Differential effects of selective cyclooxygenase-2 inhibitors on endothelial function in salt-induced hypertension.

Background: In view of the ongoing controversy about potential differences in cardiovascular safety of selective cyclooxygenase (COX)-2 inhibitors (coxibs), we compared the effects of 2 different coxibs and a traditional NSAID on endothelial dysfunction, a well-established surrogate of cardiovascular disease, in salt-induced hypertension.

Methods And Results: Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed a high-sodium diet (4% NaCl) for 56 days. From days 35 to 56, diclofenac (6 mg x kg(-1) x d(-1); DS-diclofenac), rofecoxib (2 mg x kg(-1) x d(-1); DS-rofecoxib), celecoxib (25 mg x kg(-1) x d(-1); DS-celecoxib) or placebo (DS-placebo) was added to the chow.

Detection of a novel exon 4 low-density lipoprotein receptor gene deletion in a swiss family with severe familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant disease which results in 2-3-fold elevated cholesterol levels and in accelerated atherosclerosis. FH is caused by small mutations or larger rearrangements in the low-density lipoprotein receptor (LDLR). Here, we report that screening the LDLR gene in a Swiss family (n = 15) with clinical symptoms of FH by combined single strand conformation polymorphism and long-distance PCR identified a novel 1.

Dysfunctional baroreflex regulation of sympathetic nerve activity in patients with vasovagal syncope.

Background: The interplay of resting muscle sympathetic nerve activity (MSA) and the baroreceptor reflex in patients with vasovagal syncope remains elusive. Hence, the aim of the present study was to investigate MSA, baroreceptor sensitivity, heart rate, and blood pressure under resting conditions and during orthostatic stress in patients with a history of vasovagal syncope.

Methods And Results: MSA was measured using microneurography at rest and during lower body negative pressure (LBNP) to mimic orthostatic stress in patients with a history of vasovagal syncope (n=10) and in age-matched healthy controls (n=8).

Selective COX-2 inhibition improves endothelial function in coronary artery disease.

Background: There is an ongoing debate as to whether the gastrointestinal safety of COX-2 inhibition compared with nonsteroidal antiinflammatory drugs (NSAIDs) may come at the cost of increased cardiovascular events. In view of the large number of patients at cardiovascular risk requiring chronic analgesic therapy with COX-2 inhibitors for arthritic and other inflammatory conditions, the effects of selective COX-2 inhibition on clinically useful surrogates for cardiovascular disease, particularly endothelial function, need to be determined.

Methods And Results: Fourteen male patients (mean age, 66+/-3 years) with severe coronary artery disease (average of 2.

Erythropoietin-induced excessive erythrocytosis activates the tissue endothelin system in mice.

The endothelium controls blood flow and pressure by releasing several vasoactive factors, among them the vasodilator nitric oxide (NO) and the potent vasoconstrictor endothelin-1 (ET-1). Although increased NO levels have been found in excessive erythrocytosis, little is known concerning ET-1 expression in this condition. Thus, we examined the endothelin system in transgenic mice that due to constitutive overexpression of erythropoietin (Epo) reached hematocrit levels of approximately 80%.

Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content: role of habitual versus nonhabitual drinking.

Background: Coffee is the most abundantly consumed stimulant worldwide. However, its cardiovascular safety remains controversial. Possible health hazards have been related to its main ingredient, caffeine.

Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT).

Background: The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET(A) antagonist darusentan in addition to modern standard therapy in patients with CHF.

Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. Striking similarities exist in the inflammatory and immunologic response in RA and atherosclerosis. Indeed, adhesion molecules and cytokines, tumor necrosis factor (TNF)-alpha in particular, are key mediators of joint inflammation and of vascular dysfunction and progression of atherosclerotic vascular disease.

Treatment with darusentan over 21 days improved cGMP generation in patients with chronic heart failure.

In heart failure, the cGMP to natriuretic peptide ratio is decreased and infusion of atrial natriuretic peptide (ANP) induces less cGMP generation. The ratio of the second messenger cGMP to plasma concentrations of ANP or brain natriuretic peptide (BNP) correlates with the effectiveness of natriuretic peptides. It was investigated whether blockade of the ET(A) receptor might improve the cGMP:NP ratio in heart failure.

Pattern of prepro-endothelin-1 expression revealed by reporter-gene activity in kidneys of erythropoietin-overexpressing mice.

Transgenic overexpression of erythropoietin (Epo) in mice increases haematocrit to a mean of 80% in adult mice, leading to an increase in blood viscosity and volume. As a consequence, renal tissue endothelin-1 (ET-1) concentrations are significantly elevated in erythropoietin-overexpressing (Epo+) mice (mean+/-S.E.

Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors.

