increase in the vasodilatory response (from 9.4+/-3.9% to 13.0+/-4.0% in RH; P<0.001 and from 10.1+/-3.0 to 14.6+/-4.1 in NL; P<0.001), but this was still significantly less than the response to GTN. Sildenafil citrate caused brachial artery vasodilatation similar to that caused by NO released during FMD in patients with refractory hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Nitroglycerin; Phosphodiesterase Inhibitors; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Assess the effectiveness of sildenafil in Asian males with erectile dysfunction (ED) and one or more of the co-morbidities, mild-to-moderate hypertension, dyslipidemia, and diabetes.. A six-week, double-blind, randomized, placebo-controlled, multicenter study was carried out in Thailand, Malaysia and Singapore. One hundred and fifty five male subjects were randomized (2:1) to sildenafil (n = 104) or placebo (n = 51). Sildenafil was started at 50 mg and increased (100 mg) or decreased (25 mg) at week 2 if necessary.. On the primary efficacy endpoint, sildenafil-treated subjects had significantly better scores on the International Index of Erectile Function (IIEF) questions 3 and 4 than placebo (p < 0.001, both questions). When accumulated into IIEF domains, all five domains were significant in favor of sildenafil. In addition, sildenafil-treated subjects were more satisfied with treatment and had a higher intercourse success rate. The majority of adverse events were mild in severity; the most commonly reported treatment-related events were dizziness (7.7%) and tinnitus (2.9%).. Sildenafil (25, 50, and 100 mg) was found to be an effective, safe, and well-tolerated treatment for ED in the present study population of Thai, Malaysian, and Singaporean males who also had increased cardiovascular risk

Topics: Asian People; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Erectile Dysfunction; Humans; Hypertension; Malaysia; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Assessment; Risk Factors; Sildenafil Citrate; Singapore; Sulfones; Thailand; Treatment Outcome

There are no published controlled clinical trials of regular phosphodiesterase type 5 inhibitor therapy as a long-term treatment of hypertension. In a randomized, double-blind, 2-way crossover study, 25 otherwise untreated hypertensive subjects were administered 50 mg of sildenafil or matched placebo 3 times daily for 16 days, and the effects on ambulatory blood pressure (BP), clinic BP, arterial wave reflection, carotid-femoral pulse wave velocity, and brachial artery flow-mediated dilatation were assessed. Three subjects were withdrawn because of adverse effects, and the data from the remaining 22 subjects were analyzed. Sildenafil reduced ambulatory BP (mean [SE] change from baseline for average daytime BP: systolic -8 [2] mm Hg versus 2 [2] mm Hg with placebo, P<0.01; diastolic -6 [1] mm Hg versus 0 [1] mm Hg, P<0.01) and clinic BP (change from baseline to 1 hour after drug administration on day 16: systolic -5 [2] mm Hg versus 4 [2] mm Hg, P<0.01; diastolic -5 [1] mm Hg versus 2 [2] mm Hg, P<0.01). Compared with baseline, sildenafil, but not placebo, reduced arterial wave reflection both acutely and after chronic treatment, but the chronic change in arterial wave reflection was not statistically different from the chronic change with placebo. Sildenafil did not affect pulse wave velocity or flow-mediated dilatation. The main adverse effects of sildenafil, which were generally transient and rated as mild or moderate in severity, were dyspepsia, headache, and myalgia. In conclusion, regular sildenafil constitutes effective antihypertensive therapy. Further studies are warranted to evaluate the role of longer-acting phosphodiesterase type 5 inhibitors as antihypertensive agents in clinical practice.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Blood Flow Velocity; Blood Pressure; Blood Pressure Determination; Blood Pressure Monitoring, Ambulatory; Brachial Artery; Carotid Arteries; Cross-Over Studies; Cyclic Nucleotide Phosphodiesterases, Type 5; Double-Blind Method; Drug Administration Schedule; Femoral Artery; Humans; Hypertension; Office Visits; Phosphodiesterase Inhibitors; Piperazines; Pulse; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Vasodilation

The aim of this study was to establish the prevalence of erectile dysfunction (ED) in hypertensive patients in specialized care hypertension units (SCHUs) and to assess the effectiveness and tolerability of sildenafil treatment.. This was a multicenter, prospective, open, observational pharmacoepidemiology study conducted in 25 Spanish SCHUs. A total of 2130 men with essential hypertension under treatment were recruited. In a second phase, 291 subjects with a score < or = 21 in the Sexual Health Inventory for Men (SHIM) received sildenafil (50 mg/day) as required 30 to 60 minutes before sexual activity, and were evaluated by the International Index of Erectile Function (IIEF).. A total of 975 subjects (45.8%) had a score < or = 21 in the SHIM. In the second phase, sildenafil improved the score in the erectile function domain in 232 patients (83.2%). Severity of ED significantly improved (P <.001); severe (22.3% to 7.7%), moderate (23% to 5.6%), and mild impairment (36.3% to 44.8%). The IIEF was normalized in 39.1% of patients who completed post-treatment IIEF. In all, 33 subjects (11.8%) failed to complete the study: two (0.7%) because of lack of efficacy, two (0.7%) intercurrent disease, 10 (3.6%) failure to return to the visits, three (1.1%) fear of therapy, four (1.4%) adverse effects requiring treatment discontinuation, and 12 (4.3%) protocol violations. No statistically significant association was found between the prevalence of adverse effects and antihypertensive treatment with single drug or combination therapy.. A high incidence of ED was found in hypertensive patients from Spanish SCHUs. Sildenafil showed an excellent response and safety profile.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Aged; Antihypertensive Agents; Body Mass Index; Erectile Dysfunction; Headache; Humans; Hypertension; Male; Middle Aged; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Erectile dysfunction (ED) is common among men taking antihypertensive drugs to control blood pressure. We evaluated the safety and efficacy of sildenafil citrate for treating ED in men taking multiple antihypertensive medications in a randomized, double-blind, placebo-controlled trial.. A total of 568 men (> or =18 years) with ED and hypertension who were taking two or more antihypertensives were randomized to sildenafil (n = 281) or matching placebo (n = 287) for a 6-week double-blind trial followed by a 6-week open-label phase during which all patients received sildenafil. Primary efficacy variables were questions (Q) 3 and 4 (frequency of erections and penetration) of the International Index of Erectile Function (IIEF), and secondary efficacy variables were two global efficacy assessment (GEA) questions regarding improvement in erections and intercourse.. A total of 562 men (mean age, 59 years) took > or =1 dose of study drug. At week 6, mean scores on both Q3 and Q4 improved significantly among sildenafil-treated compared with placebo-treated patients. In regard to Q3 and Q4 there were no differences between patients taking two and those taking three or more antihypertensive agents. In all, 71% and 69% of sildenafil-treated patients reported improved erections (GEA1) and intercourse (GEA2) compared with 18% and 20% of placebo-treated patients, respectively. By week 12, >80% of all patients (regardless of initial treatment group) had improved erections and intercourse. During double-blind treatment, 40% of sildenafil-treated and 25% of placebo-treated patients experienced adverse events; fewer than 2% in each group discontinued because of adverse events.. Sildenafil was an effective and well tolerated treatment for ED in men receiving multiple antihypertensives. The results suggest that there were no additional safety risks associated with the use of sildenafil in these patients.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Australia; Canada; Dose-Response Relationship, Drug; Double-Blind Method; Erectile Dysfunction; Europe; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; United States

Patients with cardiovascular diseases frequently complain of erectile dysfunction especially when treated with beta-blockers. In order to assess whether the effect of beta-blockers on erectile dysfunction is in part related to patient knowledge of the drug side effects, 96 patients (all males, age 52+/-7 years) with newly diagnosed cardiovascular disease and not suffering from erectile dysfunction entered a two phase, single cross over study.. During the first phase of the study patients received atenolol 50mg o.d. (A), 32 patients were blinded on the drug given (group A), 32 were informed on the drug given but not on its side effects (group B) and 32 took A after being informed on its side effects on erectile function (group C). After 3 months the incidence of erectile dysfunction was 3.1% in the group A, 15.6% in group B and 31.2% in group C (P<0.01). All patients reporting ED entered the second phase of the study and were randomised to receive Sildenafil 50mg and placebo in a cross over study. Sildenafil citrate and placebo were equally effective in reversing erectile dysfunction in all but one patient reporting ED with Atenolol.. Our results show that the knowledge and prejudice about side effects of beta-blockers can produce anxiety, that may cause erectile function.

Topics: Adrenergic beta-Antagonists; Angina Pectoris; Anxiety; Attitude to Health; Awareness; Cardiovascular Diseases; Cross-Over Studies; Humans; Hypertension; Impotence, Vasculogenic; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Placebos; Purines; Sildenafil Citrate; Sulfones

To evaluate the efficacy and safety of sildenafil in the treatment of erectile dysfunction in hypertensive patients taking antihypertensive drugs, and to investigate factors associated to treatment failure.. Observational prospective study comparing two groups of patients suffering from erectile dysfunction with or without hypertension. Patients were evaluated by anamnesis, physical examination, blood tests, and the International Index of Erectile Function (IIEF). Blood pressure was measured before and after treatment with an automatic digital oscillometric device.. Erections improved in 88.2% and 91.7% of the patients with an without hypertension respectively. On the initial visit 55.2% of all patients had severe dysfunction, which was reduced after sildenafil treatment to 4.7%. Diastolic arterial blood pressure, evaluated in random measures, was slightly reduced after starting treatment with Viagra. No significant adverse events were registered.. Oral treatment with sildenafil in patients with erectile dysfunction and hypertension is effective, well-tolerated and does not produce pharmacologic interactions with antihypertensive drugs.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

While sildenafil (Viagra) is widely prescribed for erectile dysfunction, its effect on arterial function is not established. The elastic properties of the aorta, as well as the magnitude and timing of wave reflection, are important factors for efficient performance of the cardiovascular system and have been identified as prognosticators of cardiovascular risk. A total of 24 subjects with coronary artery disease, of whom 14 were hypertensives, aged 69 +/- 8 years, were studied in a randomized, placebo-controlled, double-blind, cross-over design. Measurements lasted for 3 h after the sildenafil intake (50 mg, p.o.) or placebo. Aortic elastic properties were evaluated with carotid-femoral pulse wave velocity; wave reflection was evaluated with augmentation index and augmented pressure of the aortic pressure waveform. Pulse wave velocity decreased significantly (by 0.65 m/s, p = 0.005), denoting a decrease in aortic stiffness. Augmentation index and augmented pressure decreased significantly (by 4.47% absolute and by 4.01 mmHg; p < 0.001 and p = 0.001, respectively), denoting a decreased effect of wave reflection from the periphery. Aortic pulse pressure decreased significantly (by 6.74 mmHg, p < 0.05). An active effect of the drug on aortic wall appears to contribute to the decrease in pulse wave velocity, although other mechanisms such as a decrease of blood pressure and autonomic reflexes could also have contributed. The effect of sildenafil lasted throughout the study (3 h), being evident 30 min after drug intake. In conclusion, this study shows, for the first time, that sildenafil has a favorable effect on aortic stiffness and wave reflection in patients with coronary artery disease. This finding may have important implications for cardiovascular performance and exercise capacity during intercourse.

