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)

Smoking is associated with endothelial dysfunction. The purpose of this study was to determine the effect of sildenafil, an inhibitor of phosphodiesterase type 5 (PDE5), on endothelial function in smokers. We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after oral sildenafil administration (100 mg) with a strain-gauge plethysmograph in 10 young healthy male smokers and 10 young healthy male nonsmokers. FBF response to ACh was lower in smokers than in nonsmokers. The vasodilatory effects of SNP were similar in both groups. Sildenafil increased the FBF response to ACh from 9.3+/-2.0 to 12.5+/-3.5 mL/min per 100 mL tissue in smokers and from 12.6+/-5.6 to 19.6+/-8.4 mL/min per 100 mL tissue in nonsmokers, and it increased the response to SNP from 13.3+/-3.9 to 15.1+/-4.3 mL/min per 100 mL tissue in smokers and from 14.8+/-5.2 to 18.4+/-6.0 mL/min/100 mL tissue in nonsmokers (P<0.05 for all). The ratio of maximal ACh-stimulated FBF expressed as a ratio of maximal SNP-stimulated FBF significantly increased after administration of sildenafil in both groups. Infusion of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, abolished sildenafil-induced augmentation of the FBF response to ACh in both groups. The findings suggest that endothelial function is impaired in smokers compared with that in nonsmokers, that inhibition of PDE5 by sildenafil significantly increases nitric oxide-mediated vasodilation, and that the activities of PDE5 in smokers and nonsmokers may be similar.
Hypertension 2003 May
PMID:PDE5 inhibitor sildenafil citrate augments endothelium-dependent vasodilation in smokers. 1269 18

Mendelian forms of hypertension have delivered a treasure trove of novel genes. To date, the molecular mechanisms of five such syndromes have been largely clarified, including glucocorticoid-remediable aldosteronism, Liddle's syndrome, apparent mineralocorticoid excess, an activating mutation of the mineralocorticoid receptor, and pseudohypoaldosteronism type 2. Each of these conditions features salt sensitivity with increased sodium and volume reabsorption by the kidney and low plasma renin activity. None of the gene loci for these syndromes has been convincingly linked to hypertension in the general population. We are investigating kindreds who have autosomal-dominant hypertension and brachydactyly. Affected persons invariably have both anomalies. The hypertension is severe and results in death at about age 50 years from stroke. The condition resembles essential hypertension, because renin, aldosterone, and norepinephrine responses are normal and no salt sensitivity is present. The response to antihypertensive drugs is general. Another feature is diminished baroreflex sensitivity with markedly impaired blood pressure buffering. Furthermore, the ventrolateral medulla may be compromised in these patients, because neurovascular anomalies are a regular finding. We mapped the gene(s) for this disease to chromosome 12p and narrowed the chromosomal region by studying more affected families. Interestingly, the same locus was recently mapped in Chinese families with essential hypertension. Our 3-centimorgan region contains genes encoding a phosphodiesterase, an ATP-dependent potassium channel, and its regulator the sulfonylurea receptor 2. Screening of the coding regions revealed that none of these candidate genes harbor obvious mutations; however, other genetic mechanisms may nevertheless compromise their function. Our study underscores the importance of regulatory physiology to the understanding of a complex genetic syndrome.
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PMID:Mendelian hypertension with brachydactyly as a molecular genetic lesson in regulatory physiology. 1295 13

Insulin resistance is associated with vascular disease. Physiological concentrations of insulin inhibit cultured vascular smooth muscle cell (VSMC) contraction and migration by increasing nitric oxide (NO)-stimulated cGMP accumulation. The failure to do so in insulin-resistant states may aggravate vascular disease. We sought to determine the mechanism of insulin's increase in cGMP accumulation. Isobutylmethylxanthine, an inhibitor of phosphodiesterase activity, inhibited the decline in cGMP levels measured by immunoassay in cGMP-loaded cultured rat aortic VSMCs, but 1 nmol insulin did not. Thus, insulin's increase in cGMP accumulation is due to stimulated production, not inhibited hydrolysis and/or efflux. Insulin, which increases the NADH/NAD+ ratio in these cells, stimulated superoxide anion (O2-) accumulation measured by lucigenin luminescence to 256+/-25% (P<0.05) by a process that was blocked by the NADH oxidase inhibitor diphenyliodonium (DPI) and enhanced by the superoxide dismutase inhibitor diethyldithiocarbonate (DETCA). Insulin also stimulated hydrogen peroxide (H2O2) accumulation measured by horseradish peroxidase/luminol luminescence to 221+/-22% (P<0.05) by a DETCA-sensitive mechanism. H2O2 (100 micromol/L) in the absence of insulin increased NO-stimulated cGMP accumulation to 151+/-11% (P<0.05). Insulin alone increased NO-stimulated cGMP accumulation to 183+/-17% (P<0.05), and this was blocked by either DPI or DETCA. We conclude that insulin increases NADH oxidase-derived O2- production in cultured rat VSMCs. This did not cause the expected scavenging of NO resulting in the reduction of NO-stimulated guanylate cyclase activity, but enough O2- was metabolized to H2O2 to increase overall NO-stimulated cGMP production.
Hypertension 2003 Oct
PMID:Insulin-stimulated hydrogen peroxide increases guanylate cyclase activity in vascular smooth muscle. 1296 80