Background: Mental stress is a risk factor for atherosclerosis and may precipitate myocardial ischemia and infarction. Because endothelial dysfunction is an early manifestation of atherosclerosis, we investigated the impact of mental stress on endothelial function. Methods and Results- The effects of a 3-minute mental stress task on endothelium-dependent vasodilation were studied in healthy subjects without cardiovascular risk factors.

High-density lipoprotein restores endothelial function in hypercholesterolemic men.

Background: Hypercholesterolemia is a risk factor for atherosclerosis-causing endothelial dysfunction, an early event in the disease process. In contrast, high-density lipoprotein (HDL) cholesterol inversely correlates with morbidity and mortality representing a protective effect. Therefore, we investigated the effects of reconstituted HDL on endothelial function in hypercholesterolemic men.

Endothelin antagonists and heart failure.

Chronic heart failure (CHF) is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance, reduced exercise tolerance, and dyspnea. Despite considerable progress in the treatment of CHF, especially in targeting activated neurohumoral systems, mortality in these patients remains high. Therefore, new treatment approaches are warranted.

Vasopeptidase inhibition: effective blood pressure control for vascular protection.

Angiotensin converting enzyme (ACE) inhibition is a well-established principle in the treatment of hypertension, and numerous large scale clinical studies have clearly demonstrated the beneficial effects of inhibiting the renin-angiotensin-aldosterone system (RAS) in hypertension. The clinical success of ACE inhibitors encouraged attempts to inhibit other key enzymes in the regulation of vascular tone, such as the neutral endopeptidase (NEP). Similar to ACE, NEP is an endothelial cell surface metalloproteinase, which is involved in the degradation of several regulatory peptides including the natriuretic peptides, and augments vasodilatation and natriuresis through increased levels of atrial natriuretic peptide.

Influence of aldosterone vs. endothelin receptor antagonism on renovascular function in liquorice-induced hypertension.

Background: The enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor inactive 11-dehydro derivatives. Inhibition of 11beta-HSD2 by liquorice-derived glycyrrhizic acid (GA) therefore results in sodium retention and hypertension. The present study investigated the effect of the aldosterone receptor antagonist spironolactone in comparison with the endothelin ET(A) receptor antagonist darusentan on renovascular endothelial function in liquorice-induced hypertension.

Vasopeptidase inhibition restores renovascular endothelial dysfunction in salt-induced hypertension.

Renovascular hemodynamics plays a pivotal role in the regulation of BP. The effect of the vasopeptidase inhibitor omapatrilat (O) and the ACE-inhibitor captopril (C) on endothelial function in the renal circulation in salt-induced hypertension were investigated. Dahl salt-sensitive rats (n = 6 per group) on standard or salt-enriched chow were treated for 8 wk with O (36 +/- 4 mg/kg per d), C (94 +/- 2 mg/kg per d), or placebo.

Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease?

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure.

Endothelin A receptor antagonists in congestive heart failure: blocking the beast while leaving the beauty untouched?

Congestive heart failure (CHF) is a disease process characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. Thus, mediators involved in the control of myocardial function and vascular tone may be involved in its pathophysiology. The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3, and ET-4, which cause vasoconstriction, cell proliferation, and myocardial effects through activation of ET(A) receptors.

Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide.

Background: The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11beta-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11beta-HSD in the regulation of vascular tone remains to be determined.

Chronic vasopeptidase inhibition restores endothelin-converting enzyme activity and normalizes endothelin levels in salt-induced hypertension.

Background: Vasopeptidase inhibition (VPI) represents a new therapeutic principle including both inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The present study investigated the effect of the vasopeptidase inhibitor omapatrilat on endothelin-1 (ET-1)-mediated vascular function in salt-induced hypertension.

Methods: Dahl salt-sensitive rats (n=6/group) on standard or salt-enriched (4% NaCl) chow were treated for 8 weeks with either omapatrilat (36+/-4 mg/kg/day), captopril (94+/-2 mg/kg/day) or placebo.

Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future?

Congestive heart failure (CHF) is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. Thus, mediators involved in the control of myocardial function and vascular tone may be involved in its pathophysiology. The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3 and ET-4, which cause vasoconstriction, cell proliferation and myocardial effects through activation of ETA receptors.

Aldosterone receptor antagonism normalizes vascular function in liquorice-induced hypertension.

The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor-inactive 11-dehydro derivatives. The present study investigated the effects of the aldosterone receptor antagonists spironolactone and eplerenone on endothelial function in liquorice-induced hypertension. Glycyrrhizic acid (GA), a recognized inhibitor of 11beta-HSD2, was supplemented to the drinking water (3 g/L) of Wistar-Kyoto rats over a period of 21 days.