Topics: Aged; Aorta; Blood Pressure; Coronary Artery Disease; Cross-Over Studies; Diastole; Double-Blind Method; Elasticity; Heart Rate; Humans; Hypertension; Male; Piperazines; Pulsatile Flow; Purines; Radial Artery; Sildenafil Citrate; Sulfones; Systole; Vasodilator Agents

Our purpose was to assess the efficacy and safety of sildenafil as a treatment for erectile dysfunction in hypertensive patients, and to investigate those factors associated with a treatment failure.. Open, prospective study including 114 patients suffering from erectile dysfunction plus arterial hypertension who were evaluated by anamnesis, physical examination, blood tests including glycemia and lipidic and hormonal profiles, penile colour Doppler ultrasonography after intracavernosal prostaglandin E1 (PGE1) injection, and the Sexual Health Inventory for Men (SHIM). Efficacy of sildenafil was assessed by administering again the SHIM and by means of a global assessment questionnaire. Side effects were also recorded. Factors influencing treatment outcome were evaluated by univariate and multivariate statistical analysis.. Overall, sildenafil was effective in 59.2% of 103 eligible patients. Efficacy in patients with psychogenic erectile dysfunction was 75%, whereas in those with an organic etiology, the efficacy was 50.7%. Age, diabetes mellitus, nocturnal penile tumescence, response to intracavernosal PGE1 injection and erectile dysfunction severity (defined by the SHIM basal score) significantly influenced treatment response (p < 0.05) after an univariate analysis. The multivariate analysis, however, selected only diabetes mellitus and severity of erectile dysfunction as the prognostic factors. No severe side effects were noticed.. Sildenafil is a rather effective and well-tolerated treatment for erectile dysfunction in hypertensive patients. Baseline severity of erectile dysfunction and diabetes mellitus represent the prognostic factors most significantly associated with treatment outcome.

Topics: Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Piperazines; Prognosis; Prospective Studies; Purines; Regression Analysis; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil relaxes the muscle cells of the penis arterioles by inhibiting phosphodiesterase-type 5 (PD-5), inactivating the nitric oxide-stimulated cyclic guanosine monophosphate. We investigated whether this effect of Sildenafil is also displayed on the muscles of the hypertensive lower oesophageal sphincter (LES).. In 14 patients with symptomatic hypertensive LES, oesophageal motility was recorded by means of a low-compliance manometric system with five manometric ports for the oesophageal body and a sleeve for the sphincter. After a basal period of 60 min a tablet of Sildenafil 50 mg (group A; seven patients) or one of placebo (group B; seven patients) ground and dissolved in 20 cc of water was infused in the stomach, randomly and in double-blind manner. Recording continued for a further 60 min. Sphincter tone and pressure wave amplitude were measured each minute and the values averaged for each 5-min period for the post-infusion period of 60 min. The values of the whole post infusion period, the lowest values among the 5-min periods (nadir values) and the values of the last 5-min periods were compared with the basal values in each group, and those of group A were compared with the corresponding values of group B.. Sphincter tone and wave amplitude showed after Sildenafil a significant decrease comparable that of the basal period and the placebo. The inhibitory effect reached its maximum 10 min after the infusion and lasted approximately 1 h.. Sildenafil inhibits the lower oesophageal sphincter tone and pressure wave amplitude of patients with symptomatic hypertensive LES. These findings suggest a clinical application of PD-5 inhibitors in the treatment of spastic oesophageal motor disorders.

Topics: Adult; Double-Blind Method; Esophageal Diseases; Esophagogastric Junction; Female; Humans; Hypertension; Male; Manometry; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

As the effects of sildenafil are in part mediated by enhancing the action of nitric oxide and nitrates given acutely markedly reduce early wave reflection, we explored the effects of a single oral dose of sildenafil citrate (50 mg) on blood pressure and arterial wave reflection in treated hypertensive men in a single-blind randomised placebo controlled crossover study. Eight men (aged 57-76 years) with well controlled hypertension and erectile dysfunction and no contraindications to the use of sildenafil, were given either sildenafil 50 mg or placebo orally, with the second drug being given 2 weeks later. Blood pressure and heart rate with an automated digital oscillometric device (Omron) HEM-705 CP) and the augmentation index, a measure of arterial wave reflection in the aorta derived using radial applanation tonometry, were measured before and at 15-min intervals for 2 h thereafter. The extent of individual maximum reductions (mm Hg) from baseline in systolic (24 +/- 10 vs. 6 +/- 8, P < 0.05) and diastolic blood pressure (8 +/- 5 vs. 3 +/- 2, P < 0.05) occurred on the sildenafil study day. On average the brachial blood pressure at 75 min following sildenafil was 17/11 mm less than on the placebo day (P < 0.01). Augmentation index was also reduced significantly at 90 min (P < 0.05) suggesting reduced vascular tone in the arteries. The area under the brachial and aortic blood pressure and augmentation index time curve (by the trapezoidal rule corrected for baseline reading) was significantly lower (P < 0.05) on the sildenafil study day. The study shows that the peripheral vasodilatory effects of sildenafil, possibly related to nitric oxide, are accompanied by a fall in systemic blood pressure and reduced arterial wave reflection.

Topics: Aged; Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Diltiazem; Diuretics; Drug Interactions; Erectile Dysfunction; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Pulsatile Flow; Purines; Receptors, Angiotensin; Sildenafil Citrate; Single-Blind Method; Sulfones

To assess the acute effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication.. Post-hoc subanalysis of five, 12- or 24-week, prospective, randomized, double-blind, placebo-controlled studies.. Private-practice and academic urology clinics.. A total of 1685 men with erectile dysfunction of > or = 6 months duration, of whom 667 (sildenafil n = 406, placebo n = 261) were taking antihypertensive medication (diuretic, beta-blocker, alpha-blocker, angiotensin converting enzyme inhibitor, and/or calcium antagonist). Of the patients taking antihypertensive medication, 608 (91%) completed the studies (374 of 406 receiving sildenafil, 234 of 261 receiving placebo).. The last dose of oral sildenafil (25-200 mg) or placebo was taken at home on the morning of the final clinic visit. Patients taking antihypertensive medication maintained usual dosing schedules.. Sitting systolic (SBP)/diastolic blood pressure (DBP) and heart rate at baseline and after dosing with sildenafil or placebo (end-of-treatment visit).. Mean changes from baseline in SBP/DBP for men taking antihypertensive medication were -3.6/-1.9 mmHg for those receiving sildenafil and -0.8/-0.1 mmHg for those receiving placebo compared with -2.2/-2.0 mmHg and -0.1/0.4 mmHg, respectively, for men not taking antihypertensive medication. Mean changes from baseline in heart rate for men taking antihypertensive medication were -0.6 beats/min after sildenafil and 0.9 beats/min after placebo compared with 0.4 beats/min and -0.6 beats/min, respectively, for patients not taking antihypertensive medication. Differences in SBP, DBP, and heart rate between the patients taking and those not taking antihypertensive medication were small.. The acute, short-term effects of oral sildenafil on blood pressure and heart rate in men with erectile dysfunction were small and not likely to be clinically significant in those taking concomitant antihypertensive medication.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Drug Interactions; Erectile Dysfunction; Heart Rate; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Purines; Safety; Sildenafil Citrate; Sulfones

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)-cGMP pathway during sexual stimulation, which results in corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 microg/min and doubling every 5 minutes to a maximum rate of 40 microg/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 microg) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment, based on the occurrence of a >25 mm Hg decrease in blood pressure or the incidence of symptomatic hypotension (p <0.01). When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period. The changes in heart rate were negligible during both glyceryl trinitrate challenges. In conclusion, sildenafil potentiated the hypotensive effects of glyceryl trinitrate, an organic n

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Interactions; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nitroglycerin; Phosphodiesterase Inhibitors; Piperazines; Purines; Reference Values; Sildenafil Citrate; Sulfones; Vasodilator Agents

Forty-two Wistar rats were divided into seven groups. Hypertension was induced via oral administration of 40 mg/kg of L-NAME for 21 days. Thereafter, the hypertensive rats were treated with. The results showed that L-NAME caused a significant (. Findings presented in this study provide useful information on the antihypertensive property of

Topics: Angiotensins; Animals; Antihypertensive Agents; Antioxidants; Arginase; Fruit; Hypertension; NG-Nitroarginine Methyl Ester; Plant Extracts; Rats; Rats, Wistar; Sildenafil Citrate; Terminalia

The pulse wave response to salbutamol (PWRS) - change in augmentation index (AIx) - provides a means to assess endothelial vasodilator function in vivo . Endothelial dysfunction plays a relevant role in the pathogenesis of hypertension and cardiovascular disease and appears to underlie many of the complications of coronavirus disease 2019 (COVID-19). However, to what degree this persists after recovery is unknown.. Individuals previously hospitalized with COVID-19, those recovered from mild symptoms and seronegative controls with well known risk factors for endothelial dysfunction were studied. To assess the involvement of nitric oxide-cyclic guanosine monophosphate pathway (NO-cGMP) on PWRS, sildenafil was also administrated in a subsample.. One hundred and one participants (60 men) aged 47.8 ± 14.1 (mean ± SD) years of whom 33 were previously hospitalized with COVID-19 were recruited. Salbutamol had minimal effect on haemodynamics including blood pressure and heart rate. It reduced AIx in controls ( n  = 34) and those recovered from mild symptoms of COVID-19 ( n  = 34) but produced an increase in AIx in those previously hospitalized: mean change [95% confidence interval] -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % for controls, those recovered from mild symptoms and those previously hospitalized, respectively ( P  = 0.001). In a sub-sample ( n  = 22), sildenafil enhanced PWRS (change in AIx 0.05 [-2.15,2.24] vs. -3.96 [-7.01. -2.18], P  = 0.006) with no significant difference between hospitalized ( n  = 12) and nonhospitalized participants ( n  = 10).. In patients previously hospitalized with COVID-19, there is long-lasting impairment of endothelial function as measured by the salbutamol-induced stimulation of the NO-cGMP pathway that may contribute to cardiovascular complications.

Topics: Adrenergic Agents; Albuterol; COVID-19; Endothelium, Vascular; Humans; Hypertension; Male; Sildenafil Citrate; Vasodilation; Vasodilator Agents

Lead (Pb) reduces NO bioavailability, impairs the antioxidant system, and increases the generation of reactive oxygen species (ROS). Pb-induced oxidative stress may be responsible for the associated endothelial dysfunction. Sildenafil has shown nitric oxide (NO)-independent action, including antioxidant effects. Therefore, we examined the effects of sildenafil on oxidative stress, reductions of NO and endothelial dysfunction in Pb-induced hypertension. Wistar rats were distributed into three groups: Pb, Pb + sildenafil and Sham. Blood pressure and endothelium-dependent vascular function were recorded. We also examined biochemical determinants of lipid peroxidation and antioxidant function. ROS levels, NO metabolites and NO levels in human umbilical vein endothelial cells (HUVECs) were also evaluated. Sildenafil prevents impairment of endothelium-dependent NO-mediated vasodilation and attenuates Pb-induced hypertension, reduces ROS formation, enhances superoxide dismutase (SOD) activity and antioxidant capacity in plasma and increases NO metabolites in plasma and HUVECs culture supernatants, while no changes were found on measurement of NO released from HUVECs incubated with plasma of the Pb and Pb + sildenafil groups compared with the sham group. In conclusion, sildenafil protects against ROS-mediated inactivation of NO, thus preventing endothelial dysfunction and attenuating Pb-induced hypertension, possibly through antioxidant effects.

Topics: Animals; Antioxidants; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Lead; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Sildenafil Citrate

cGMP-dependent protein kinase 1α (PKG1α) promotes left ventricle (LV) compensation after pressure overload. PKG1-activating drugs improve heart failure (HF) outcomes but are limited by vasodilation-induced hypotension. Signaling molecules that mediate PKG1α cardiac therapeutic effects but do not promote PKG1α-induced hypotension could therefore represent improved therapeutic targets. We investigated roles of mixed lineage kinase 3 (MLK3) in mediating PKG1α effects on LV function after pressure overload and in regulating BP. In a transaortic constriction HF model, PKG activation with sildenafil preserved LV function in MLK3+/+ but not MLK3-/- littermates. MLK3 coimmunoprecipitated with PKG1α. MLK3-PKG1α cointeraction decreased in failing LVs. PKG1α phosphorylated MLK3 on Thr277/Ser281 sites required for kinase activation. MLK3-/- mice displayed hypertension and increased arterial stiffness, though PKG stimulation with sildenafil or the soluble guanylate cyclase (sGC) stimulator BAY41-2272 still reduced BP in MLK3-/- mice. MLK3 kinase inhibition with URMC-099 did not affect BP but induced LV dysfunction in mice. These data reveal MLK3 as a PKG1α substrate mediating PKG1α preservation of LV function but not acute PKG1α BP effects. Mechanistically, MLK3 kinase-dependent effects preserved LV function, whereas MLK3 kinase-independent signaling regulated BP. These findings suggest augmenting MLK3 kinase activity could preserve LV function in HF but avoid hypotension from PKG1α activation.

