Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sitaxentan, a highly-selective endothelin receptor antagonist (ETRA) and bosentan a non-selective ETRA are both approved for the treatment of idiopathic pulmonary arterial hypertension (iPAH). Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor used in the treatment of iPAH. Tadalafil is a long acting PDE-5 inhibitor largely unexplored for the treatment of iPAH. Following failure of monotherapy combination therapy with an ETRA and a PDE-5 inhibitor is often used, a frequently used combination being bosentan with sildenafil. We report our clinical experience in three patients with iPAH treated with a combination of sitaxentan and tadalafil, who previously discontinued bosentan. There was sustained symptomatic and haemodynamic improvement in all three patients treated with the combination. No adverse effect related to the combination treatment was noted. Sitaxentan and tadalafil, both being once a day treatments, can also possibly increase compliance.
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PMID:Combination of sitaxentan and tadalafil for idiopathic pulmonary arterial hypertension following relapse on bosentan. 1917 88

Erectile dysfunction (ED) is a highly prevalent disorder which adversely affects quality of life. The prevalence of erectile dysfunctions affects more than half of the male population over 60 years. Cardiovascular diseases are also highly prevalent conditions and frequently occur concommitantly with ED, mainly because of common several pathophysiological and risk factors. Impressive advances in the management of erectile dysfunction have occurred over the past decade when oral therapy with vasoactive agents has become a first-line treatment. The most widely used class of agents for these kind of disorders is 5-phosphodiesterase inhibitors (5-PDEI). Because the enzyme that they inhibit--PDE-5 is found in smooth muscle cells of the systemic arteries and veins throughout the body, these agents have mild vasodilator effects and thus, have the potential to impact the cardiovascular system. In this article, we review the physiology and the pathophysiology of erection, the influence of 5-PDEI over circulatory system and interactions with drugs commonly used in circulatory disorders. The other purpose of the review (based on the Princeton Consensus I and II) is to present guidelines for safe management of cardiac patients regarding sexual activity and the treatment of ED. We also imply that the recognition of ED is a warning sign of silent vascular disease. Thus a man with ED and no cardiac symptoms may be a cardiac or vascular patient. The conclusion is that, with regard to described rules, PDE-5 inhibitors are safe and effective for the treatment of ED patients with cardiac diseases, including patients with chronic coronary artery disease and hypertension.
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PMID:[The safety of 5-phosphodiesterase inhibitors in the treatment of erectile dysfunction in patients with cardiovascular disease]. 1970 9

Many men with erectile dysfunction (ED) also have associated underlying cardiovascular and metabolic conditions, for which they are likely to be taking medication. Therefore, cardiovascular safety and potential drug interactions are two of the major concerns when using PDE-5 inhibitors in these patients. The PDE-5 inhibitor, vardenafil, is characterized by a rapid onset of action, increased duration of erection, high rates of first-dose success and reliable efficacy that can be maintained with continued use. In both clinical trials and real-life observational studies, vardenafil has demonstrated a favorable efficacy and safety profile in men with ED, including those with associated underlying conditions such as diabetes, hypertension and dyslipidemia. Importantly, the concomitant use of medication for these conditions is not associated with any noteworthy changes in the efficacy and safety of vardenafil. The evidence presented in this review supports the use of vardenafil as a first-line treatment for men with ED, including those with underlying conditions.
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PMID:Vardenafil for the treatment of erectile dysfunction: an overview of the clinical evidence. 2005 11

The pathology of pulmonary arterial hypertension (PAH) is characterized by vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. Experimental studies have shown the beneficial effect of phosphodiesterase type 5 (PDE-5) inhibitors on pulmonary vascular remodeling and vasodilatation. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil which significantly improve clinical status, exercise capacity and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in management of PAH. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia.
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PMID:[Phosphodiesterase type 5 inhibitors in the treatment of pulmonary arterial hypertension]. 2081 51

Our previous studies show that inhibition of phosphodiesterase 4 (PDE4) augments agonist-induced renovascular 3',5'-cAMP secretion more in isolated, perfused kidneys from spontaneously hypertensive rats (SHR) versus Wistar-Kyoto normotensive rats (WKY); however, whether this is because of PDE4 inhibition in renovascular smooth muscle cells or endothelial cells is unknown. Therefore, we examined the effects of 3-isobutyl-1-methylxanthine (broad-spectrum PDE inhibitor) and RO 20-1724 (selective PDE4 inhibitor) on isoproterenol-induced 3',5'-cAMP levels in cultured WKY and SHR preglomerular vascular smooth muscle and endothelial cells. 3-Isobutyl-1-methylxanthine and RO 20-1724 augmented isoproterenol-induced 3',5'-cAMP levels similarly in WKY versus SHR endothelial cells. In contrast, 3-isobutyl-1-methylxanthine and RO 20-1724 augmented isoproterenol-induced 3',5'-cAMP levels significantly more in SHR, compared to WKY, smooth muscle cells (P<0.0001). In both cell types from both rat strains, mRNA levels for the PDE4B subtype exceeded levels for the PDE4A, PDE4C, and PDE4D subtypes, and small interfering RNA knockdown of PDE4B mRNA in SHR smooth muscle cells increased isoproterenol-induced 3',5'-cAMP. mRNA levels for the PDE4B2 variant exceeded levels for the PDE4B1, PDE4B3, PDE4B4, and PDE4B5 variants. In vivo, infusions of RO 20-1724 increased the urinary excretion of 3',5'-cAMP more in SHR than WKY (P=0.0211). We conclude that (1) the greater effect of PDE4 inhibition on renovascular 3',5'-cAMP is mediated by inhibition of PDE4 in renovascular smooth muscle cells, not endothelial cells; (2) the major PDE4 subtype in both renovascular smooth muscle and endothelial cells is PDE4B with variant PDE4B2 likely being dominant; and (3) inhibition of PDE4 in vivo increases renal 3',5'-cAMP levels more in genetically hypertensive rats.
Hypertension 2010 Dec
PMID:Regulation of 3',5'-cAMP in preglomerular smooth muscle and endothelial cells from genetically hypertensive rats. 2097 32

Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI(2) (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure.
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PMID:Contribution of oxidative stress to pulmonary arterial hypertension. 2116 Jun 9

Pulmonary arterial hypertension used to be considered an ultimately fatal disease despite the formerly available therapy. It is a disease characterized by progressive elevation of pulmonary vascular resistance and pulmonary arterial pressure, eventually resulting in right ventricular failure and death. The purpose of this article is to review the basic pathophysiologic processes involved in pulmonary arterial hypertension, to discuss patient presentation, classification, and diagnostic workup. Regarding treatment, all patients with PAH should be considered for standard therapy with anticoagulation, oxygen, and diuretics for management of right heart failure. Calcium channel blockers are only indicated for patients with a positive acute vasoreactivity test. Patients with a negative vasoreactivity test and considered low risk can be treated with oral agents such as endothelin receptor antagonists or PDE-5 inhibitor. Patients at high risk should be treated with prostacyclin analogs. Finally, a brief mention of new and future potential therapeutic strategies is also included.
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PMID:Pulmonary arterial hypertension: from pathophysiology to management. 2169

Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5) that was originally developed for the treatment of male erectile dysfunction and recently approved for the treatment of pulmonary arterial hypertension (PAH). The antipulmonary hypertensive effects of nitric oxide and the natriuretic peptides are mediated via increasing intracellular cGMP and enzymatic degradation by PDE-5 is the major route of cGMP inactivation in the lung. Evidence is accruing that PDE-5 activity is increased in pulmonary vascular diseases and may contribute to the pathogenesis of PAH. The longer half-life of tadalafil allows for once-daily dosing as compared with three-times daily dosing for sildenafil, the only other PDE-5 inhibitor currently approved for treatment of PAH. This article reviews the role of cGMP and PDE-5 in PAH, presents the results of recent clinical trials and discusses the role of tadalafil in the treatment of this rare but difficult-to-treat disease.
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PMID:Tadalafil for the treatment of pulmonary arterial hypertension. 2170 53

In recent years, there has been a marked improvement in the treatment of pulmonary arterial hypertension (PAH) due to the development of targeted therapies. There are now several treatment options available--oral, inhaled, and those delivered by subcutaneous or intravenous methods. These treatments have greatly improved patient survival, which in the past was 2.5 years on average. Efficient treatment choice generally proceeds from oral therapies--PDE-5 inhibitors (sildenafil) and endothelin receptor antagonists (bosentan or ambrisentan)--to inhaled prostanoids (iloprost) or subcutaneous (treprostinil). Intravenous prostacyclins are used in treating the more severe cases. The different pathways of action of each class of drugs allow a synergistic effect of combination therapy similar to malignancy or patients in congestive heart failure. The updated treatment algorithm includes combinations of therapies that target different pathways. This article will review the literature regarding combination therapy for the treatment of PAH. Combining PAH therapies that target different pathways is now a well-established treatment option, based on numerous international clinical trials, and offers new hope to patients suffering from this severe disease.
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PMID:[Combination treatment in pulmonary arterial hypertension]. 2216 22

PDE inhibitors could increase cellular cGMP levels and are used to treat erectile dysfunction as well as pulmonary arterial hypertension. cGMP production was reported to be necessary for UVB-induced melanin synthesis, however, the effect of PDE5 inhibitor on melanin synthesis has not been examined. We found that PDE5 inhibitor (sildenafil or vardenafil) and the cGMP analog 8-CPT-cGMP stimulated CREB phosphorylation, leading to increased tyrosinase expression and melanin synthesis, which was counteracted by KT5823, a selective cGMP-dependent protein kinase (PKG) inhibitor. However, KT5823 did not affect cAMP-elevating agent-mediated melanin synthesis, indicating that KT5823 selectively inhibited cGMP-induced melanin synthesis. This is the first study to find that PDE5 inhibitor can promote melanin synthesis and reveal that PKG-dependent CREB phosphorylation and tyrosinase expression is involved in cGMP-induced melanin synthesis. Our results suggest that PDE5 inhibitor may be beneficial for the treatment of hypopigmentation diseases.
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PMID:PDE5 inhibitor promotes melanin synthesis through the PKG pathway in B16 melanoma cells. 2244 38


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