The vascular endothelium in hypertension.

The vascular endothelium plays a fundamental role in the basal and dynamic regulation of the circulation. Thus, it has a crucial role in the pathogenesis of hypertension. A spectrum of vasoactive substances is synthesised in the endothelium; of these, nitric oxide (NO), prostacyclin (PGI2) and endothelin (ET)-1 are the most important. There is a continuous basal release of NO determining the tone of peripheral blood vessels. Systemic inhibition of NO synthesis or scavenging of NO through oxidative stress causes an increase in arterial blood pressure. Also, the renin-angiotensin-aldosterone system has a major role in hypertension as it has a direct vasoconstrictor effect and important interactions with oxygen free radicals and NO. Prostacyclin, in contrast to NO, does not contribute to the maintenance of basal vascular tone of conduit arteries, but its effect on platelets is most important. ET acts as the natural counterpart to endothelium-derived NO and has an arterial blood pressure-raising effect in man. Anti-hypertensive therapy lowers blood pressure and may influence these different mediators, thus influencing endothelial function. In summary, due to its position between the blood pressure and smooth muscle cells responsible for peripheral resistance, the endothelium is thought to be both victim and offender in arterial hypertension. The delicate balance of endothelium-derived factors is disturbed in hypertension. Specific anti-hypertensive and anti-oxidant treatment is able to restore this balance.

Protection of endothelial function.

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances and therefore plays a fundamental role in the basal and dynamic regulation of the circulation. Nitric oxide (NO)--originally described as endothelium-derived relaxing factor--is released from endothelial cells in response to shear stress produced by blood flow, and in response to activation of a variety of receptors. After diffusion from endothelial to vascular smooth muscle cells, NO increases intracellular cyclic guanosine-monophosphat concentrations by activation of the enzyme guanylate cyclase leading to relaxation of the smooth muscle cells. NO has also antithrombogenic, antiproliferative, leukocyte-adhesion inhibiting effects, and influences myocardial contractility. Endothelium-derived NO-mediated vascular relaxation is impaired in spontaneously hypertensive animals. NO decomposition by free oxygen radicals is a major mechanism of impaired NO bioavailability. The resulting imbalance of endothelium-derived relaxing and contracting substances disturbs the nor- mal function of the vascular endothelium. Endothelin acts as the natural counterpart to endothelium-derived NO. In man, besides its effect of increasing arterial blood pressure, ET-1 induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. Current therapeutic strategies concentrate mainly on lowering of low-density lipoprotein cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms play an important role in vascular disease and inflammatory plasma markers correlate with prognosis. Novel therapeutic strategies specifically targeting inflammation thus bear great potential for the prevention and treatment of atherosclerotic vascular disease.

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. In contrast, endothelial ET(B) receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ET(A) receptor antagonist into the brachial artery in healthy humans leads to vasodilation whereas infusion of an ET(B) receptor antagonist causes vasoconstriction. ET-1 plasma levels are elevated in CHF and correlate both with the hemodynamic severity and with symptoms. Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death in patients after myocardial infarction and with CHF. ET-1 contributes to increased systemic and pulmonary vascular resistance, vascular dysfunction, myocardial ischemia, and renal impairment in CHF. Selective ET(A) as well as combined ET(A/B) receptor antagonists have been studied in patients with CHF showing impressive hemodynamic improvements (i.e. reduced peripheral vascular and pulmonary resistance as well as increased cardiac output). These results indicate that ET receptor antagonists indeed have a potential to improve hemodynamics, symptoms, and potentially prognosis of CHF which still carries a high mortality.

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. In contrast, endothelial ETB receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ETB receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ETA-receptor antagonist into the brachial artery in healthy humans leads to vasodilation, whereas infusion of an ETB-receptor antagonist causes vasoconstriction. Endothelin-1 plasma levels are elevated in CHF and correlate both with hemodynamic severity and symptoms. Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death after myocardial infarction as well as in CHF. Endothelin-1 contributes to increased systemic and pulmonary vascular resistance, vascular dysfunction, myocardial ischemia and renal impairment in CHF. Selective ETA, as well as combined ETA/B-receptor antagonists, have been studied in patients with CHF, and their use has shown impressive hemodynamic improvement (i.e., reduced peripheral vascular and pulmonary resistance as well as increased cardiac output). These results indicate that ET-receptor antagonists, indeed, have a potential to improve hemodynamics, symptoms and, potentially, prognosis in patients with CHF, which still carries a high mortality.

Therapeutic potential for endothelin receptor antagonists in cardiovascular disorders.

The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from 'big endothelins' originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET(A) and ET(B) receptors on vascular smooth muscle cells. In contrast, ET(B )receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin. Additionally, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET(A) receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET(A/B )as well as selective ET(A) receptor antagonism ameliorates the clinical status of patients, i.e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET(A/B) receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET(A/B) receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomized clinical trials are under way to evaluate the effects of ET receptor antagonism on morbidity and mortality.

Current strategies and perspectives for correcting endothelial dysfunction in atherosclerosis.