Topics: Animals; Aorta; Blood Pressure; Cyclic GMP-Dependent Protein Kinase Type I; Heart Failure; HEK293 Cells; Humans; Hypertension; Male; MAP Kinase Kinase Kinases; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase Kinase Kinase 11; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrroles; Sildenafil Citrate; Vascular Stiffness; Vasodilator Agents; Ventricular Dysfunction, Left

Portopulmonary hypertension (PoPH) is a clinical condition associated with end-stage liver disease, described by the coexistence of pulmonary arterial hypertension (PAH) and portal hypertension. In PoPH patients, there is a right ventricle (RV) remodeling to compensate for the increased resistance in the lung circulation. There are no studies on the effects of the PAH-targeted pharmacological treatment on the RV dimension and function. The present study summarizes our experience in patients with PoPH treated with sildenafil in a period of 6 years (from 2013 to 2019). We enrolled 64 consecutive patients identified as PoPH, all treated with sildenafil (57.6% in monotherapy; in the other cases in association with macitentan; in 19.0% with initial combination therapy). A hemodynamic invasive cardiopulmonary study was performed at baseline and after 6 months of sildenafil treatment. In our population we showed a significative improvement in RV performance, with a significant increase in RV stroke volume (+33%), RV ejection fraction (+31%) and RV stroke work index (+17.5%). We registered the reduction of the RV cavity dimension over time in all patients treated with sildenafil (RV end diastolic diameter decreased by 15% after 6 months of follow-up). Regarding diastolic function, we highlighted a very significant reduction in RV end-diastolic pressure (-50% concerning baseline). Sildenafil was effective both when used as monotherapy and in combination with macitentan. In conclusion, Sildenafil had a positive impact on RV systolic and diastolic function in patients with PoPH and was able to conditionate the reverse remodeling of the RV.

Topics: Humans; Hypertension; Pulmonary Arterial Hypertension; Sildenafil Citrate; Stroke Volume; Ventricular Dysfunction, Right; Ventricular Remodeling

Preeclampsia is a disorder of pregnancy with accompanying high disease and economic burdens in the United States. Evidence supporting longstanding effects of preeclampsia on the offspring of affected pregnancies is high, but the effects of current antihypertensive therapies for preeclampsia on cardio-renal outcomes are largely unknown. The purpose of this study was to test the hypothesis that sildenafil citrate, a phosphodiesterase-5 inhibitor, reprograms the risk of hypertension and kidney disease in offspring of preeclamptic pregnancies by altering responses to secondary stressors.. Dahl SS/Jr rats on a 0.3% NaCl diet were mated. At gestational day 10, pregnant dams were randomized to vehicle diet or diet with sildenafil (50 mg/kg per day), which was continued until birth. Pups were weaned at 4 weeks of age and allowed to age on a 0.3% NaCl diet until 3 months of age. At this point, pups were randomized into three groups: baseline or no intervention, 2% NaCl diet challenge for 4 weeks, or a subpressor infusion of angiotensin II (200 ng/kg per minute) for 2 weeks.. There were no differences among maternal treatment groups at baseline. Upon introduction of 2% NaCl diet, male offspring of sildenafil-treated dams exhibited an attenuated rise in BP; however, this protection was not observed during angiotensin II infusion.. Our findings indicate that intrapartum sildenafil does not reprogram the risk of hypertension and kidney disease in offspring of preeclamptic pregnancies.

Topics: Animals; Female; Hypertension; Male; Pre-Eclampsia; Pregnancy; Rats; Rats, Inbred Dahl; Renal Insufficiency, Chronic; Sildenafil Citrate

Arterial hypertension is a condition associated with endothelial dysfunction, accompanied by an imbalance in the production of reactive oxygen species (ROS) and NO. The aim of this study was to investigate and elucidate the possible mechanisms of sildenafil, a selective phosphodiesterase-5 inhibitor, actions on endothelial function in aortas from spontaneously hypertensive rats (SHR). SHR treated with sildenafil (40 mg/kg/day, p.o., 3 weeks) were compared to untreated SHR and Wistar-Kyoto (WKY) rats. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and vascular reactivity was determined in isolated rat aortic rings. Circulating endothelial progenitor cells and systemic ROS were measured by flow cytometry. Plasmatic total antioxidant capacity, NO production and aorta lipid peroxidation were determined by spectrophotometry. Scanning electron microscopy was used for structural analysis of the endothelial surface. Sildenafil reduced high SBP and partially restored the vasodilator response to acetylcholine and sodium nitroprusside in SHR aortic rings. Using selective inhibitors, our experiments revealed an augmented participation of NO, with a simultaneous decrease of oxidative stress and of cyclooxygenase-1 (COX-1)-derived prostanoids contribution in the endothelium-dependent vasodilation in sildenafil-treated SHR compared to non-treated SHR. Also, the relaxant responses to sildenafil and 8-Br-cGMP were normalized in sildenafil-treated SHR and sildenafil restored the pro-oxidant/antioxidant balance and the endothelial architecture. In conclusion, sildenafil reverses endothelial dysfunction in SHR by improving vascular relaxation to acetylcholine with increased NO bioavailability, reducing the oxidative stress and COX-1 prostanoids, and improving cGMP/PKG signaling. Also, sildenafil reduces structural endothelial damage. Thus, sildenafil is a promising novel pharmacologic strategy to treat endothelial dysfunction in hypertensive states reinforcing its potential role as adjuvant in the pharmacotherapy of cardiovascular diseases.

Topics: Animals; Antihypertensive Agents; Aorta; Blood Pressure; Cyclic GMP; Cyclooxygenase 1; Disease Models, Animal; Endothelial Progenitor Cells; Endothelium, Vascular; Hypertension; Lipid Peroxidation; Male; Membrane Proteins; NADP; Nitric Oxide; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Sildenafil Citrate; Vasodilation; Vasodilator Agents

In trying to understand the biochemical mechanism involved in the recent pandemic COVID-19, there is currently growing interest in angiotensin-converting enzyme II (ACE2). Nevertheless, the attempts to counteract COVID-19 interference with this enzymatic cascade are frustrating, and the results have thus far been inconclusive. Let's start again by considering the involved factors in an alternative way: we could postulate that COVID-19 could be more aggressive/fatal due to a high level of "basal" inflammation with low Nitric Oxide (NO) levels in hypertensive, diabetic and obese patients. Interestingly, the "protective" effects of several factors (such as estrogens) may play a role by increasing the formation of endogenous NO. From a therapeutic point of view, phosphodiesterase type 5 inhibitors such as oral Tadalafil, could be used in order to increase the basal NO levels. In this way, we don't fight the virus, but we may be able to mitigate its effects.

Topics: Angiotensin-Converting Enzyme 2; Animals; Betacoronavirus; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Estrogens; Humans; Hypertension; Inflammation; Interleukins; Models, Animal; Models, Biological; Nitric Oxide; Obesity; Off-Label Use; Pandemics; Peptidyl-Dipeptidase A; Phosphodiesterase 5 Inhibitors; Pneumonia, Viral; Receptors, Virus; SARS-CoV-2; Sildenafil Citrate; Tadalafil

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKA

Topics: Acetates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiomegaly; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Desoxycorticosterone; Female; Hyperglycemia; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mineralocorticoids; Phosphodiesterase 5 Inhibitors; Renal Insufficiency; Sildenafil Citrate; Sodium Chloride; Tyramine

Spontaneously hypertensive rats (SHR) exhibit impaired endothelial vasodilation and enhanced vasoconstriction. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Sild) potentiates the nitric oxide (NO)-mediated effects exerting antioxidative and anti-inflammatory actions. In the present study, we hypothesized that Sild could improve endothelial function in SHR.. Male rats were treated daily for 60 days by oral gavage with Sild (45 mg/kg) before the onset of the hypertensive state (pre-hypertensive protocol). The aortic relaxation to acetylcholine (ACh), sodium nitroprusside (SNP) and the phenylephrine (Phe)-induced contraction was evaluated in SHR. Protein expression of eNOS, p-eNOS, caveolin, COX-1, COX-2, ERK and p-ERK was measured by Western blot.. Resting blood pressure was not modified by Sild administration. Treatment with Sild did not alter the relaxation response to SNP but improved the ACh-induced relaxation and reduced Phe-induced contraction in aortic rings from SHR. This protective effect of Sild could be attributed to reduced superoxide anions (O. Sild improves endothelial function in SHR aorta without affecting resting blood pressure values. These results indicate that PDE5 inhibition has a potential role in the improvement of vascular function and could be an adjuvant in the treatment of essential hypertension.

Topics: Animals; Cardiomegaly; Cells, Cultured; Cyclooxygenase 2; Endothelium, Vascular; Hypertension; Male; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred SHR; Sildenafil Citrate; Vasodilator Agents

The primary aim of this study was to evaluate penile endothelial microvascular function in patients with primary arterial hypertension and age-matched normotensive subjects using laser speckle contrast imaging (LSCI). Additionally, we analyzed the acute penile microvascular effects induced by oral phosphodiesterase type 5 inhibitor (sildenafil; SIL) administration. Endothelium-dependent microvascular reactivity was evaluated in the penises and forearms of hypertensive patients (aged 58.8±6.6 years, n=34) and age-matched healthy volunteers (n=33) at rest and 60 min following oral SIL (100 mg) administration. LSCI was coupled with cutaneous acetylcholine (ACh) iontophoresis using increasing anodal currents. Basal penile cutaneous vascular conductance (CVC) values were not significantly different between control subjects and hypertensive individuals. Penile CVC values increased significantly after SIL administration in control (P<0.0001) and hypertensive (P<0.0001) subjects. Peak CVC values were not different between the two groups during penile ACh iontophoresis before SIL administration (P=0.2052). Peak CVC values were higher in control subjects than in hypertensive subjects after SIL administration (P=0.0427). Penile endothelium-dependent microvascular function is, to some extent, preserved in patients presenting with primary arterial hypertension under effective anti-hypertensive treatment. LSCI may be a valuable non-invasive tool for the evaluation of penile vascular responses to phosphodiesterase type 5 inhibitor.