In recent years, the better understanding of the pathobiology and pathogenesis of pulmonary arterial hypertension (PAH) has led to the development of new drugs for its treatment. Epoprostenol, which was the first drug approved for PAH, has shown an improvement in the survival at 3 years in patients with primary pulmonary hypertension. Recently, the Food and Drug Administration has approved two new compounds, Bosentan (an oral, non-selective endothelin receptor blocker) and Treprostinil (a subcutaneous prostacyclin analog). At least three multicenter, international studies are currently in progress. These studies include the use of a diet supplement rich in arginine (nitric oxide precursor), the evaluation of an endothelin A-receptor blocker (Sitaxsentan), and the evaluation of Sildenafil (a 5-phosphodiesterase inhibitor). As long as research continues to scrutinize the pathogenesis of this disease, clues to possible new therapies are warranted.
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PMID:[What is new in the treatment of pulmonary artery hypertension?]. 1296 61

Primary Lung Hypertension is a serious disease of unknown cause. Various genetic, vasoconstriction, proliferation and procoagulation factor participate in etiology and pathogenesis. In establishing the diagnosis it is necessary to exclude secondary, particularly embolic cause of pulmonary hypertension. There are diseases with associated primary pulmonary hypertension. Present therapy improves symptoms of the disease, three years after the diagnosis is established, 75% of patients survive. In the therapy of primary pulmonary hypertension, the recommended drugs are calcium channel blockers, epoprostenol, oxygen therapy and anticoagulant drugs. The new, clinically tested drugs include inhalation and oral analogs of prostacyclins, endothelin receptor antagonists and phosphodiesterase blockers.
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PMID:[Primary pulmonary hypertension--aspects of diagnosis and therapy]. 1450 69

Erectile dysfunction (ED) is a serious condition that becomes more common as men age. Many older men, however, report satisfactory erectile capacity and enjoy satisfying sexual relationships. Physicians have been slow to discuss ED with patients even in the presence of multiple risk factors. New information provides strong reasons for ED inquiry and management in the primary care physician's office. The presence of ED can reveal as yet undiscovered neurovascular and psychological disorders including diabetes, hypertension, dyslipidaemia, depression and anxiety as well as early neuromuscular disorders. By inquiring about ED, physicians can better decrease iatrogenic sexual dysfunction caused by certain commonly used medications. The successful management of ED, made much easier by the development of phosphodiesterase type 5 inhibitors, has additional potential benefits including improvement of quality of life for both the patient and his partner; decreasing the symptoms of depression in depressed men who also have ED; improving relationships, a significant factor related to good health; and enhancing overall patient health. Other potential values for the physician include a better clinician-patient and increased physician work satisfaction. Primary care physicians need to recognise the value of ED inquiry and management and integrate these activities into practice.
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PMID:The potential value of erectile dysfunction inquiry and management. 1452 62