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances such as nitric oxide and endothelin. In atherosclerosis, the delicate balance between endothelium-derived factors is disturbed. Endothelin acts as the natural counterpart to endothelium-derived nitric oxide, which exerts vasodilating, antithrombotic and antiproliferative effects, and inhibits leukocyte adhesion to the vascular wall. Besides its blood pressure increasing effect in man, endothelin also induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. The derangement of endothelial function in atherosclerosis is likely to be caused in part by genetic factors, but is also due to cardiovascular risk factors. Endothelial dysfunction in atherosclerosis is crucial for the development of the disease process in the vasculature and is therefore an important therapeutic target. However, the efficacy of pharmacotherapy aimed at an improvement in endothelial function depends on the individual risk factor profile of the patient.

Vascular effects of newer cardiovascular drugs: focus on nebivolol and ACE-inhibitors.

Alterations in the function and structure of the blood vessel wall account for most clinical events in the coronary and cerebrovascular circulation such as myocardial infarction and stroke. Cardiovascular drugs may exert beneficial effects on the vascular wall both at the level of the endothelium and vascular smooth muscle cells. Therefore, endothelial mediators, in particular nitric oxide (NO) and endothelin (ET), are of special interest. Drugs can modulate the expression and actions of NO, a vasodilator with antiproliferative and antithrombotic properties, and of ET, a potent vasoconstrictor and proliferative mitogenic agent. The most successful drugs in this context are statins and angiotensin-converting enzyme (ACE)-inhibitors. While statins increase the expression of NO synthase. ACE-inhibitors increase the release of NO via bradykinin-mediated mechanisms. Antioxidant properties of drugs are also important, as oxidative stress is crucial in atherosclerotic vascular disease. These properties may explain part of the effects of calcium antagonists and ACE-inhibitors. Indeed, angiotensin II stimulates NAD(P)H oxidases responsible for the formation of superoxide, which inactivates NO. ACE-Inhibitors thus increase the bioavailability of NO. Newer cardiovascular drugs such as nebivolol are able to directly stimulate NO release from the endothelium both in isolated arteries and in the human forearm circulation. ET receptor antagonists may exert beneficial effects in the vessel wall by preventing the effects of ET at its receptors and by reducing ET production. In summary, cardiovascular drugs have important effects on the vessel wall, which may be clinically relevant for the prevention and treatment of cardiovascular disease.

Working under pressure: the vascular endothelium in arterial hypertension.

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances like nitric oxide (NO) and endothelin (ET). In hypertension, the delicate balance of endothelium-derived factors is disturbed. ET acts as the natural counterpart to endothelium-derived NO, which exerts vasodilating, antithrombotic, and antiproliferative effects, and inhibits leukocyte-adhesion to the vascular wall. Besides its blood pressure rising effect also in man, ET induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. The derangement of endothelial function in hypertension is likely to be caused in part by genetic factors, but also due to elevated blood pressure itself. Due to its position between blood pressure and smooth muscle cells responsible for peripheral resistance, the endothelium is thought to be both target and mediator of arterial hypertension. Oxidative stress plays an important role in the pathogenesis of hypertension. Superoxide anions, ie, oxygen radicals produced in part by angiotensin II-activated NAD(P)H oxidase, can scavenge NO to form peroxynitrite, which can nitrosylate membrane proteins and oxidize lipids. Another source of superoxide is cyclooxygenase. Paradoxically, dysfunctional endothelial NO synthase may also be a source of superoxide anions. Surprisingly and in contrast to animal experiments, not all antihypertensive treatments consistently restore endothelium-dependent vasodilation in patients with arterial hypertension. Endothelial dysfunction in hypertension is crucial both for the development of the disease process in the vasculature and an important therapeutic target.

Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans.

OBJECTIVES: We sought to investigate baroreceptor regulation of sympathetic nerve activity and hemodynamics after inhibition of nitric oxide (NO) synthesis. BACKGROUND: Both the sympathetic nervous system and endothelium-derived substances play essential roles in cardiovascular homeostasis and diseases. Little is known about their interactions. METHODS: In healthy volunteers, we recorded muscle sympathetic nerve activity (MSA) with microneurography and central hemodynamics measured at different levels of central venous pressure induced by lower body negative pressure. RESULTS: After administration of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 1 mg/kg/min), systolic blood pressure increased by 24 mm Hg (p = 0.01) and diastolic blood pressure by 12 mm Hg (p = 0.009), while stroke volume index (measured by thermodilution) fell from 53 to 38 mL/min/m2 (p < 0.002). Administration of L-NMMA prevented the compensatory increase of heart rate, but not MSA, to orthostatic stress. The altered response of heart rate was not due to higher blood pressure, because heart rate responses were not altered during infusion of the alpha-1-adrenoceptor agonist phenylephrine (titrated to an equal increase of systolic blood pressure). In the presence of equal systolic blood pressure and central venous pressure, we found no difference in MSA during phenylephrine and L-NMMA infusion. CONCLUSIONS: This study demonstrates a highly specific alteration of baroreceptor regulation of heart rate but not muscle sympathetic activity after inhibition of NO synthesis in healthy volunteers. This suggests an important role of NO in reflex-mediated heart rate regulation in humans.

Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators.

OBJECTIVES: To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF). BACKGROUND: Nonselective ET(A/B( receptor antagonists improve hemodynamics in patients with CHF. Since ET(B( receptors mediate the release of nitric oxide and the clearance of ET-1, selective ET(A) antagonists are of special interest. METHODS: The hemodynamic effects of a single oral dose of the selective ET(A) receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II-III) with an ejection fraction < or = 35%. RESULTS: Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37-0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = -0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03-0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035- < 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant. CONCLUSIONS: In patients with CHF, a single oral dose of the selective ET(A) receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.

Efficacy and tolerability of fluvastatin and bezafibrate in patients with hyperlipidemia and persistently high triglyceride levels.

Hyperlipidemia is an important cardiovascular risk factor. Lipid-lowering therapy has been shown to decrease morbidity and mortality in these patients. Combination therapy with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and a fibric-acid derivative has been reported to be more efficacious to reduce low-density lipoprotein (LDL) cholesterol and triglycerides but may be associated with an increased risk of myositis. The aim of this study was to investigate the efficacy and tolerability of fluvastatin, an HMG-CoA reductase inhibitor, alone and in combination with bezafibrate, a fibric-acid derivative. In a randomized controlled trial with 454 hypercholesterolemic patients (mean cholesterol, 8.6 +/- 1.6 mM), fluvastatin (20 mg/day) significantly lowered total plasma cholesterol levels (-12.5%; p < 0.0001 vs. placebo), LDL cholesterol (-14%; p < 0.0001), and triglycerides (-4%; p = 0.05). A small increase in high-density lipoprotein (HDL) cholesterol levels (3%, NS) also was observed. Combination therapy with fluvastatin and bezafibrate (400 mg/day) in 71 patients with persistent hypertriglyceridemia during treatment with the statin resulted in a more pronounced reduction in triglyceride (-47%; p < 0.0001) and total cholesterol levels (-15%; p < 0.0001) than did fluvastatin alone. Furthermore, the additional bezafibrate significantly increased HDL cholesterol (+5%; p < 0.001). No significant increases in creatine phosphokinase levels or in frequency of myalgia were observed. In summary, fluvastatin decreases both cholesterol and triglyceride levels. In patients with persistent hypertriglyceridemia, combination therapy with fluvastatin and bezafibrate may be safely used to lower triglyceride and cholesterol levels more efficiently.

Autonomic nervous system-controlled cardiac pacing: a comparison between intracardiac impedance signal and muscle sympathetic nerve activity.

A recently introduced rate responsive cardiac pacing system is based on information derived from the intracardiac impedance signal containing information on the inotropic state of the ventricle. This study compared the inotropic state index (ISI) with muscle sympathetic activity (MSA), both being modulated by the autonomic nervous system. Nine patients (66 +/- 3 years, mean +/- SEM) with Inos2DR pacemakers were included. Each patient was studied at rest and during cold pressor test (CPT). Microneurography of the peroneal nerve was performed to measure MSA continuously, which was digitally stored along with continuous surface ECG and blood pressure. The intracardiac impedance signal was transmitted by the pacemaker and stored simultaneously. Linear correlation between ISI and MSA was calculated for the period of the CPT. During CPT, mean systolic blood pressure increased from 122 +/- 4 to 149 +/- 6 mmHg (P < 0.0001), diastolic blood pressure increased from 74 +/- 8 to 86 +/- 4 mmHg (P = 0.02), and intrinsic heart rate increased from 69 +/- 7 to 75 +/- 7 beats/mill (P = 0.019). ISI increased by 21 +/- 7% (P = 0.018), MSA by 26 +/- 6% (P = 0.004). ISI and MSA were positively correlated during the CPT in eight of nine patients (R2 = 0.86-0.99, P < 0.0001). Negative correlation was found in one patient (R2 = 0.94). This study demonstrates parallel increases of the ISI and MSA during CPT. ISI and MSA showed a close linear relationship during provoked changes of sympathetic activity. These results provide further evidence that the sympathetic nervous system is responsible for the observed ISI changes.

[Sympathy and heartache: new information on the sympathetic nervous system]. / Mitleid und Herzschmerz: Neues vom Sympathikus.

The sympathetic nervous system is an important regulator of the circulation. Interactions with other regulating systems, e.g. the renin angiotensin system, play important roles. By means of microneurography, sympathetic activity in humans can be assessed directly in the nerve. Insights into the dynamic regulation of the circulation under physiological and pathophysiological conditions are possible. Activation of the sympathetic nervous system in cardiovascular diseases affects course, prognosis, and therapy. Prognosis in heart failure depends on sympathetic activation, which can be decreased by inhibition of angiotensin II synthesis by ACE-inhibitors. In contrast to nitrates, these drugs do not increase sympathetic activity. The sympathetic nervous system is also heavily involved in the pathogenesis of hypertension. Borderline hypertensives and offspring of hypertensive parents show increased sympathetic nerve activities. Investigation of the sympathetic nervous system under physiological and pathophysiological conditions may serve as a basis for new therapeutic strategies.