Topics: Aged; Case-Control Studies; Endothelium, Vascular; Healthy Volunteers; Humans; Hypertension; Laser-Doppler Flowmetry; Male; Microcirculation; Middle Aged; Penis; Phosphodiesterase 5 Inhibitors; Regional Blood Flow; Sildenafil Citrate; Vasodilation

Stimulation of thermogenic pathways appears to be a promising approach to find new ways of tackling metabolic diseases like obesity and diabetes mellitus type 2. Thermogenic, weight reducing and insulin sensitizing effects of phosphodiesterase 5 (PDE 5) inhibitors have recently been postulated, suggesting that modulators of endogenous cGMP signaling have the therapeutic potential to treat metabolic disorders. However, most studies have been performed in vitro or in animals that were not glucose intolerant. We, thus, aimed to test the metabolic effects of the PDE 5 inhibitor sildenafil by treating diet-induced obese (DIO) mice orally for 8 days. Surprisingly, our results revealed no changes in body temperature, brown adipose tissue (BAT) thermogenesis and gene expression in BAT and inguinal white adipose tissue (iWAT), thus excluding a thermogenic or 'browning' effect of sildenafil in preexisting obesity. In contrast, sildenafil-treated DIO mice displayed changes in liver metabolism and glucose homeostasis resulting in impaired glucose tolerance (P < 0.05), demonstrating for the first time an unfavorable metabolic effect of increased hepatic cGMP signaling in obesity. As sildenafil is commonly prescribed to treat pulmonary arterial hypertension and erectile dysfunction in diabetic and/or obese patients, follow up studies are urgently required to re-evaluate the drug safety.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Blood Glucose; Cyclic GMP; Erectile Dysfunction; Glucose Intolerance; Homeostasis; Hypertension; Liver; Male; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphodiesterase 5 Inhibitors; Signal Transduction; Sildenafil Citrate; Thermogenesis

By acting on multiple targets and promoting diverse actions, angiotensin II (Ang II) plays a pivotal role in vascular function. Recent studies suggested that phosphodiesterase-5 (PDE-5) inhibitors exhibit therapeutic effects in cardiovascular diseases. Here, the effects of sildenafil on vascular disturbances were analyzed in a mouse model of Ang II-induced hypertension.. Male C57BL/6 mice were used as untreated animals (control) or infused with Ang II (1000 ηg/kg/min) for 28 days and treated with sildenafil (40 mg/kg/min) or vehicle (Ang II) during the last two weeks. After 4 weeks, the Ang II animals exhibited a high systolic blood pressure (186±3 mmHg vs. 127±3 mmHg for control mice), which was attenuated by sildenafil (163±7 mmHg). The mesenteric vessels from the Ang II animals revealed damage to the endothelial layer, an increase in the cross-section area (1.9-fold) and vascular cell production of peroxynitrite (512±13 a.u.), which was ameliorated in the Ang II-Sil group (1.2-fold and 400±17 a.u.). Analysis of the vascular responsiveness showed an increased contractility response to norepinephrine in Ang II animals (Rmax: 70%), which was abolished by sildenafil through increased nitric oxide (NO) bioavailability and decreased reactive oxygen species (ROS) and vasoconstrictor prostanoids.. Sildenafil attenuates the morphofunctional deleterious effects of Ang II on resistance vessels. The benefits of sildenafil seem to occur through restoring the balance of ROS/NO/eicosanoids. Therefore, this study opened new avenues for further clinical targeting of the treatment of cardiovascular diseases related to activation of the renin-angiotensin system.

Topics: Angiotensin II; Animals; Hypertension; Male; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Reactive Oxygen Species; Sildenafil Citrate

To evaluate treatment response in men with erectile dysfunction (ED) and concomitant comorbidities.. Data were pooled from 42 placebo-controlled, flexible-dose sildenafil trials. In most trials, the sildenafil dose was 50 mg, taken ~1 hour before sexual activity but not more than once daily, with adjustment to 100 or 25 mg as needed. The overall population (N=9413) was stratified by age (<45, 46-64, ≥65 years). Treatment response was defined as a minimal clinically important difference (MCID) from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score of >2, >5 and >7 for men with mild, moderate and severe ED at baseline, respectively, or an IIEF-EF domain score ≥26 (no ED) at end-point.. In the overall population, treatment response using the IIEF-EF MCID definition was significantly greater (P<.0001) with sildenafil vs placebo in men with no comorbidity (77% vs 33%), cardiovascular disease/hypertension only (71% vs 27%), diabetes only (63% vs 24%) or depression only (78% vs 29%). Using an IIEF-EF score ≥26, treatment response was significantly greater (P<.0001) with sildenafil vs placebo in men with no comorbidity (49% vs 17%), cardiovascular disease/hypertension only (48% vs 12%), diabetes only (40% vs 12%) or depression only (60% vs 17%). With each definition, the treatment response for each age and comorbidity was significantly greater (P≤.0065) with sildenafil vs placebo.. The treatment response was significantly greater with sildenafil vs placebo in men with ED and each comorbidity regardless of age.

Topics: Aged; Cardiovascular Diseases; Depression; Diabetes Mellitus, Type 2; Erectile Dysfunction; Health Status; Humans; Hypertension; Male; Middle Aged; Remission Induction; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Vasodilator Agents

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Male; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Renal Artery; Renal Circulation; Sildenafil Citrate; Vasodilation; Vasodilator Agents; Vinca Alkaloids

Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKIβ only in smooth muscle (βRM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, βRM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged βRM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg ⋅ kg(-1) ⋅ d(-1)) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in βRM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGFβ, and CTGF mRNA in Ctr but not in βRM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.

Topics: Angiotensin II; Animals; Cardiomegaly; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic Nucleotide Phosphodiesterases, Type 5; Fibrosis; Genetic Markers; Hypertension; Mice; Muscle, Smooth; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasoconstrictor Agents

Sildenafil treatment ameliorates progressive renal injury resulting from extensive renal ablation; however, modifications induced by sildenafil in the glomerular hemodynamic pathophysiology of the remnant kidney have not been investigated.. To determine the effects of sildenafil in the glomerular microcirculation and their relation to histological damage in the renal ablation model.. Micropuncture studies were performed 60 days after 5/6 nephrectomy in rats that received no treatment, sildenafil (5 mg/kg/day) and reserpine, hydralazine and hydrochlorothiazide to maintain the blood pressure within normal levels. Sham-operated rats untreated and treated with sildenafil served as controls.. As expected, renal ablation induced systemic and glomerular hypertension, hyperfiltration, proteinuria, glomerulosclerosis and tubulointerstitial inflammatory damage in the remnant kidney. Sildenafil treatment prevented single-nephron hyperfiltration and hypertension, suppressed renal arteriolar remodeling, ameliorated systemic hypertension and proteinuria, increased urinary excretion of cGMP and NO(2)(-)/NO(3)(-), decreased oxidative stress and improved histological damage in the remnant kidney. Normalization blood pressure with reserpine, hydralazine and hydrochlorothiazide did not modify glomerular hemodynamics, proteinuria or histological changes induced by renal ablation.. Beneficial effects of sildenafil in the remnant kidney are associated with a reduction in the arteriolar remodeling, renal inflammatory changes and prevention of changes in the glomerular microcirculation.

Topics: Animals; Hypertension; Kidney Glomerulus; Male; Nephrectomy; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Preeclampsia and fetal growth restriction are responsible for the majority of maternal and perinatal morbidity and mortality associated with complicated pregnancies. Although their etiologies are complex and multifactorial, both are associated with increased uterine artery resistance. Sildenafil citrate is able to rescue the dysfunction observed ex vivo in uterine arteries of women with preeclampsia. The ability of sildenafil citrate to increase uterine artery vasodilation, thereby decreasing uterine artery resistance and, hence, ameliorated preeclampsia and fetal growth restriction, was tested in a mouse model of preeclampsia, the catechol-O-methyl transferase knockout mouse (COMT(-/-)). COMT(-/-) and C57BL/6J mice were treated (0.2 mg/mL in drinking water, n=6-12) from gestational day 12.5 to 18.5. Measures of pup growth, including body weight, crown/rump length, and abdominal circumference, were reduced in COMT(-/-) mice; this was normalized after treatment with Sildenafil. COMT(-/-) mice also demonstrated abnormal umbilical Doppler waveforms, including reverse arterial blood flow velocity. This was normalized after treatment with Sildenafil. Abnormal uterine artery Doppler waveforms were not demonstrated in COMT(-/-) mice, although ex vivo responses of uterine arteries to phenylephrine were increased; moreover, treatment with Sildenafil did improve ex vivo sensitivity to an endothelium-dependent vasodilator. The data presented here demonstrate that Sildenafil can rescue pup growth and improve abnormal umbilical Doppler waveforms, providing support for a potential new therapeutic strategy targeting fetal growth restriction.

Topics: Animals; Blood Flow Velocity; Catechol O-Methyltransferase; Disease Models, Animal; Female; Fetal Growth Retardation; Hypertension; Mice; Mice, Inbred C57BL; Mice, Knockout; Myometrium; Piperazines; Pre-Eclampsia; Pregnancy; Proteinuria; Purines; Sildenafil Citrate; Sulfones; Ultrasonography, Doppler; Umbilical Arteries; Vasodilation; Vasodilator Agents

Sildenafil, the first selective phosphodiesterase-5 (PDE5) inhibitor to be widely used for treating erectile dysfunction, has been investigated with regard to its cardioand renoprotective effects in animal models. This study further investigated the renoprotective effects of sildenafil and their molecular mechanisms in deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats.. DOCA strips (200 mg/kg) were implanted in rats 1 week after unilateral nephrectomy. These rats were fed on a control diet, with or without sildenafil (50 mg·kg(-1)day(-1)), for 2 weeks. Systolic blood pressure (SBP) was measured by the tail cuff method, and the urinary albumin-to-creatinine ratio (ACR) was calculated. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson's trichrome stain. Renal expression of ED-1, transforming growth factor-β1 (TGF-β1), Bax, and Bcl-2 were determined by semiquantitative immunoblotting, polymerase chain reaction (PCR), and immunohistochemistry. TUNEL staining was used for detecting apoptotic cells.. The increased SBP in DSH rats was not attenuated by sildenafil treatment. The decreased creatinine clearance and increased ACR in DSH rats, compared with control animals, were attenuated by sildenafil treatment. Further, sildenafil treatment attenuated glomerulosclerosis and tubulointerstitial fibrosis in DSH rats and counteracted the increased expression of ED-1, TGF-β1, and Bax and the decreased expression of Bcl-2 in the kidneys of these rats. The increase in the number of apoptotic cells in DSH rats was attenuated by sildenafil treatment.. Sildenafil effectively prevented the progression of renal injury in DSH rats via its anti-inflammatory, antifibrotic, and antiapoptotic effects.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Disease Progression; Hypertension; Kidney; Kidney Diseases; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Proto-Oncogene Proteins c-bcl-2; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Transforming Growth Factor beta1

Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE) 1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic guanosine 3' 5'-monophosphate (cGMP), and contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng·min(-1)) or saline for 14 days. Phenylephrine (PE)-induced contractions were increased in aorta (E(max)168% ± 8% vs 136% ± 4%) and small mesenteric arteries (SMA; E(max)170% ± 6% vs 143% ± 3%) from Ang II-infused rats compared to control. PDE1 inhibition with vinpocetine (10 μmol/L) reduced PE-induced contraction in aortas from Ang II rats (E(max)94% ± 12%) but not in controls (154% ± 7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (-log of half maximal effective concentration 5.1 ± 0.1 vs 5.9 ± 0.06), but not in controls (6.0 ± 0.03 vs 6.1 ± 0.04). Sildenafil (10 μmol/L), a PDE5 inhibitor, reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1 μmol/L), and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (E(max)82% ± 12% vs 445 ± 5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation compared to control (-log of half maximal effective concentration 6.1 ± 0.3 vs 5.3 ± 0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from Ang II, contributing to increased contractile responsiveness.

Topics: Analysis of Variance; Angiotensin II; Animals; Antihypertensive Agents; Arteries; Blood Pressure; Blotting, Western; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Dose-Response Relationship, Drug; Hypertension; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasoconstriction; Vinca Alkaloids

The effectiveness and tolerability of 12 weeks of open-label treatment with sildenafil citrate for erectile dysfunction (ED) associated with a diagnosis of diabetes mellitus and/or hypertension were assessed in clinical practice in three Middle Eastern countries. The dose was initially 50 mg and was adjusted by the physician as needed (permissible dose range 25 - 100 mg). Total mean ± SD score on the five-item version of the International Index of Erectile Function (severe ED, score 0 - 7; no ED, score 22 - 25) was 13.6 ± 5.7 at baseline (4556 patients) and increased significantly to 21.7 ± 4.1 at week 12. Global effectiveness was rated as good or very good by 91.4% of patients, 93.9% rating their sexual activity as spontaneous and 91.4% as natural. Discontinuation of sildenafil due to adverse events was infrequent (0.5%). Tolerability was rated as good or very good by 95.7% of patients. It is concluded that sildenafil was a well-tolerated and highly effective treatment of ED in outpatients with diabetes and/or hypertension from the three Middle Eastern countries studied.

