Chronic Sildenafil Treatment Corrects Endothelial Dysfunction and Improves Hypertension

Yaguas, Keila; Bautista, Rocí­o; Quiroz, Yasmir; Ferrebuz, Atilio; Pons, Héctor; Franco, Martha; Vaziri, Nosratola D.; Rodríguez‐Iturbe, Bernardo

doi:10.1159/000279307

Cited by 26 publications

(17 citation statements)

References 65 publications

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“…NO exerts many of the biological actions via cGMP, which is rapidly degraded by cGMP PDE. Thus, PDEi has the potential to improve the endothelial function, which has been shown in animal and clinical studies [7–10]. …”

Section: Discussionmentioning

confidence: 99%

“…However, there are plenty of studies reporting the safe use of PDE-5 inhibitors in humans, including those evaluating the effect of PDE-5 inhibitors on the coronary arteries in humans[10–12]. There exist at least 11 isoforms of PDE, and the differential distribution of PDE isoforms in various tissues is the basis for the potential tissue-specific effect of a PDE inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…Many of the biological actions of NO are mediated by 3’5’-guanosine monophosphate (cGMP), which is rapidly degraded by cGMP phosphodiesterase (PDE). Recently, phosphodiesterase-5-inhibitor (PDEi) has been reported to improve the endothelial function in animal and clinical studies [7–10]. PDE inhibitors improve cardiac performance in patients with heart failure [11] and reduce infarct size and attenuate cardiac dysfunction after ischemia/reperfusion injury or permanent coronary artery occlusion [12].…”

Section: Introductionmentioning

confidence: 99%

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Understanding of chest pain in microvascular disease proved by cardiac magnetic resonance image (UMPIRE): study protocol for a randomized controlled trial

Park

Choi

et al. 2014

Trials

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BackgroundMicrovascular angina (MVA) is characterized by anginal chest pain, an abnormal stress test, and normal coronary arteries on coronary angiography. Although the exact pathogenesis remains unclear, endothelial dysfunction is a contributing factor. To date, there exists no specific therapy for this disease. Phosphodiesterase-5 inhibitor improves the endothelial function and subsequently microvascular circulation. The aim of this study is to identify whether udenafil offers benefits in the treatment of MVA in female patients, who have a perfusion defect in their cardiac magnetic resonance image (CMR), but normal coronary arteries.Methods/DesignThe ‘Understanding of Chest Pain in Microvascular Disease Proved by Cardiac Magnetic Resonance Image: (UMPIRE)’ trial is a multicenter, prospective, randomized, placebo controlled trial, designed to evaluate the effect of udenafil on myocardial ischemia and symptoms in female patients with MVA. The myocardial ischemia will be quantified by myocardial stress perfusion defect in CMR. A total of 80 patients with proven perfusion defect in adenosine-stress CMR will be randomly assigned to either the udenafil treatment group (daily dose of 100 mg) or the placebo group for three months. The primary endpoint is >25% improvement in perfusion defect size in adenosine-stress CMR from baseline. The secondary endpoints include <25% improvement in perfusion defect size, chest pain frequency, ST depression in stress test, Duke score in stress test, quality of life (QoL) assessment by SF-36 questionnaire, sexual dysfunction assessment by BISF-W (Brief Index of Sexual Functioning for Women) self-assessment questionnaire, and biomarkers for endothelial function.DiscussionThe UMPIRE trial is the first randomized controlled trial to evaluate the efficacy of udenafil in female MVA patients. If udenafil demonstrates cardioprotective effects, it may provide a novel therapeutic option to reduce myocardial ischemia and improve cardiac function in female MVA patients.Trial registrationClinical Trials.gov: NCT01769482 (registered on 20 November 2012).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Understanding of chest pain in microvascular disease proved by cardiac magnetic resonance image (UMPIRE): study protocol for a randomized controlled trial

Park

Choi

et al. 2014

Trials

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“…As determined by tail-cuff plethysmography as well as by direct intra-arterial determinations (fig. 1a, b), sildenafil treatment ameliorated hypertension, an effect that is observed in rats treated chronically with this drug [7,24] but not regularly in short-term studies [25,26,27]. To determine whether reduction of the blood pressure would by itself play a role in the beneficial effects of sildenafil, we studied the rats of the TRX group that despite normalization of blood pressure had no improvement in the remnant kidney glomerular hemodynamics or histological damage.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil Treatment Prevents Glomerular Hypertension and Hyperfiltration in Rats with Renal Ablation

Tapia¹,

Sánchez-Lozada²,

Soto

et al. 2012

Kidney Blood Press Res

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Background: 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. Aim: To determine the effects of sildenafil in the glomerular microcirculation and their relation to histological damage in the renal ablation model. Methods: 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. Results: 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 NO₂^–/NO₃^–, 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. Conclusions: 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.

