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W Kübler

Publications and source records attributed to W Kübler.

At least 37 records · Page 2Linked to original sources
PubMed2002

[Secondary and primary prevention of coronary heart disease: platelet aggregation inhibitors and anticoagulants].

This review presents the results of primary and secondary prevention of coronary heart disease (CHD) with antiplatelet drugs and anticoagulants; therapeutic recommendations are derived. According to the results of the trials and due to its low price aspirin (ASS) can be still considered as the drug of choice. Its protective action has been documented for secondary prevention in patients with previous myocardial infarction, coronary angioplasty (PCI), unstable and stable angina, but not in patients with coronary artery bypass surgery, heart failure as well as in primary prevention. The doses recommended are 75-325 mg/d. If ASS is not tolerated clopidogrel is an alternative, but an expensive one. Anticoagulation for primary prevention of CHD may be considered in high risk patients, who do not tolerate ASS (alternative: clopidogrel). In secondary prevention anticoagulation is only recommended for special conditions, such as ASS intolerance (alternative: clopidogrel), ventricular aneurysm, ventricular thrombus, severe heart failure and/or atrial fibrillation.

Anticoagulants↗
PubMed2001

Differential effects of radiocontrast agents on human umbilical vein endothelial cells: cytotoxicity and modulators of thrombogenicity.

UNLABELLED: The endothelium plays a central role in the regulation of blood flow and coagulation. The impact of radiocontrast agents on endothelial cells is therefore potentially clinically important, particularly in percutaneous interventions for acute coronary thrombosis. The effects of radiocontrast agents on endothelial cell viability and determinants of thrombogenicity were studied in human umbilical vein endothelial cells (HUVECs) in vitro. Intercellular tight junctions were assessed using immunofluorescence microscopy and measurement of the transmonolayer electrical resistance (TMR). The concentrations of endothelin-1 (E), von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and thrombomodulin (T) were measured in the cell culture media. The ionic, high osmolal radiocontrast agent diatrizoate induced concentration-dependent cell death and an opening of tight junctions with the attendant abolition of the TMR. The concentration of E decreased, vWF increased in the cell culture media, the concentration of PAI-1 and T was not significantly changed by diatrizoate. Radiocontrast agents with reduced osmolality (ioxaglate: ionic; iopamidol: non-ionic) induced an increase in PAI-1 and vWF, but E and T were not significantly changed. CONCLUSIONS: Radiocontrast agents have differential effects on endothelial cells in vitro including the secretion of modulators of thrombogenesis. The effects are most pronounced in the markedly hyperosmolal compound diatrizoate suggesting a contributory role of hypertonicity. Ioxaglate and iopamidol both increased the prothrombotic factors vWF and PAI-1 to the same degree indicating a similar risk of thrombogenicity between low-osmolal ionic and non-ionic radiocontrast agents in this in vitro model.

Blood Coagulation↗
PubMed2001

Respiratory muscle dysfunction in congestive heart failure: clinical correlation and prognostic significance.

BACKGROUND: In congestive heart failure (CHF), the prognostic significance of impaired respiratory muscle strength has not been established. METHODS AND RESULTS: Maximal inspiratory pressure (Pi(max)) was prospectively determined in 244 consecutive patients (207 men) with CHF (ischemic, n=75; idiopathic dilated cardiomyopathy, n=169; age, 54+/-11 years; left ventricular ejection fraction [LVEF], 22+/-10%). Pi(max) was lower in the 244 patients with CHF than in 25 control subjects (7.6+/-3.3 versus 10.5+/-3.7 kPa; P=0.001). The 57 patients (23%) who died during follow-up (23+/-16 months; range, 1 to 48 months) had an even more reduced Pi(max) (6.3+/-3.2 versus 8.1+/-3.2 kPa in survivors; P=0.001). Kaplan-Meier survival curves differentiated between patients subdivided according to quartiles for Pi(max) (P=0.014). Pi(max) was a strong risk predictor in both univariate (P=0.001) and multivariate Cox proportional hazard analyses (P=0.03); multivariate analyses also included NYHA functional class, LVEF, peak oxygen consumption (peak VO(2)), and norepinephrine plasma concentration. The areas under the receiver-operating characteristic curves for prediction of 1-year survival were comparable for Pi(max) and peak VO(2) (area under the curve [AUC], 0.68 versus 0.73; P=0.28), and they improved with the triple combination of Pi(max), peak VO(2), and LVEF (AUC, 0.82; P=0.004 compared with AUC of Pi(max)). CONCLUSIONS: In patients with CHF, inspiratory muscle strength is reduced and emerges as a novel, independent predictor of prognosis. Because testing for Pi(max) is simple in clinical practice, it might serve as an additional factor to improve risk stratification and patient selection for cardiac transplantation.

Adult↗
PubMed2001

The neuronal norepinephrine transporter in experimental heart failure: evidence for a posttranscriptional downregulation.