Topics: Aged; Diabetes Complications; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Middle East; Outpatients; Phosphodiesterase 5 Inhibitors; Piperazines; Practice Patterns, Physicians'; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

We investigated the influence of sildenafil on cardiac contractility and diastolic relaxation and examined the distribution of phosphodiesterase-5 in the hearts of hypertensive rats that were treated with by NG-nitro-L-arginine methyl ester (L-NAME).. Male Wistar rats were treated with L-NAME and/or sildenafil for eight weeks. The Langendorff method was used to examine the effects of sildenafil on cardiac contractility and diastolic relaxation. The presence and location of phosphodiesterase-5 and phosphodiesterase-3 were assessed by immunohistochemistry, and cGMP plasma levels were measured by ELISA.. In isolated hearts, sildenafil prevented the reduction of diastolic relaxation (dP/dt) that was induced by L-NAME. In addition, phosphodiesterase-5 immunoreactivity was localized in the intercalated discs between the myocardial cells. The staining intensity was reduced by L-NAME, and sildenafil treatment abolished this reduction. Consistent with these results, the plasma levels of cGMP were decreased in the L-NAME-treated rats but not in rats that were treated with L-NAME + sildenafil.. The sildenafil-induced attenuation of the deleterious hemodynamic and cardiac morphological effects of L-NAME in cardiac myocytes is mediated (at least in part) by the inhibition of phosphodiesterase-5.

Topics: Animals; Arterioles; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 5; Diastole; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Heart; Hypertension; Male; Myocytes, Cardiac; NG-Nitroarginine Methyl Ester; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Time Factors

In vitro studies suggest that phosphorylation of titin reduces myocyte/myofiber stiffness. Titin can be phosphorylated by cGMP-activated protein kinase. Intracellular cGMP production is stimulated by B-type natriuretic peptide (BNP) and degraded by phosphodiesterases, including phosphodiesterase-5A. We hypothesized that a phosphodiesterase-5A inhibitor (sildenafil) alone or in combination with BNP would increase left ventricular diastolic distensibility by phosphorylating titin.. Eight elderly dogs with experimental hypertension and 4 young normal dogs underwent measurement of the end-diastolic pressure-volume relationship during caval occlusion at baseline, after sildenafil, and BNP infusion. To assess diastolic distensibility independently of load/extrinsic forces, the end-diastolic volume at a common end-diastolic pressure on the sequential end-diastolic pressure-volume relationships was measured (left ventricular capacitance). In a separate group of dogs (n=7 old hypertensive and 7 young normal), serial full-thickness left ventricular biopsies were harvested from the beating heart during identical infusions to measure myofilament protein phosphorylation. Plasma cGMP increased with sildenafil and further with BNP (7.31±2.37 to 26.9±10.3 to 70.3±8.1 pmol/mL; P<0.001). Left ventricular diastolic capacitance increased with sildenafil and further with BNP (51.4±16.9 to 53.7±16.8 to 60.0±19.4 mL; P<0.001). Changes were similar in old hypertensive and young normal dogs. There were no effects on phosphorylation of troponin I, troponin T, phospholamban, or myosin light chain-1 or -2. Titin phosphorylation increased with sildenafil and BNP, whereas titin-based cardiomyocyte stiffness decreased.. Short-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.

Topics: Age Factors; Aging; Animals; Biopsy; Compliance; Connectin; Cyclic GMP; Diastole; Dogs; Hypertension; Muscle Proteins; Myocytes, Cardiac; Natriuretic Peptide, Brain; Phosphorylation; Piperazines; Protein Kinases; Purines; Sarcomeres; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventricular Function, Left; Ventricular Pressure

Aetiology (case control) Level of Evidence 3b OBJECTIVE To evaluate the effect of N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)-5 inhibitor, sildenafil, can reverse the effects of nitric oxide (NO) deficiency, as HT is a risk factor for erectile dysfunction (ED) and the NO synthase (NOS) inhibitor L-NAME induces NO-deficient HT.. Thirty-six adult Sprague-Dawley male rats were divided into three groups, i.e. a control, L-NAME-HT (40 mg/rat/day in the drinking water for 4 weeks), and sildenafil-treated L-NAME-HT (1.5 mg/rat/day sildenafil, by oral gavage concomitantly with L-NAME). The erectile response expressed as a ratio of intracavernosal pressure (ICP)/mean arterial pressure (MAP), evaluated after electrical stimulation of the right cavernous nerve. The isometric tension of corpus cavernosum smooth muscle (CCSM) was measured in organ-bath experiments. NOS expression was determined immunohistochemically for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein. cGMP levels were evaluated by enzyme-linked immunosorbent assay.. The erectile response was diminished in the HT group. Nitrergic and endothelium-dependent relaxation was reduced, while the relaxation response to sodium nitroprusside and contractile response to phenylephrine were not altered in CCSM from L-NAME-treated rats. HT rats showed decreased expression of nNOS, whereas eNOS and iNOS protein expression was increased. Sildenafil partly restored endothelial and molecular changes in CCSM from HT rats, but did not reverse the decreased erectile response, even as cGMP levels returned to normal levels.. Sildenafil treatment did not correct the ED in L-NAME-treated HT rats. Under sustained high blood pressure, up-regulation of PDE5 expression failed to reverse the depletion of neuronal NO and/or impaired nNOS activity. However, endothelium-dependent relaxation was restored. Drug targeting of neuronal dysfunction might delay the onset of ED in HT.

Topics: Animals; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Erectile Dysfunction; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Up-Regulation

The regulation of arterial contractility is essential for blood pressure control. The GTPase RhoA promotes vasoconstriction by modulating the cytoskeleton of vascular smooth muscle cells. Whether other Rho/Rac pathways contribute to blood pressure regulation remains unknown. By studying a hypertensive knockout mouse lacking the Rho/Rac activator Vav2, we have discovered a new signaling pathway involving Vav2, the GTPase Rac1, and the serine/threonine kinase Pak that contributes to nitric oxide-triggered blood vessel relaxation and normotensia. This pathway mediated the Pak-dependent inhibition of phosphodiesterase type 5, a process that favored RhoA inactivation and the subsequent depolymerization of the F-actin cytoskeleton in vascular smooth muscle cells. The inhibition of phosphodiesterase type 5 required its physical interaction with autophosphorylated Pak1 but, unexpectedly, occurred without detectable transphosphorylation events between those 2 proteins. The administration of phosphodiesterase type 5 inhibitors prevented the development of hypertension and cardiovascular disease in Vav2-deficient animals, demonstrating the involvement of this new pathway in blood pressure regulation. Taken together, these results unveil one cause of the cardiovascular phenotype of Vav2-knockout mice, identify a new Rac1/Pak1 signaling pathway, and provide a mechanistic framework for better understanding blood pressure control in physiological and pathological states.

Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Hypertension; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neuropeptides; Nitric Oxide; p21-Activated Kinases; Phosphodiesterase 5 Inhibitors; Piperazines; Proto-Oncogene Proteins c-vav; Purines; rac GTP-Binding Proteins; rac1 GTP-Binding Protein; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Sildenafil Citrate; Sulfones; Vasodilation

Arterial hypertension is one of the major diseases in industrial countries and a major cause of mortality. One of the main vascular factors responsible for the relaxation of blood vessels and regulation of blood pressure is nitric oxide (NO). NO acts predominantly via NO-sensitive guanylyl cyclase (NO-GC), which is made up of 2 different subunits (alpha and beta). Deletion of the beta(1) subunit leads to a global NO-GC knockout, and these mice are hypertensive. However, global deletion of NO-GC in mice does not allow identification of the cell/tissue type responsible for the elevated blood pressure.. To determine the relative contribution of smooth muscle cells to the hypertension seen in NO-GC knockout mice, we generated smooth muscle-specific knockout mice for the beta(1) subunit of NO-GC using a tamoxifen-inducible system. Male mice were investigated because the Cre transgene used is located on the Y chromosome. Tamoxifen injection led to a rapid reduction of NO-GC expression in smooth muscle but did not affect that in other tissues. Parallel to a reduction in NO-induced cGMP accumulation, NO-induced relaxation of aortic smooth muscle was gradually lost after induction by tamoxifen. Concomitantly, these animals developed hypertension within 3 to 4 weeks.. We generated a model in which the development of hypertension can be visualized over time by deletion of a single gene in smooth muscle cells. In sum, our data provide evidence that deletion of NO-GC solely in smooth muscle is sufficient to cause hypertension.

Topics: Animals; Blood Platelets; Blood Pressure; Brain; Cyclic GMP; Disease Models, Animal; Endothelium-Dependent Relaxing Factors; Gene Expression; Guanylate Cyclase; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Protein Subunits; Purines; Receptors, Cytoplasmic and Nuclear; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfones; Tamoxifen; Transgenes; Vasodilation

Nitric oxide (NO) availability plays a critical role in the regulation of blood pressure, endothelial function and arterial structure. Many of the biological actions of NO are mediated by 3'5'-guanosine monophosphate (cGMP), which is rapidly degraded by cGMP phosphodiesterase (PDE). Short-term cardiovascular effects of PDE inhibitors have been studied but the changes resulting from their chronic administration in hypertension have not been evaluated. We investigated if retarding the degradation of cGMP by long-term inhibition of PDE-5 would have beneficial consequences in spontaneously hypertensive rats (SHR), a commonly used experimental model of human essential hypertension.. Subgroups of hypertensive 13-week-old male SHR and normotensive Wistar-Kyoto rats were treated with sildenafil, 2.5 mg/kg/day, or vehicle, by gastric gavage for 6 months.. As expected, the untreated SHR had endothelial dysfunction and a steady increment of the blood pressure. In contrast, chronic sildenafil administration reversed endothelial dysfunction, reduced renal oxidative stress and renal macrophage accumulation, and ameliorated the severity of hypertension in SHR.. These results demonstrate beneficial effects of long-term PDE-5 inhibition in SHR and suggest that its use as an adjunct therapy in essential hypertension should be investigated.

Topics: Animals; Endothelium, Vascular; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Inbred SHR; Sildenafil Citrate; Sulfones

We hypothesize that sildenafil attenuates pulmonary hypertension through suppressing pulmonary vascular remodeling. Thirty male adult Sprague-Dawley rats were randomized to receive saline injection (Group 1), subcutaneous monocrotaline (MCT) (60 mg/kg) (Group 2), and MCT plus oral sildenafil (30 g/kg per day) (Group 3) 5 days after MCT administration. By Day 35, Western blot showed lower connexin43 and membranous protein kinase C epsilon expressions but higher oxidative stress in right ventricle in Group 2 compared with the other groups. Additionally, pulmonary Smad1/5 was lowest, whereas connexin43 and Smad3 were highest in Group 2. Pulmonary mRNA expressions of tumor necrosis factor-alpha, caspase-3, plasminogen activator inhibitor-1, and transforming growth factor-beta were higher, whereas bone morphogenetic protein Type II receptor, Bcl-2, and endothelial nitric oxide synthase were lower in Group 2 than in the other groups. Similarly, mRNA expressions of tumor necrosis factor-alpha, caspase-3, and beta-myosin heavy chain were increased, whereas Bcl-2, endothelial nitric oxide synthase, and alpha-myosin heavy chain expressions in right ventricle were reduced in Group 2 compared with the other groups. Number of lung arterioles was lowest, whereas number of arterioles with muscularization of the medial layer was highest in Group 2. Right ventricle systolic pressure and weight were elevated in Group 2 compared with the other groups. In conclusion, sildenafil effectively alleviates MCT-induced pulmonary hypertension through suppressing pulmonary vascular remodeling.