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“…Because there are only single-dose studies to evaluate, it is unclear as to whether the observed BP lowering with this combination reflects a physiological rather than a pharmacological effect on the NO-cGMP pathway or whether it is a byproduct of rectifying the endothelial dysfunction common in difficult-to-treat hypertension. 8,9 Moreover, this combination would be of the greatest use in patients having failed other more traditional therapies for the resistant hypertensive, such as spironolactone. These 2 drugs given together are not necessarily a benign combination, and there will be a subset of excessive responders raising for consideration whether the first time the combination is given that it is under supervised conditions.…”

mentioning

confidence: 99%

Drug Combinations in the Treatment of Hypertension

Sica

2010

Hypertension

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N ot uncommonly, to effectively treat hypertension, multiple drugs must be given. Multidrug combinations that dominate clinical practice typically include a thiazide-type diuretic together with either an angiotensin-converting enzyme inhibitor, an angiotensin-receptor blocker, or less so a ␤-blocker. On the other hand, there are several approaches that can also incrementally reduce blood pressure (BP) but are used less regularly and, as such, go underappreciated as to their effectiveness. Such approaches may include within-class switching of diuretics, combining a thiazide-type diuretic with a calcium-channel blocker (CCB), using 2 CCBs from different subclasses, adding a peripheral ␣-blocker to an angiotensin-converting enzyme inhibitor, or tacking on an aldosterone receptor antagonist or nitrate therapy to any of several other drug classes. All of these presumably novel approaches offer useful options for treatment in the otherwise difficult-to-control hypertensive patient. 1 These aforementioned fresh therapeutic approaches succeed in lowering BP based on the nature of the pharmacokinetic and pharmacodynamic interplay between select drug classes. A pharmacokinetic interaction that can be exploited clinically in the patient with difficult-to-treat hypertension is that of combining a dihydropyridine CCB, such as nifedipine, with a nondihydropyridine CCB, such as diltiazem or verapamil. The latter 2 compounds are known inhibitors of the cytochrome CYP3A4 isozyme. The dihydropyridine CCB nifedipine, as is the case for all CCBs, is extensively metabolized by CYP3A4 with little inhibitory effect on this isozyme itself. When nifedipine is combined with diltiazem or verapamil, the latter dose-dependently inhibits the clearance of nifedipine. This interaction occurs quickly, relates to the relatively steep dose-response relationship for nifedipine plasma levels and BP reduction when nifedipine is given in submaximal doses, and is nearly optimized within 3 days of dosing. 2 Another such pharmacokinetic interaction of some clinical use is that of combining verapamil with eplerenone, with the former inhibiting the CYP3A4-mediated metabolism of eplerenone. 3 This can be viewed as the "poor man's" way of reaching higher plasma levels of eplerenone without incurring the substantial cost of higher prescribed doses of the "pricey" eplerenone.Drug-drug interactions that display pharmacodynamic additivity for BP lowering most typically rely on 1 drug blocking counterregulatory responses prompted by the other; this has been the basis for the development of a number of fixed-dose antihypertensive combinations. 4 Acute and chronic BP reductions often activate an interlinked series of mechanisms designed to restore BP. Reflex increases in cardiac output, peripheral vasoconstriction, and salt/water retention can result from baroreflex-mediated activation of the sympathetic nervous and renin-angiotensin systems (RASs).This pattern of response is illustrated by the greater reduction in BP when a vasodilating drug, such as hydralazine ...

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Chronic Sildenafil Treatment Corrects Endothelial Dysfunction and Improves Hypertension

Cited by 26 publications

References 65 publications

Understanding of chest pain in microvascular disease proved by cardiac magnetic resonance image (UMPIRE): study protocol for a randomized controlled trial

Understanding of chest pain in microvascular disease proved by cardiac magnetic resonance image (UMPIRE): study protocol for a randomized controlled trial

Sildenafil Treatment Prevents Glomerular Hypertension and Hyperfiltration in Rats with Renal Ablation

Drug Combinations in the Treatment of Hypertension

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