An impairment of norepinephrine (NE) re-uptake by the neuronal NE transporter (NET) has been shown to contribute to the increased cardiac net-release of NE in congestive heart failure (CHF). The present study investigated which mechanisms are involved in the impairment of NET. Rats with supracoronary aortic banding characterized by myocardial hypertrophy, elevated left ventricular end diastolic pressures and severe pulmonary congestion were used as an experimental model for CHF. Compared to sham-operated controls, aortic-banded rats had enhanced plasma NE concentrations and decreased cardiac NE stores. In isolated perfused hearts of aortic-banded rats, functional impairment of NET was indicated by a 37% reduction in [(3)H]-NE-uptake. In addition, pharmacological blockade of NET with desipramine led to a markedly attenuated increase in the overflow of endogenous NE from hearts of aortic-banded rats. Determination of cardiac NET protein and of NET mRNA in the left stellate ganglion by [(3)H]-desipramine binding and competitive RT-PCR, respectively, revealed a 41% reduction of binding sites but no difference in gene expression. The density of sympathetic nerve fibers within the heart was unchanged, as shown by glyoxylic acid-induced histofluorescence. In conclusion, as impairment of intracardiac NE re-uptake by a reduction of NET binding sites is neither mediated by a decreased NET gene expression nor by a loss of noradrenergic nerve terminals, a posttranscriptional downregulation of NET per neuron is suggested in CHF.

Animals↗
PubMed2001

d,l-sotalol enhances baroreflex sensitivity in conscious rats surviving acute myocardial infarction.

The aim of the present study was to characterize the influence of D,L-sotalol on arterial baroreflex sensitivity (BRS) which is generally considered as an estimate of vagal activity and has prognostic value in patients after myocardial infarction (MI). Conscious rats were studied 3 days after left anterior descending coronary artery ligation (n= 5) or sham-operation (SH, n= 6). BRS was determined by linear regression analysis of the RR-interval (interval between heart beats) and mean arterial pressure changes evoked by i.v. bolus injections of methoxamine (inducing reflex bradycardia, RB) and nitroprusside (inducing reflex tachycardia, RT). In MI-rats heart rate and mean arterial pressure were not significantly different from values in SH-rats, left ventricular end-diastolic pressure was increased and contractility was depressed. The BRS (RB: MI: 0.48 +/- 0.04(*), SH: 0.79 +/- 0.08; RT: MI: 0.41 +/- 0.05(*), SH: 0.86 +/- 0.08 ms mmHg(-1)) ((*)P< 0.05 vs SH) was markedly reduced. d, l -Sotalol (1.5 mg kg(-1)i.v.) reduced heart rate (MI: -11 +/- 3 %(*), SH: -11 +/- 3 %(*)) and mean arterial pressure only moderately [MI: -6 +/- 4 %(n.s.), SH: -7 +/- 2 %(*)], while BRS depression in MI-rats was completely neutralized [RB: MI: 1.08 +/- 0.14(*), SH: 1.19 +/- 0.11(*); RT: MI: 0.84 +/- 0.08(*), SH: 0.88 +/- 0.12 (n.s.) ms mmHg(-1)] ((*)P< 0.05 vs pretreatment). The BRS is reduced in rats early after MI, indicating a depressed reflex vagal activity. Treatment with D,L-sotalol at a dose with little effect on heart rate and mean arterial pressure markedly enhances and, thus, restores BRS in MI-rats. These data suggest that D,L-sotalol has both peripheral and central effects leading to an increase of reflex vagal control of heart rate in rats.

Acute Disease↗
PubMed2001

Troponin T elevation after successful directional atherectomy.

BACKGROUND: The incidence and correlates of postinterventional cardiac troponin T (cTnT) elevation have not been evaluated in patients with successful directional atherectomy (DCA). METHODS: Total creatine kinase (CK) activity, CK-MB mass concentrations and cTnT levels were measured in 36 patients before, and serially 4, 24, 48 and 72 hours after successful DCA. Patients were followed for death, Q-wave infarction, need for emergency bypass surgery, periprocedural vascular complications (transient in-lab vessel closure, side branch compromise, large dissection), and non-Q-wave infarction on ECG. Patients were followed for clinical outcomes and angiographic restenosis for 6 months. Vascular correlates were studied by coronary angiography and intravascular ultrasound before, immediately after and 4 hours after elective and successful DCA. RESULTS: 25 patients (69.4%) had elevated levels of cTnT, whereas CK-MB mass > or = 6 ng/ml and mild elevations of total CK activity were present in only 36.1 and 5.6%, respectively. Elevated cTnT was related to vascular complications in 44% of cases. Inapparent microembolization of platelets or plaque debris was considered responsible for most of the remaining micronecroses. During 6 month follow-up rates of clinical restenosis (44 vs 9%, p = 0.059) tended to be higher in patients with as compared to patients without cTnT release after DCA. CONCLUSION: Successful DCA is associated with postprocedural elevations of cTnT which relate to minor vascular complications and presumably microembolization of platelets or plaque debris. The superior diagnostic performance of cTnT compared to CK-MB mass may relate to more sensitive identification of microinfarction. Further studies are mandatory to confirm the association between elevation of cTnT and risk of restenosis and TVR.