Topics: Animals; Arterioles; Blood Vessels; Caspase 3; Connexin 43; Hypertension; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Nitric Oxide Synthase Type III; Piperazines; Purines; Random Allocation; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Tumor Necrosis Factor-alpha; Ventricular Myosins

Topics: Adolescent; Antihypertensive Agents; Bosentan; Child; Eisenmenger Complex; Endothelin A Receptor Antagonists; Exercise Test; Humans; Hypertension; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones

Hypertension (HTN) is a risk factor for erectile dysfunction, but its effect on vas deferens (VD) contractility and the ejaculatory response has not been delineated. NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, was used for induction of nitric oxide (NO)-deficient HTN. Our aim was to evaluate the effects of L-NAME-induced HTN on rat VD contractility and to determine whether sildenafil affects VD contractility. A total of 36 male rats were divided into (1) control, (2) L-NAME-HTN, (3) sildenafil treated L-NAME-HTN groups. Group 2 was treated with L-NAME (40 mg kg(-1) per day) in drinking water for 4 weeks. Group 3 received sildenafil (1.5 mg kg(-1) per day, by oral gavage) concomitantly with L-NAME. The prostatic portion of the VD was subjected to electrical field stimulation (EFS, 1-20 Hz), and the P2X(1) agonist alpha,beta-methylene ATP (alpha,beta-meATP, 100 micromol L(-1)-1 micromol L(-1)) and the alpha1-adrenoceptor agonist phenylephrine (Phe, 100 micromol L(-1)-1 mmol L(-1)) were used to construct concentration-response curves. These experiments were repeated in the presence of P2X receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 30 micromol L(-1)). VD contractions in response to EFS, alpha,beta-meATP and Phe were significantly enhanced by L-NAME. Sildenafil treatment in the L-NAME group improved the contractile response of VD to EFS (20 Hz). In the presence of PPADS, the enhanced contractile response of VD to EFS and alpha,beta-meATP in hypertensive rats was reversed. In the rat model of chronic NO depletion, the purinergic and adrenergic components and EFS affect VD contractility. The VD contractile response may be mediated more by the purinergic system than the adrenergic system, and sildenafil may alter the ejaculatory response in men with PE.

Topics: Adenosine Triphosphate; Animals; Electric Stimulation; Enzyme Inhibitors; Hypertension; Male; Muscle Contraction; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Phenylephrine; Piperazines; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Purines; Pyridoxal Phosphate; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2X; Receptors, Purinergic P2X3; Sildenafil Citrate; Sulfones; Vas Deferens; Vasodilator Agents

Cyclic GMP (cGMP)-specific phosphodiesterase 5 (PDE5) inhibition by sildenafil (SIL) activates myocardial cGMP-dependent protein kinase G (PKG) and blunts cardiac hypertrophy. To date, the only documented target of PKG in myocardium is the serine-threonine phosphatase calcineurin (Cn), which is central to pathological cardiac hypertrophy. We tested whether Cn suppression is necessary in order to observe anti-hypertrophic effects of SIL.. Mice lacking the Cn-Abeta subunit (CnAbeta(-/-)) and wild-type (WT) controls were subjected to transverse aorta constriction (TAC) with or without SIL (200 mg/kg/day, p.o.) for 3 weeks. TAC-induced elevation of Cn expression and activity in WT was absent in CnAbeta(-/-) hearts, and the latter accordingly developed less cardiac hypertrophy (50 vs. 100% increase in heart weight/tibia length, P < 0.03) and chamber dilation. SIL remained effective in CnAbeta(-/-) mice, increasing PKG activity similarly as in WT, suppressing hypertrophy and fetal gene expression, and enhancing heart function without altering afterload. TAC-stimulated calcium-calmodulin kinase II, Akt, and glycogen synthase kinase 3beta in both groups (the first rising more in CnAbeta(-/-) hearts), and SIL also suppressed these similarly. Activation of extracellular signal-regulated kinase observed in WT-TAC but not CnAbeta(-/-) hearts was also suppressed by SIL.. PDE5A inhibition and its accompanying PKG activation blunt hypertrophy and improve heart function even without Cn activation. This occurs by its modulation of several alternative pathways which may result from concomitant distal targeting, or activity against a common proximal node.

Topics: Animals; Calcineurin; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomegaly; Cyclic GMP-Dependent Protein Kinases; Extracellular Signal-Regulated MAP Kinases; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hypertension; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. Gq protein-coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial Gq signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by Gq activation, induced a normal cardiac response, while Rgs2 deletion in Galphaq-overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing Gq-stimulated vascular contraction. In normal mice, but not Rgs2-/- mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppressed maladaptive cardiac hypertrophy, inhibiting Gq-coupled stimuli. Importantly, PKG was similarly activated by PDE5 inhibition in myocardium from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2-/- myocytes than in controls and was unaffected by PDE5 inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors.

Topics: Animals; Cardiomegaly; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic GMP-Dependent Protein Kinases; GTP-Binding Protein alpha Subunits, Gq-G11; Hypertension; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; RGS Proteins; Sildenafil Citrate; Sulfones

Topics: Cardiomyopathy, Hypertrophic; Female; Heart Transplantation; Humans; Hypertension; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

The association of erectile dysfunction (ED) with cardiovascular diseases is so common. This study was carried out to investigate possible impact of sildenafil; the prototype phosphodiesterase 5 inhibitor used for treatment of ED, on the beneficial hemodynamic and histopathological effects of the prototype third generation calcium antagonist, amlodipine, in nitric oxide (NO)-deficient hypertensive rats. Hypertension was induced by 4-weeks treatment with N(omega)-nitro-l-arginine-methyl ester (l-NAME). Animals were allocated into five groups: normal control, hypertensive control, amlodipine-treated group, sildenafil-treated group and combined treatment group. Drug treatment was started 2 weeks after l-NAME and continued together with l-NAME to the end of the treatment period. Systolic blood pressure (SBP), plasma nitrate/nitrite (NO(x)) and plasma cGMP levels were evaluated at the end of the treatment period. Aortic and renal structural alterations were also investigated. l-NAME treatment caused elevation of SBP, reduction in plasma NO(x) and cGMP levels as well as adverse histological alterations in the tissues studied. Amlodipine normalized SBP, restored plasma NO(x) and cGMP levels and ameliorated the adverse histological changes seen in NO-deficient rats. When combined with sildenafil, both hemodynamic and histopathological effects of amlodipine were augmented with an underlying enhanced elevation of both plasma NO(x) and cGMP levels to statistically higher values than amlodipine alone. These results show that sildenafil augments the beneficial hemodynamic and histopathological effects of amlodipine in NO-deficient hypertensive rats with a pivotal role being played by NO-cGMP pathway. Whether this pharmacodynamic interaction could exist in other models of hypertension that do not share such biochemical derangement warrants further investigations.

Topics: Amlodipine; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cyclic GMP; Enzyme Inhibitors; Heart Rate; Hypertension; Kidney; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Signal Transduction; Sildenafil Citrate; Sulfones

Topics: Adrenergic beta-Antagonists; Aged; Antihypertensive Agents; Atenolol; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Diltiazem; Dose-Response Relationship, Drug; Drug Interactions; Drugs, Chinese Herbal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypotension; Male; Optic Nerve; Optic Neuropathy, Ischemic; Phosphodiesterase Inhibitors; Piperazines; Purines; Retinal Artery; Risk Factors; Sildenafil Citrate; Simvastatin; Sulfones; Vision, Low

Topics: Amlodipine; Antihypertensive Agents; Disease Progression; Dose-Response Relationship, Drug; Drug Interactions; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Optic Nerve; Optic Neuropathy, Ischemic; Phosphodiesterase Inhibitors; Piperazines; Prostatectomy; Prostatic Neoplasms; Purines; Retinal Artery; Risk Factors; Sildenafil Citrate; Sulfones; Time; Vision, Low

Topics: Cerebral Arteries; Cerebral Hemorrhage; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Hypertension; Internal Capsule; Magnetic Resonance Imaging; Male; Middle Aged; Paresis; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Recovery of Function; Sildenafil Citrate; Sulfones; Thalamus; Tomography, X-Ray Computed; Vasodilation; Vasodilator Agents

Since the launch in 1998 of the anti-impotence drug sildenafil (viagra), the American food and drug administration has identified 50 cases of drug-related blindness, the so-called nonarteritic anterior ischemic optic neuropathy. This, very serious, side effect frequently leads to sudden, mostly irreversible loss of vision, and there is no proven effective treatment to cure patients or to prevent recurrence. The mechanism of ischemic optic neuropathy is not clear, but it could be related to the fact that the ophthalmic and central retinal arteries have an autoregulation of their own blood flow without any autonomic nerve supply; vasoreactivity could be lower albeit efficient, and therefore more vulnerable to systemic modifications of the circulation. But decreased visual acuity and loss of visual ability also are, although uncommon, anesthesiological and surgical complications. These data are consistent with the hypothesis that sildenafil, surgery and anesthesia, taken together, could be a potentially dangerous cocktail of risk factors for sudden irreversible loss of vision. To reduce the risk, sildenafil use should be avoided at least one week before surgical operations, since the reported cases of blindness developed 36h after drug ingestion.

Topics: Anesthesia; Blindness; Carbon Dioxide; Humans; Hypertension; Ischemia; Male; Optic Nerve; Optic Nerve Diseases; Optic Neuropathy, Ischemic; Piperazines; Postoperative Complications; Purines; Risk; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

During the past 18 years, sildenafil has evolved from a potential anti-angina drug to an on-demand treatment for erectile dysfunction and more recently to a new orally active treatment for pulmonary hypertension. Recent studies suggest that the drug has powerful cardioprotective effect against ischemia/reperfusion injury, doxorubicin-induced cardiomyopathy and anti-hypertensive effect induced by chronic inhibition of nitric oxide synthase in animals. Based on several recent basic and clinical studies, it is clear that sildenafil and other clinically approved type-5 phosphodiesterase-5 inhibitors including vardenafil and tadalafil will eventually be developed for several cardiovascular indications including essential hypertension, endothelial dysfunction, ischemia/reperfusion injury, myocardial infarction, ventricular remodeling and heart failure.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antihypertensive Agents; Carbolines; Cardiomyopathies; Cardiovascular Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Doxorubicin; Endothelium, Vascular; Enzyme Inhibitors; Erectile Dysfunction; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents; Ventricular Remodeling

Phosphodiesterase-5 inhibitors are beneficial in pulmonary hypertension and congestive heart failure, the two conditions associated with coronary heart disease and ischaemia. We investigated whether sildenafil counteracts the cardiovascular alterations induced by N -nitro-L-arginine methyl ester (L-NAME) in the rat.. Sildenafil was given orally to rats at doses of 0.37, 0.75 or 1.5 mg kg-1day-1 for four weeks, either alone or with L-NAME (35-40 mg kg-1 day-1 in the drinking water). Systolic blood pressure and urinary parameters (6-keto-prostaglandin F1alpha, thromboxane B2, 8-isoprostane-prostaglandin F2 and nitrite/nitrate) were measured in conscious rats. Isolated hearts were subjected to low flow ischaemia-reperfusion, and myocardial levels of guanosine 3', 5'cyclic monophosphate (cGMP) were determined. Endothelial vascular dysfunction was examined in aortic rings.. Sildenafil dose-dependently prevented the rise in systolic blood pressure in L-NAME-treated rats. This activity was associated with a normalization of urinary 8-isoprostane-prostaglandin F2alpha and other biochemical parameters. In perfused hearts, the post-ischaemic ventricular dysfunction was worse in preparations from L-NAME-treated rats than in controls. Sildenafil dose-dependently reduced this effect, and creatine kinase and lactate dehydrogenase release were lower too. cGMP levels, which were low in myocardial tissue from L-NAME-treated rats, were restored by sildenafil. In noradrenaline-precontracted aortic rings from L-NAME-treated rats acetylcholine lost its vasorelaxant effect, and sildenafil restored it.. In a rat model of chronic nitric oxide deprivation, where hypertension and aggravation of post-ischaemic ventricular dysfunction are associated with loss of vascular endothelium-relaxant function, sildenafil provided significant cardiovascular protection, primarily by maintaining tissue cGMP levels.

