endothelin-1 and sapropterin

Heart disease is among the leading causes of death in all populations. Cardiac dysfunctions are major complications in patients with advanced viral or bacterial infection, severe trauma and burns accompanied with multiple organ failure - collectively known as systemic inflammatory response syndrome (SIRS). SIRS, which is often subsequent to sepsis, is clinically featured by hypotension, tachypnea, hypo- or hyperthermia, leukocytosis and myocardial dysfunction. The striking association between inflammation and cardiac dysfunction not only prognoses likelihood of survival in patients with SIRS but also prompts the necessity of understanding the pathophysiology of cardiac dysfunction in SIRS, so that effective therapeutic regimen may be identified. Compelling evidence has shown significant and independent link among inflammation, sepsis, insulin resistance and cardiac dysfunction. Several cytokine signaling molecules have been speculated to play important roles in the onset of cardiac dysfunction under SIRS including endothelin-1 and toll-like receptor. Involvement of these pathways in cardiac dysfunction has been convincingly validated with transgenic studies. Nevertheless, the precise mechanism of action underscoring inflammation-induced cardiac contractile dysfunction is far from being clear. Given the substantial impact of inflammation and SIRS on health care, ecosystems and national economy, it is imperative to understand the cellular mechanisms responsible for cardiac contractile dysfunction under inflammation and sepsis so that new and effective therapeutic strategy against such devastating heart problems may be developed.

Topics: Animals; Biopterins; Cytokines; Diabetes Mellitus; Endothelin-1; Heart Diseases; Humans; Inflammation; Insulin Resistance; Myocardium; Nitric Oxide; Sepsis; Shock, Septic; Systemic Inflammatory Response Syndrome; Toll-Like Receptors

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-monophosphate 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 normal function of the vascular endothelium. Endothelin acts as the natural counterpart to endothelium-derived NO. Besides its arterial blood pressure rising effect in humans, endothelin-1 induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. Current therapeutic strategies concentrate mainly on lowering 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. The production of reactive oxygen species under pathological conditions may represent an important inflammatory trigger. Novel therapeutic strategies specifically targeting inflammation thus bear great potential for the prevention and treatment of atherosclerotic vascular disease. In this context, the vascular actions of flavanol-rich cocoa, particularly with regard to enhanced NO synthesis and endothelial function observed in humans following consumption, warrants further attention. This review discusses pharmacological and dietary intervention.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Arginine; Atherosclerosis; Biopterins; Cacao; Calcium Channel Blockers; Cyclooxygenase Inhibitors; Dyslipidemias; Endothelin-1; Endothelins; Endothelium, Vascular; Flavonoids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipoproteins, HDL; Nitric Oxide; Oxidative Stress; Reactive Oxygen Species

Tetrahydrobiopterin (BH4) is the essential cofactor of endothelial nitric oxide synthase (eNOS) and intracellular levels of BH4 is regulated by oxidative stress. The aim of this paper was to describe the influence of exogenous endothelin-1 on intracellular BH4 and its oxidation products dihydrobiopterin (BH2) and biopterin (B) in a wide range of vascular tissue.. Segments of internal mammary artery (IMA) and human saphenous vein (SV) from 41 patients undergoing elective surgery were incubated in ET-1 (0.1 μM). Aorta and lung from transgenic mice overexpressing ET-1 in the endothelium (ET-TG) were analysed with regards to intracellular biopterin levels. Human umbilical vein endothelial cells (HUVEC) were incubated in ET-1 (0.1 μM) and intracellular biopterin levels were analysed. From 6 healthy women undergoing caesarean section, subcutaneous fat was harvested and the resistance arteries in these biopsies were tested for ET-mediated endothelial dysfunction.. In HUVEC, exogenous ET-1 (0.1 μM) did not significantly change intracellular BH4, 1.54 ± 1.7 vs 1.68 ± 1.8 pmol/mg protein; p = .8. In IMA and SV, exogenous ET-1(0.1 μM) did not change intracellular BH4 n = 10, p = .4. In aorta from wild type vs ET-TG mice there was no significant difference in intracellular BH4 between the groups: 1.3 ± 0.49 vs 1.23 ± 0.3 pmol/mg protein; p = .6. In resistance arteries (n = 6) BH4 together with DTE (an antioxidant) was not able to prevent ET-mediated endothelial dysfunction.. ET-1 did not significantly alter intracellular tetrahydrobiopterin levels in IMA, SV, HUVEC or aorta from ET-TG mice. These findings are important for future research in ET-1 mediated superoxide production and endothelial dysfunction.

