Chronic treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolaemia.

BACKGROUND: Reduced availability of tetrahydrobiopterin (BH(4)), an essential cofactor of nitric oxide (NO) synthase (NOS), decreases NO production and increases reactive oxygen species. Both mechanisms contribute to atherosclerotic vascular disease. Although acute supplementation of BH(4) improves endothelial dysfunction, the effect of chronic BH(4) in humans is unknown. OBJECTIVE: To investigate the effect of chronic BH(4) supplementation on endothelial function and oxidative stress in hypercholesterolaemia. DESIGN: Randomised double-blind, placebo-controlled trial. SETTING: University Hospital. PATIENTS: 22 hypercholesterolaemic patients (low-density lipoprotein (LDL) >4.5 mmol/l) were randomised to 4 weeks of oral BH(4) (400 mg twice daily) or placebo. Age-matched healthy volunteers served as controls. MAIN OUTCOME MEASURES: Endothelium-dependent and -independent vasodilatation was assessed by venous occlusion plethysmography. To elucidate the mechanisms of BH(4) effect, NO release and superoxide anion (O(2)(-)) production were measured in human aortic endothelial cells exposed to native LDL (2.6 mmol cholesterol/l). RESULTS: BH(4) plasma levels were significantly increased by oral supplementation. NO-mediated vasodilatation to acetylcholine was reduced in patients compared with controls and restored by BH(4). No effect of BH(4) on endothelium-independent vasodilatation was seen. Furthermore, 8-F(2 )isoprostane plasma levels, a marker of vascular oxidative stress, were reduced by BH(4). In LDL-treated endothelial cells, BH(4) levels and NO release were reduced and O(2)(-) production increased compared with control cells. Exogenous BH(4) normalised NO and O(2)(-) production. CONCLUSIONS: In hypercholesterolaemia, endothelial dysfunction and oxidative stress can be reversed by chronic oral treatment with BH(4). Thus, BH(4) availability is essential for maintaining NO synthesis and low O(2)(-) production by endothelial NOS in vivo, and may provide a rational therapeutic approach to prevent cardiovascular disease.

[First-trimester-test--support-tool for the individual decision or screening-tool for public health planning?]. / Der Ersttrimester-Test - persönliche Entscheidungshilfe oder Screeningtool der öffentlichen Gesundheitsvorsorge?

International studies about women's knowledge of the first-trimester-test show that they are quite often not sufficiently informed for their personal decision-making: The information needed is not given in an understandable way; they are not informed that the test is only a risk assessment and not a diagnosis; and they often don't understand the concept of false positive and false negative results. Other studies show, that this sophisticated and complex information about the first-trimester-test can be given in an understandable way. But even with adequate information most women are unable to make an informed choice as long as the test is presented as a routine for screening. However, for an informed and free choice, an individual decision-making-process has to take place. For this reason a counseling concept has been developed in Switzerland. It introduces the first-trimester-test not as a screening-tool for the public health planning but as a support-tool for the individual decision. It consists of an information brochure for the pregnant woman and her partner, a counseling framework for the physicians and a two days training program. The counseling concept has been evaluated by a research project of the Swiss National Science Foundation and has been adopted as an official counseling standard by the Swiss Society of Obstetrics and Gynaecology. Recommendations for the communication skills together with a short time training program were added, such that the concept can serve as an integrative tool for decision-making support concerning first-trimester tests.

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. METHODS AND RESULTS: lycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11beta-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls; P<0.01). After 11beta-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (all P<0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (P<0.05 versus controls). Chronic ET(A) receptor blockade with LU135252 (50 mg. kg(-1). d(-1)) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (P<0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11beta-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids. CONCLUSIONS: Chronic ET(A) receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11beta-HSD inhibitor-induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11beta-HSD activity.

Vascular protective effects of angiotensin converting enzyme inhibitors and their relation to clinical events.

Endothelial cells are a rich source of a variety of vasoactive substances, which either cause vasodilation or vasoconstriction. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide and endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin. nitric oxide exerts potent anti-atherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. Endothelium-derived contracting factors include the 21 amino acid peptide endothelin (ET). vasoconstrictor prostanoids such as thromboxane A2 and prostaglandin H2, as well as free radicals and components of the renin angiotensin system. In hypertension, elevated blood pressure transmits into cardiovascular disease by causing endothelial dysfunction. Hence, modem therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Angiotensin converting enzyme (ACE) inhibitors are a primary candidate for that concept as they inhibit the circulating and local renin angiotensin system. Angiotensin converting enzyme is an endothelial enzyme which converts angiotensin-I (A-I) into angiotensin-II (A-II). This effect of the ACE inhibitor prevents direct effects of angiotensin-II such as vasoconstriction and proliferation in the vessel wall but also prevents activation of the ET system and of plasminogen activator inhibitor. Furthermore, inhibition of ACE prolongs the half-life of bradykinin and stabilizes bradykinin receptors linked to the formation of nitric oxide and prostacyclin. In isolated arteries ACE inhibitors prevent the contractions induced by angiotensin II and enhance relaxation induced by bradykinin. Chronic treatment of experimental hypertension with ACE inhibitors normalizes endothelium-dependent relaxation to acetylcholine and other agonists. In addition, the dilator effects of exogenous nitric oxide donors are enhanced, at least in certain models of hypertension. In humans with essential hypertension ACE inhibitors augment endothelium-dependent relaxation to bradykinin, while those to acetylcholine remain unaffected, at least in the time frame of the published studies, i.e. 3-6 months. In patients with coronary artery disease, however, paradoxical vasoconstriction to acetylcholine is markedly reduced after 6 months of ACE inhibition. After myocardial infarction ACE inhibitors reduce the development of overt heart failure, the occurrence of reinfarction and cardiovascular death in hypertensive patients. These effects have also been demonstrated in a subgroup analysis of the SOLVD (Studies of Left Ventricular Dysfunction) trial. Thus, in summary, ACE inhibitors are an important class of drugs providing cardiovascular protection in patients with increased cardiovascular risk.