Topics: Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Cardiovascular Agents; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Heart Rate; Hypertension; Male; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Severity of Illness Index; Sildenafil Citrate; Sulfones; Time Factors; Vasodilation; Vasodilator Agents; Ventricular Function

We evaluated the long-term effect of NO-donor, pentaerythrityl tetranitrate (Petn), and sildenafil citrate (sildenafil) on the cardiovascular system of the spontaneously hypertensive rat (SHR). Petn (100 mg/kg/day) and sildenafil (10 mg/kg/day) were administered to SHR individually or together from week 4 (pre-hypertensive period) to week 9 of age. Blood pressure (BP) was measured using a plethysmographic method. The animals were perfused with a glutaraldehyde fixative (120 mmHg). Carotid (AC) and coronary artery (RS) were processed according to electron microscopy procedure. Geometry of the arteries was measured on semi-thin sections using light microscopy. Administration of Petn and sildenafil to SHR individually or together did not prevent an increase of BP, but evoked a decrease of cardiac hypertrophy. Petn and sildenafil affected the geometry of RS and AC differently. In the RS, an increase of inner diameter (ID) without an increase of wall thickness (WT) resulted in increased WT/ID and circumferential stress. In the AC, changes in ID were accompanied by changes in WT and, thereby, WT/ID and circumferential stress remained unchanged. The arterial wall mass of both arteries was increased. The data suggest that administration of the NO donor, Petn, and/or sildenafil does not result in a beneficial effect on the myocardium or on the geometry of the carotid and coronary arteries.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Cardiovascular System; Carotid Arteries; Coronary Vessels; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Hypertension; Nitric Oxide Donors; Pentaerythritol Tetranitrate; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Inbred SHR; Rats, Wistar; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Blood Pressure; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Erectile dysfunction (ED) is highly associated to cardiovascular disease, especially arterial hypertension. Phosphodiesterase type 5 (PDE5) inhibitors and angiotensin II receptor blockers (ARB) are both common and efficient therapy in patients with ED and arterial hypertension, respectively.. To evaluate the effect of PDE5 inhibitor, sildenafil (S), and of ARB Losartan (L) in a continuous combined therapy for a long term on penile structures in a hypertensive rat model.. During 6 months, four groups of male spontaneously hypertensive rats (SHR) and one of Wistar-Kyoto (WKY) rats, as control group, were studied: no-treatment SHR, SHR with L, SHR with S, SHR with S + L, and no-treatment WKY. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries, collagen type III (COL-III), and endothelial nitric oxide synthase (eNOS) expression in cavernous space were evaluated.. Functional and morphological differences between S and L in a continuous combined therapy vs. either drug as monotherapy on penile structures.. After 6 months, SHR that received L, S, or combined therapy showed a similar reduction in blood pressure compared with untreated SHR. Nevertheless, SHR + L + S and control WKY showed significantly lower values of (i) CSM (P < 0.01), (ii) VSM (P < 0.01), and (iii) COL-III (P < 0.01) when compared with the untreated SHR and also with the SHR with monotherapy. Additionally, SHR + L + S, presented a higher eNOS expression in sinusoidal endothelium in comparison with the untreated SHR and the SHR with monotherapy (P < 0.01). In vitro studies revealed that SHR + L + S displayed a better relaxation response to acetylcholine than the untreated SHR and the SHR with monotherapy (P < 0.01).. These results suggest that a long-term combined therapy using L and S is a useful tool for functional and structural modification in cavernous tissue from SHR.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hypertension; Impotence, Vasculogenic; Longitudinal Studies; Losartan; Male; Muscle, Smooth, Vascular; Penis; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Inbred SHR; Rats, Wistar; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

To determine the association between Viagra (sildenafil) and Cialis (tadalafil) and non-arteritic anterior ischaemic optic neuropathy (NAION).. A retrospective matched case-control study was conducted. 38 cases of NAION in males were identified from an academic ophthalmology practice in Birmingham, Alabama, and matched (on age) to 38 controls without a history of NAION. Self reported information regarding past and current use of Viagra and/or Cialis was obtained via a telephone questionnaire from interviewers who were not blind to case status.. Overall, males with NAION were no more likely to report a history of Viagra or Cialis use compared to similarly aged controls (odd ratio (OR) 1.75, 95% confidence interval (CI) 0.48 to 6.30 and OR 1.82, 95% CI 0.21 to 15.39). However, for those with a history of myocardial infarction, a statistically significant association was observed (OR 10.7, 95% CI 1.3 to 95.8). A similar association was observed for those with a history of hypertension though it lacked statistical significance (OR 6.9, 95% CI 0.8 to 63.6).. For men with a history of myocardial infarction or hypertension the use of Viagra or Cialis may increase the risk of NAION. Physicians prescribing these medications to patients with these conditions should warn them about the potential risk of NAION.

Topics: Carbolines; Case-Control Studies; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Optic Neuropathy, Ischemic; Phosphodiesterase Inhibitors; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Tadalafil; Vasodilator Agents

Many of the physiological responses to nitric oxide (NO) are mediated by cyclic 5'-guanosine monophosphate (cGMP), the intracellular levels of which are regulated by phosphodiesterase type 5 (PDE5). In situations of reduced NO formation, the inhibition of PDE5 by selective inhibitors such as sildenafil could be beneficial in restoring physiological functions by enhancing the intracellular levels of cGMP. In this study, we evaluated the effects of sildenafil on the hemodynamic and histological alterations induced by the chronic treatment of rats with N(omega)-nitro-L-arginine-methyl ester (L-NAME). After 8 weeks of concomitant treatment with sildenafil and L-NAME, arterial blood pressure was significantly lower (P<0.05) than in L-NAME-treated rats. The fall in blood pressure was associated with a slight reduction in the total peripheral vascular resistance (P<0.05). Sildenafil partially prevented the decrease in cardiac output seen in L-NAME-treated rats. Morphologically, sildenafil reduced the total area of the myocardial lesions and attenuated the cardiomyocyte and vascular smooth muscle remodeling seen with L-NAME. These results show that sildenafil prevented the deleterious hemodynamic and morphological alterations associated with L-NAME-induced hypertension. This beneficial effect was probably mediated by an increase in cardiac and vascular cGMP levels as reflected in circulating plasma cGMP levels.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blood Pressure; Cardiomyopathies; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Heart; Hypertension; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones

Topics: Atrial Fibrillation; Carbolines; Humans; Hypertension; Male; Middle Aged; Migraine with Aura; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil

Topics: Antihypertensive Agents; Bronchitis; Central Venous Pressure; Child, Preschool; Epoprostenol; Fontan Procedure; Humans; Hypertension; Hypoplastic Left Heart Syndrome; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antihypertensive Agents; Drug Interactions; Glaucoma; Humans; Hypertension; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adolescent; Antihypertensive Agents; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypertension; Hypotension; Nitroprusside; Piperazines; Purines; Sildenafil Citrate; Sulfones

The pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, were compared after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg to spontaneously hypertensive rats (SHRs) at 16 and 6 weeks old and their respective age-matched control normotensive Kyoto-Wistar rats (KW rats), and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats) at 16 weeks old and their age-matched control Sprague-Dawley rats. After oral administration of DA-8159 to 16-week-old SHRs, the AUC values of both DA-8159 (157 versus 103 microg min/ml) and DA-8164 (215 versus 141 microg min/ml) were significantly greater, but the values of DA-8159 were reversed in 16-week-old DOCA-salt rats (125 versus 200 microg min/ml). However, the AUC values of both DA-8159 and DA-8164 were not significantly different between the 6-week-old SHRs and their control rats. The above AUC differences in 16-week-old SHRs may be due to neither hereditary characteristics of SHRs nor the hypertensive state itself.

Topics: Administration, Oral; Animals; Area Under Curve; Chromatography, High Pressure Liquid; Desoxycorticosterone; Half-Life; Hypertension; Injections, Intravenous; Kidney; Liver; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Sildenafil Citrate; Sodium Chloride; Sulfonamides; Sulfones

The hypothetical case of a man with erectile dysfunction and multiple cardiovascular risk factors is presented to illustrate the use of the second Princeton Consensus Conference Guidelines. Methods to optimize efficacy of the phosphodiesterase inhibitors are described. The overall cardiovascular safety of the phosphodiesterase inhibitors and their interaction with organic nitrates and alpha blockers are discussed.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Angiotensin-Converting Enzyme Inhibitors; Coronary Artery Disease; Diabetes Complications; Enzyme Inhibitors; Erectile Dysfunction; Exercise; Guidelines as Topic; Humans; Hypertension; Male; Middle Aged; Obesity; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones

Erectile dysfunction (ED) is frequent in patients with essential hypertension (EH); a likely common pathogenetic pathway could be a reduced ability of arteriolar vascular smooth muscle (VSM) to relax. Increasing intracellular levels of cGMP reduce the contractile status of VSM; on the contrary, type 5 cGMP-specific phosphodiesterase (PDE5, codified by PDE5A gene) regulates cGMP levels through its clearance. The PDE5A gene represents a good candidate for the intermediate phenotype EH/ED: genetic variants of the PDE5A may predispose to EH and ED and could affect the local and systemic response to sildenafil administration. Thus, a functionally relevant portion of PDE5 5'-flanking promoter region was analyzed by PCR and direct sequencing in patients with EH and idiopathic ED. The sequences obtained showed a T/G polymorphism at position -1142, near an AP1 regulatory element, that was not apparently associated with the intermediate phenotype. We also studied the relationship between this polymorphism and the effects of oral sildenafil on blood pressure (BP) and heart rate (HR) in men with ED. Sildenafil caused a significant decrease of BP, but had no effects on HR; statistical analysis showed no differences in BP and HR variations among PDE5A genotypes. In conclusion, our data showed no correlations of a novel polymorphism of the PDE5A promoter gene with the intermediate phenotype EH/ED and the BP and HR response to sildenafil administration. Further studies are necessary to define the role of this polymorphism and to study the genetic predisposition for EH with ED.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; 5' Flanking Region; Adult; Aged; Alleles; Cyclic Nucleotide Phosphodiesterases, Type 5; DNA; Erectile Dysfunction; Genotype; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Piperazines; Purines; Reverse Transcriptase Polymerase Chain Reaction; Sildenafil Citrate; Sulfones; Transcription Factor AP-1; Vasodilator Agents

Topics: Cerebral Hemorrhage; Cerebrovascular Circulation; Coitus; Dyskinesias; Humans; Hypertension; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Subthalamic Nucleus; Sulfones; Thalamic Nuclei; Tomography, X-Ray Computed

To assess sexual dysfunction in sexually active men after radical cystectomy (RC) and to determine whether sildenafil citrate can improve erectile dysfunction after surgery.. The baseline and follow-up data from 49 sexually active male patients (mean age 57.8 +/- 9.1 years) undergoing RC (1995 to 2002) were obtained. Of the 49 patients, 16 (33%) had undergone nerve-sparing RC; 38 (78%) had undergone orthotopic diversion; 8 (16%) had undergone ileal conduit diversion; and 3 (6%) had undergone cutaneous continent diversion. The data were assessed using the abridged 5-item International Index of Erectile Function questionnaire, referred to as the Sexual Health Inventory for Men (SHIM).. At a mean follow-up of 47.6 +/- 22.7 months, the total mean SHIM score decreased from 22.08 +/- 3.96 to 4.33 +/- 5.72 after RC (P <0.05). Of the 49 patients, 42 (86%) did not have erections sufficient for vaginal penetration. Of these 42 patients, 22 (52%) tried sildenafil citrate. Of these 22 patients, only 2 (9%) responded positively, with a total mean SHIM score of 23.50 +/- 2.12. Although the mean SHIM score after orthotopic substitution (5.24 +/- 6.21) was statistically significant compared with that after ileal conduit (1.13 +/- 0.33) and cutaneous continent (1.33 +/- 0.58) diversions, this was not clinically significant.. Male erectile dysfunction after RC is a prevalent problem. In our series, only 9 (14%) of 49 sexually active men were potent after surgery. Of these 9 potent patients, 8 (89%) had undergone nerve-sparing RC. Of concern, only 52% of the patients with erectile dysfunction sought treatment after RC.