Topics: Aged; Animals; Antioxidants; Aorta; Biopterins; Cell Line; Endothelin-1; Female; Human Umbilical Vein Endothelial Cells; Humans; Lung; Male; Mammary Arteries; Mice, Transgenic; Middle Aged; Nitric Oxide Synthase Type III; Pregnancy; Saphenous Vein; Subcutaneous Fat; Superoxides; Tissue Culture Techniques; Vasodilation

The effects of simulated heat waves on body weight, body temperature, and biomarkers of cardiac function in ApoE-/- mice were investigated. Heat waves were simulated in a meteorological environment simulation chamber according to data from a heat wave that occurred in July 2001 in Nanjing, China. Eighteen ApoE-/- mice were divided into control group, heat wave group, and heat wave BH4 group. Mice in the heat wave and BH4 groups were exposed to simulated heat waves in the simulation chamber. Mice in BH4 group were treated with gastric lavage with BH4 2 h prior to heat wave exposure. Results showed that the heat waves did not significantly affect body weight or ET-1 levels. However, mice in the heat wave group had significantly higher rectal temperature and NO level and lower SOD activity compared with mice in the control group (p < 0.01), indicating that heat wave had negative effects on cardiac function in ApoE-/- mice. Gastric lavage with BH4 prior to heat wave exposure significantly reduced heat wave-induced increases in rectal temperature and decreases in SOD activity. Additionally, pretreatment with BH4 further increased NO level in plasma. Collectively, these beneficial effects demonstrate that BH4 may potentially mitigate the risk of coronary heart disease in mice under heat wave exposure. These results may be useful when studying the effects of heat waves on humans.

Topics: Animals; Atherosclerosis; Biomarkers; Biopterins; Body Temperature; Body Weight; Coronary Disease; Drug Evaluation, Preclinical; Endothelin-1; Extreme Heat; Infrared Rays; Male; Mice; Mice, Knockout; Nitric Oxide; Random Allocation; Superoxide Dismutase

We previously demonstrated that cyclosporine (CyA) impairs endothelial function as a result of alterations in nitric oxide (NO) and endothelin-1 (ET-1) regulation. Bosentan (BOS), an ET-1 antagonist, and tetrahydrobiopterin (BH₄), an eNOS cofactor, may reduce endothelial dysfunction by improving ET-1/NO homeostasis.. Lewis rats received intraperitoneal injections of CyA with BOS or with BOS+BH₄ daily for 2 weeks. Control (Con) animals received saline injections. Thoracic aortic segments were assessed for endothelial-dependent (E(dep)) and -independent (E(ind)) relaxation (E(max%)) after exposure to acetylcholine and sodium nitroprusside. Vessel sensitivity to ET-1-induced vasospasm was evaluated.. CyA use resulted in impaired E(dep) vasorelaxation when compared with Con, whereas BOS and BH₄ treatment preserved E(dep) vasorelaxation. CyA significantly altered E(ind) vasorelaxation, whereas BOS and BH₄ therapy attenuated CyA-induced effects. Compared with Con, CyA and BH₄ exposure demonstrated increased sensitivity to ET-1 vasospasm. BOS therapy abrogated the CyA and BH₄-induced sensitivity to vasospasm. CyA treatment resulted in higher 8-isoprostane levels compared with Con. CyA-mediated vascular dysfunction is characterized by impaired NO and ET-1 homeostasis.. Our study suggests potential therapeutic strategies to prevent endothelial dysfunction as combined therapy with ET-1 antagonism and NO augmentation completely abrogated CyA-induced vascular injury.

Topics: Animals; Autonomic Nervous System Diseases; Biopterins; Bosentan; Cyclosporine; Drug Therapy, Combination; Endothelial Cells; Endothelin-1; Homeostasis; Male; Nitric Oxide; Oxidative Stress; Rats; Rats, Inbred Lew; Reactive Oxygen Species; Sulfonamides; Vasodilation; Vasodilator Agents; Vasomotor System

Cyclosporine A (CsA) is associated with negative side effects such as endothelial injury, which may lead to transplant vasculopathy. CsA can impair nitric oxide (NO) homeostasis. Therefore, tetrahydrobiopterin (BH4), a NO synthase cofactor, may limit endothelial injury by improving NO production. Our study examines the effect of CsA and BH4 exposure on endothelial function.. Lewis rats were injected with CsA, BH4, CsA+BH4, or saline intraperitoneally daily for 2 weeks. With use of a small vessel myograph, thoracic aortic segments were assessed for endothelial-dependent (Edep) and independent relaxation after exposure to acetylcholine and sodium nitroprusside. Sensitivity to vasospasm was evaluated after exposure to endothelin (ET)-1.. CsA exposure resulted in impaired Edep vasorelaxation compared with control (P=0.01). BH4 attenuated the deleterious effects of CsA. Compared with control, all treatment groups demonstrated significantly increased sensitivity to ET-1. Furthermore, endothelial nitric oxide synthase expression in the thoracic aorta was reduced after CsA treatment, and this reduction was attenuated by BH4 therapy (P<0.01). ETA receptor expression in the aorta was increased after CsA treatment, but BH4 treatment prevented CsA-induced ETA over-expression (P=0.004). However, ETB receptor expression was increased by BH4 treatment compared with CsA and control (P=0.02).. Our findings suggest that CsA-induced vasomotor dysfunction is a result of alterations in both NO and ET-1 regulation and that BH4 may prevent the deleterious effects of CsA. However, the beneficial effects of BH4 are associated with increased sensitivity to ET-1. Therefore, a combination of BH4 and ET-1 blockade may prove to be an ideal combination for preservation of endothelial function.