Cardiologists are seeing increasing numbers of patients with erectile dysfunction (ED), which frequently coexists with cardiovascular disease. The pharmacologic profile of the new class of phosphodiesterase (PDE) inhibitors-specifically PDE5 inhibitors-and their potential effects on hemodynamic variables have therefore become significant factors in therapeutic decision making. Most of the published data linking PDE5 inhibitor effects and cardiovascular disease relate to sildenafil, although >or=2 new agents are in various stages of development and clinical trials. Sildenafil and other PDE5 inhibitors act on vascular smooth muscle, predominantly in the corpus cavernosum. PDE5 is not found in cardiomyocytes, and no effect of PDE5 inhibition on cardiac contractility has been demonstrated. On the basis of a safety database comprising thousands of men with ED, sildenafil has demonstrated minimal adverse effects in men with stable ischemia, hypertension, and/or severe coronary artery disease. Sildenafil has modest effects on hemodynamic variables and has been shown to increase coronary artery flow reserve. Alone or combined with >or=1 antihypertensive medication, sildenafil did not increase the incidence of adverse events or hypotensive episodes. Sildenafil-associated decreases in systolic and diastolic blood pressure, the result of its vasodilator activity, have been modest. Sildenafil has decreased both elevated pulmonary vascular resistance and elevated pulmonary artery pressures in patients with pulmonary vascular disease. Beneficial changes in hemodynamics have been observed with the use of sildenafil in patients with congestive heart failure with underlying ischemic and other dilated cardiomyopathies. No association between sildenafil and increased cardiovascular morbidity or mortality has emerged in analyses of clinical trial data.
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PMID:Sildenafil in patients with cardiovascular disease. 1460 21

Tadalafil is a potent, selective, reversible phosphodiesterase 5 inhibitor under investigation for the treatment of erectile dysfunction (ED). Because some oral agents for ED have vasodilator properties, interaction studies were performed between tadalafil and commonly prescribed antihypertensive agents. In addition, cardiovascular safety assessments were made from a safety database of phase 3 studies comparing patients who were and who were not receiving antihypertensives. In patients receiving concomitant antihypertensive therapy, tadalafil administration may result in a reduction in blood pressure, which is, in general, mild and not likely to be of clinical concern. In the phase 3 studies, no statistically significant differences were observed between tadalafil and placebo in the mean changes in blood pressure from baseline in patients taking >or=2 antihypertensive agents. The incidence rates of cardiovascular events were comparable between patients who were and were not treated with concomitant antihypertensive therapy, with the exception of events recorded as hypertension, which would be expected to occur periodically in this patient population despite treatment. Hypotension or postural hypotension was not reported in any tadalafil-treated patient, compared with 1 report of each in the placebo-treated patients. Syncope was reported in 1 tadalafil-treated patient (0.1%) who was not on concomitant antihypertensive medication and in 2 patients (1.9%) who received placebo with concomitant antihypertensive agents. The data presented herein suggest that tadalafil is safe in patients receiving >or=1 concomitant antihypertensive agent.
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PMID:Cardiovascular effects of tadalafil in patients on common antihypertensive therapies. 1460 23

Erectile dysfunction (ED) often is caused by endothelial dysfunction and may be a sign that a patient has vascular disease elsewhere in the body. Risk factors for coronary artery disease such as lipid abnormalities, smoking, diabetes, and hypertension also are risk factors for ED. Oral therapy for ED, such as sildenafil, inhibits phosphodiesterase-5 (PDE-5) and the breakdown of cyclic guanosine monophosphate. PDE-5 inhibitors have been shown to be safe and effective for the therapy for ED, but remain contraindicated in patients receiving organic nitrates. These agents are mild vasodilators and are being investigated for their treatment potential for patients with pulmonary hypertension, heart failure, and endothelial dysfunction.
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PMID:Erectile dysfunction in the cardiac patient. 1462

We are studying a Turkish family with autosomal-dominant hypertension and brachydactyly; affected persons die of stroke before 50 years of age. With interphase fluorescence in situ hybridization, we found a chromosome 12p deletion, reinsertion, and inversion in affected persons. This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1, its regulator the sulfonyl urea receptor SUR2, and the phosphodiesterase PDE3A. We further studied 6 affected and 4 nonaffected persons. Buttocks biopsies were done, small vessels were tested on a myograph, and mRNA was extracted. We performed forearm blood flow studies with intrabrachial artery diazoxide, isoproterenol, and milrinone infusions. Systemic pharmacological testing was done with intravenous diazoxide, nitroprusside, and isoproterenol. PDE3A mRNA was high in vessels from 3 affected subjects, but not high in 3 others. The vessels responded similarly to forskolin, with or without glibenclamide, and to cromakalim. However, there was a suggestion that the dilatation after milrinone might be exaggerated. The forearm infusion studies showed no differences in the responses to diazoxide, isoproterenol, or milrinone. Systemically, affected persons showed a greater blood pressure response to diazoxide and nitroprusside, and a greater heart rate response to isoproterenol than nonaffected persons. The results shed doubt on Kir6.1 and SUR2. The differences in PDE3A expression and responses may be the result of hypertension rather than the cause. Although our 3 candidate genes are no longer likely, the rearrangement we describe greatly enhances the perspectives of this project.
Hypertension 2004 Feb
PMID:Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12. 1470 63


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