Topics: Aged; Carcinoma; Comorbidity; Coronary Disease; Cystectomy; Diabetes Mellitus; Drug Evaluation; Drug Resistance; Erectile Dysfunction; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Patient Acceptance of Health Care; Patient Satisfaction; Peripheral Nerve Injuries; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Spouses; Sulfones; Surveys and Questionnaires; Urinary Bladder Neoplasms; Urinary Diversion

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Calcium Channel Blockers; Coitus; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Retinal Artery Occlusion; Sildenafil Citrate; Sulfones; Verapamil

Topics: Acute Disease; Aged; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Hypercholesterolemia; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Cohort Studies; Contraindications; Double-Blind Method; Humans; Hypertension; Male; Middle Aged; Piperazines; Placebos; Primary Health Care; Purines; Risk Factors; Sildenafil Citrate; Sulfones; United Kingdom; Vasodilator Agents

Sildenafil is commonly used in the treatment of erectile dysfunction in hypertensive male cardiac transplant recipients (CTR); however, little is known about the vascular effects of sildenafil in these patients.. Central and peripheral arterial blood pressure (BP), heart rate, and brachial artery reactivity were determined in 15 hypertensive male CTR before and after oral sildenafil (50 mg) administration.. Sildenafil improved brachial and aortic systolic BP, pulse pressure, aortic augmentation index, left ventricular tension time index, travel time of the reflected aortic pressure wave, and brachial artery reactivity (P <.01 for each comparison). No patient became hypotensive with sildenafil despite continuation of usual antihypertensive medications.. Sildenafil (50 mg) is well tolerated in hypertensive CTR and improves BP, aortic augmentation index, and endothelial function. By decreasing the amplitude of the reflected pressure wave and delaying its return to the heart, sildenafil reduces left ventricular afterload and systolic stress.

Topics: Aged; Aorta; Blood Pressure; Brachial Artery; Erectile Dysfunction; Heart Transplantation; Humans; Hypertension; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventricular Function, Left

Topics: Aged; Epistaxis; Humans; Hypertension; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adult; Aged; Alprostadil; Diabetes Complications; Drug Therapy, Combination; Erectile Dysfunction; Humans; Hypertension; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adult; Aged; Erectile Dysfunction; Heart Diseases; Hospitals, General; Humans; Hypertension; Male; Middle Aged; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Vasodilator Agents

This study was designed to measure cyclic guanosine 3'5' monophosphate (cGMP) formation and relaxation response to sildenafil given either alone or in combination with sodium nitroprusside in saphenous veins obtained from normotensive and hypertensive patients.. Saphenous vein rings were obtained from 13 hypertensive and nine normotensive patients undergoing coronary artery bypass surgery. The vein rings were suspended in organ bath chambers for isometric recording of tension. The effect of sildenafil on sodium nitroprusside-induced cGMP formation was also assessed.. Sildenafil (10 nmol/L to 100 micromol/L) and sodium nitroprusside (0.01 to 100 nmol/L) caused concentration-dependent relaxations that were of greater magnitude in veins from normotensive patients. Sildenafil (1 to 10 micromol/L) amplified the relaxation induced by sodium nitroprusside in both groups of veins, but this effect was more pronounced in veins from hypertensive patients. Levels of cGMP in response to sodium nitroprusside were significantly lower in veins from hypertensive subjects. However, in the presence of sildenafil, the increase in cGMP levels in response to sodium nitroprusside was significantly greater in the hypertensive as compared with the normotensive group.. Although the relaxant effects of sildenafil are less pronounced in veins from hypertensive patients, the synergistic interaction sildenafil-sodium nitroprusside is more effective in veins from hypertensive patients, mainly due to an increase in cGMP accumulation.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Cyclic GMP; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Nitroprusside; Phosphodiesterase Inhibitors; Piperazines; Purines; Saphenous Vein; Sildenafil Citrate; Sulfones; Vasodilator Agents

To find the factors linked to erectile dysfunction, to evaluate this as a possible marker of health status, to analyse the evolution of clinical parameters of associated illnesses and the response to Viagra.Design. Intervention study without a control.. Alguazas Health Centre (Murcia).. All the patients in the programme (125), with a figure on the sexual health in men index (SHIM) below 21.Interventions. Health education and administration of Viagra.. Concomitant illnesses, pathologies previously unknown to the patient, changes in erectile function valued on the international index of erectile function (IIEF), and changes in blood pressure, glucaemia and lipids.. Factors linked to erectile dysfunction were diabetes (50.4%), hypertension (33.6%), hypercholesterolaemia (22.4%), urological pathology (12.8%) and mental health disorders (33.6%). The hidden pathology detected was 15 cases of hypertension, 3 diabetes, 2 cardiopathies, 20 dyslipaemias, 3 depressions, 13 anxiety and 5 urological problems. The variations in clinical parameters at 3 months were: glucaemia, -38.3 mg (P<.001, Student s t=-5.186); HbA1c, -0.9 (P<.05, Student s t=-2.16); systolic blood pressure, -16 mm Hg (P<.01, Student s t=-3.486) and diastolic pressure -13 mm Hg (P<.001, Student s t=-4.594); and total cholesterol, -14.2% (P<.001, Student s t=7.01). Erectile function improved by 74% with Viagra.. 2 out of every 3 patients with erectile dysfunction presented associated diseases; one in every 3 were ignorant of their health problem. Monitoring of chronic illnesses improved significantly. Finally, 3 in every 4 responded to Viagra.

Topics: Adult; Age Factors; Aged; Anxiety; Data Interpretation, Statistical; Depression; Diabetes Complications; Erectile Dysfunction; Health Status; Heart Diseases; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Urologic Diseases; Vasodilator Agents

Topics: Antihypertensive Agents; Apomorphine; Clinical Trials as Topic; Dopamine Agonists; Drug Interactions; Erectile Dysfunction; Humans; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

To determine the occurrence of clinically significant decreases in blood pressure (BP) with sildenafil use in normotensive and hypertensive men by means of ambulatory BP monitoring.. On 2 nights, 49 men (22 hypertensive, 27 normotensive) had their ambulatory systolic BP (SBP), diastolic BP (DBP), and heart rate monitored during the first 3 hours (waking period) and every 30 minutes after midnight for 3 additional hours (sleeping period). No medication was taken on one night; sildenafil 100 mg was taken on the other.. Sildenafil decreased SBP (-6.0 mm Hg; P = 0.0003), DBP (-4.5 mm Hg; P = 0.001), and mean arterial pressure (-5.3 mm Hg; P = 0.00008). The BP-lowering effects of sildenafil did not differ significantly in the normotensive and hypertensive men. Age significantly affected the BP reductions; decreases in SBP, DBP, and mean arterial pressure were greater in men 49 years old and older than in those younger than 49 years old. According to readings averaged over the entire control and treatment periods, 22.7% of hypertensive men and 3.7% of normotensive men experienced SBP reductions of 20 mm Hg or greater (P = 0.08 for comparison of the two groups); the respective values for DBP were 9.1% and 3.7% (P not significant). These reductions were not associated with any hypotensive symptoms. All participants tolerated sildenafil well.. Sildenafil caused small, clinically insignificant reductions in ambulatory BP in active and resting normotensive and hypertensive men. The results of this study suggest that, when used in accordance with the prescribing information and current treatment guidelines, sildenafil should be safe in younger and older men with or without hypertension.

Topics: Adult; Age Factors; Antihypertensive Agents; Blood Pressure; Electrocardiography, Ambulatory; Heart Rate; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

To prospectively define the potential predictors of asymptomatic ischemic heart disease in patients with vasculogenic erectile dysfunction using a simple and practical method. Most patients with vasculogenic erectile dysfunction are known to have at least one significant cardiovascular risk factor.. After baseline evaluations, patients with erectile dysfunction of presumed vascular origin, who were older than 45 years and with no history of ischemic heart disease, were enrolled in the study. According to the results of repeated pharmacologic erection tests, we divided patients into responders and nonresponders. The cardiologic evaluations consisted of a comprehensive history taking, the assessment of cardiovascular risk factors, a physical examination, and an exercise treadmill test.. A total of 97 patients completed the study. Fifteen (32.6%) of 46 responders and 25 (49.0%) of 51 nonresponders, respectively, had two or more cardiovascular risk factors (P = 0.101). Ischemic ST-segment changes on the exercise treadmill test were only observed in 8 nonresponders (15.7%) (P = 0.006). All these patients were older than 55 years, and seven had two or more cardiovascular risk factors, including hypertension.. On the basis of these preliminary data, we suggest that cardiovascular evaluations may prove beneficial before prescribing sildenafil to patients with vasculogenic erectile dysfunction who are nonresponders to the pharmacologic erection test, are older than 55 years, and have two or more risk factors, including hypertension.

Topics: Age Factors; Comorbidity; Contraindications; Electrocardiography; Exercise Test; Humans; Hypertension; Impotence, Vasculogenic; Male; Middle Aged; Myocardial Ischemia; Physical Examination; Piperazines; Probability; Purines; Risk Factors; Sexual Behavior; Sildenafil Citrate; Sulfones

After p.o. administration to rats in doses up to 30 mg/kg, Viagra showed no antithrombotic effect. However, it enhanced the inhibition of thrombus formation by RE 2047 from 9% to 17% (5 + 5 mg/kg) or 19% to 27% (10 + 10 mg/kg) in arterioles. This effect was even more obvious in venules where an inhibition of 9% (5 + 5 mg/kg) or 15% (10 + 10 mg/kg) was seen whereas the individual drugs had no effect. The antithrombotic activity of molsidomine was not altered. The blood pressure (b.p.) of spontaneously hypertensive rats was reduced by the combination of Viagra and RE 2047 (5 + 5 mg/kg) to 94% of normal after 2 h while the individual drugs had no effect at this dose. The coadminstration of 10 mg/kg of each drug reduced the b.p. to 87% of normal. The combination of Viagra with molsidomine decreased b.p. to 84% (5 + 5 mg/kg) or 79% (10 + 10 mg/kg), respectively.

Topics: Animals; Arterioles; Blood Pressure; Drug Interactions; Fibrinolytic Agents; Hypertension; Molsidomine; Nitric Oxide Donors; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Purines; Rats; Rats, Inbred SHR; Sildenafil Citrate; Sulfones; Sydnones; Thrombosis; Venules

Topics: Antihypertensive Agents; Erectile Dysfunction; Humans; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Impotence, a common problem especially among older men, can now be treated with Viagra, This oral pill, unlike previous approved treatments mostly involving local injections, does not directly cause penile erection, but increases response to sexual stimulation. It acts by enhancing the relaxant effects of nitric acid on smooth muscle, and thus increases blood flow to certain areas of the penis, leading to erection. It has been evaluated in many randomized trials and in all was more successful in inducing erection than placebos. The most common side-effects include headache, flushing and indigestion, but there have also been reports of fatalities. We describe a 75-year-old man who had an acute myocardial infraction in the past and who had maturity-onset diabetes and hypertension. In the week prior to admission he had a cardiac scan following a few weeks of exacerbation of anginal pain for which he had been taking nitrites. He took a Viagra pill without prescription or medical advice and 2 hours later, during intercourse with his wife, developed audible respiratory distress and lost consciousness. His wife started cardiac massage but not mouth-to-mouth breathing. The emergency team found ventricular fibrillation and gave 5 electrical shocks and amines and atropine. He remained unconscious, but his pulse returned and he was hospitalized. He then had several generalized convulsions treated with i.v. valium. 20 minutes after admission there was asystole and all attempts at resuscitation failed. Cardiovascular status must be considered prior to prescribing Viagra, and the associated risk evaluated.

Topics: Aged; Diabetes Mellitus, Type 2; Erectile Dysfunction; Fatal Outcome; Humans; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Respiratory Distress Syndrome; Sildenafil Citrate; Sulfones; Unconsciousness