Topics: Animals; Biopterins; Cyclosporine; Endothelial Cells; Endothelin-1; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Rats, Inbred Lew; Receptors, Endothelin; Vasodilation

We recently reported that arterial superoxide (O2-) is augmented by increased endothelin-1 (ET-1) in deoxycorticosterone acetate (DOCA)-salt hypertension, a model of low renin hypertension. Tetrahydrobiopterin (BH4), a potent reducing molecule with antioxidant properties and an essential cofactor for endothelial nitric oxide synthase, protects against O2--induced vascular dysfunction. However, the interaction between O2- and BH4 on endothelial function and the underlying mechanisms are unknown.. The present study tested the hypothesis that BH4 deficiency due to ET-1-induced O2- leads to impaired endothelium-dependent relaxation and that gene transfer of human guanosine 5'-triphosphate (GTP) cyclohydrolase I (GTPCH I), the first and rate-limiting enzyme for BH4 biosynthesis, reverses such deficiency and endothelial dysfunction in carotid arteries of DOCA-salt rats. There were significantly increased arterial O2- levels and decreased GTPCH I activity and BH4 levels in DOCA-salt compared with sham rats. Treatment of arteries of DOCA-salt rats with the selective ETA receptor antagonist ABT-627, NADPH oxidase inhibitor apocynin, or superoxide dismutase (SOD) mimetic tempol abolished O2- and restored BH4 levels. Basal arterial NO release and endothelium-dependent relaxations were impaired in DOCA-salt rats, conditions that were improved by apocynin or tempol treatment. Gene transfer of GTPCH I restored arterial GTPCH I activity and BH4 levels, resulting in reduced O2- and improved endothelium-dependent relaxation and basal NO release in DOCA-salt rats.. These results indicate that a BH4 deficiency resulting from ET-1-induced O2- via an ETA/NADPH oxidase pathway leads to endothelial dysfunction, and gene transfer of GTPCH I reverses the BH4 deficiency and endothelial dysfunction by reducing O2- in low renin mineralocorticoid hypertension.

Topics: Acetophenones; Animals; Antioxidants; Atrasentan; Biopterins; Carotid Arteries; Cyclic N-Oxides; Desoxycorticosterone; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Gene Transfer Techniques; Genetic Therapy; GTP Cyclohydrolase; Humans; Hypertension; In Vitro Techniques; Male; Nitric Oxide; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sodium Chloride; Spin Labels; Superoxides; Vasodilation

Topics: Animals; Biopterins; Cholesterol; Coronary Disease; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin-1; Hypercholesterolemia; Superoxides; Swine

Topics: Biopterins; Coronary Artery Bypass; Endothelin-1; Endothelium, Vascular; Graft Occlusion, Vascular; Humans; Insulin Resistance; Vascular Resistance

To investigate the interaction between endothelin (ET) and the nitric oxide system, we examined the effects of ET-1 and ET-3 on the induction of inducible nitric oxide synthase (iNOS) and guanosine triphosphate cyclohydrolase I (GTP:CHI), the rate-limiting enzyme of de novo synthesis of the cofactor tetrahydrobiopterin (BH4), in rat mesangial cells. ET-1 inhibited the nitrite accumulation induced by a combination of interleukin-1 beta, tumor necrosis factor-alpha, and lipopolysaccharide in a concentration-dependent manner. The inhibitory effect of ET-3 was less potent than that of ET-1. A selective ETA antagonist, BQ-485, and an ETA and ETB antagonist, TAK-044, abolished the inhibitory effects of ET-1, whereas the selective ETB antagonist BQ-788 had no effect on the inhibition produced by ET-1. These observations indicate that ET-1 inhibits cytokine-stimulated nitrite accumulation through the ETA receptor. Western blot analysis showed that the suppression of nitrite accumulation was accompanied by a decrease in iNOS protein. Northern blot analysis showed that ET-1 inhibited the expression of both iNOS and GTP:CHI mRNA. In conclusion, ET-1 inhibits cytokine-stimulated nitric oxide production through the ETA receptor by suppressing the expression of iNOS and GTP:CHI mRNA in rat mesangial cells.

Topics: Animals; Antioxidants; Azepines; Biopterins; Blotting, Northern; Blotting, Western; Cells, Cultured; Cytokines; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Induction; Glomerular Mesangium; GTP Cyclohydrolase; Male; Nitric Oxide Synthase; Nitrites; Oligopeptides; Rats; Rats, Sprague-Dawley; RNA, Messenger