Atherectomy, Coronary↗
PubMed2001

4-hydroxynonenal induces apoptosis, NF-kappaB-activation and formation of 8-isoprostane in vascular smooth muscle cells.

Oxidation of lipids is considered a key feature of atherogenesis. Lipid peroxidation products such as oxidized LDL or the bioactive aldehyde 4-hydroxynonenal (HNE) exert mitogenic effects on vascular smooth muscle cells (VSMC). These effects appear to be concentration-dependent since in addition to our previous reports on growth promotion at lower concentrations we here indicate induction of apoptosis in VSMC by 4-hydroxynonenal (HNE) at higher concentrations (100 micromol/L). In a line with HNE's previously documented effects on key mitogenic signaling elements, we also report on activation by this aldehyde of the redox-sensitive transcription factor NF-kappaB, a key regulator of apoptosis: HNE (1.0 micromol/L) induced DNA-binding of NF-kappaB in VSMC. The effect was inhibited by antioxidants, N-acetylcysteine and pyrrolidine dithio-carbamate. HNE caused phosphorylation but not degradation of the inhibitory subunit IkappaB-alpha. HNE itself acts as an oxidant as was investigated with measurements of 8-isoprostane which ranks among the most valuable available biomarkers of lipid peroxidation: HNE (1.0 micromol/L) increased 8-isoprostane levels in VSMC by 4.5-fold (p < 0.05). Compared to the controls, plasma samples from apoEnull mice exhibited elevated levels of 8-isoprostane (40 pg/mL, 3.2-fold increase) and the combined aldehydes HNE and malonaldehyde (1.5 micromol/L, 2.5-fold increase), (p < 0.05, resp). In addition, immunohistochemistry indicated the presence of HNE-protein adducts in atheroscerlotic lesions of apoEnull mice. Thus HNE is present in atherosclerotic tissue at concentrations that are bioactive in vitro. The data further indicate the involvement of the lipid peroxidation product HNE in atherogenesis.

Aldehydes↗
PubMed2001

Effects of propafenone on anisotropic conduction properties within the three-dimensional structure of the canine ventricular wall.

BACKGROUND: Structural complexities of the intact ventricular wall cause a very complex spread of activation. The effects of regional tissue damage and of antiarrhythmic drugs on directional differences in activation should help to further elucidate intramural conduction patterns. METHODS AND RESULTS: In 10 healthy dogs and in 5 dogs with subacute anterior wall infarction, 6 parallel rows of 6 needle electrodes with 4 bipolar electrode pairs per needle were inserted into the left anterior ventricular wall. Using a computerized multiplexer-mapping system, the spread of activation in epi-, endo- and midmyocardial muscle layers and in the surviving epicardium, respectively, was reconstructed. Marked differences in conduction velocities relative to fiber orientation were evident in the surviving epicardium of infarcted hearts. Directional differences in conduction velocities, although less pronounced, were still preserved throughout the intact ventricular wall. Epicardial transverse conduction in intact hearts was significantly faster than transverse conduction in infarcted hearts (0.87 +/- 0.11 m/s vs 0.68 +/- 0.1 m/s). In normal hearts, propafenone (2 mg/kg) decreased conduction velocities primarily in longitudinal directions (-27 +/- 10%), but also moderately in transverse directions (-13 +/- 7 %) of all muscle layers, with no significant effect on straight (-4 +/- 8 %), but on oblique transmural conduction (-33 +/- 18 %). In infarcted hearts propafenone decreased conduction particularly in longitudinal direction (-23 +/- 14 %) without affecting conduction transverse to the fiber orientation (+3 +/- 6%). CONCLUSIONS: Longitudinal intramural shortcircuits reduce directional differences in activation. Transmural infarction results in a loss of alternative intramural pathways, unmasking marked anisotropy in the surviving epicardium. Conduction delay in intramural pathways explains the effects of propafenone on transverse and oblique transmural conduction. Primarily longitudinal conduction delay results in reduced tissue anisotropy.

Animals↗
PubMed2001

Phosphorylation of cytokeratin 8 and 18 in human vascular smooth muscle cells of atherosclerotic lesions and umbilical cord vessels.

Expression of cytokeratins (CK) is considered a hallmark of the state of epithelial differentiation. CK also occur in certain vascular smooth muscle cells (VSMC), inferring an association with a less differentiated phenotype. Recently, CK posttranslational modification was shown to occur in epithelial cells in stress, mitosis or apoptosis. The aim of this study was to determine potential CK phosphorylation patterns in human VSMC. Tissue samples of normal peripheral and coronary arteries, atherosclerotic lesions and umbilical cord vessels were evaluated by immunofluorescence microscopy applying antibodies specific for cytokeratins 8 and 18, specific cytokeratin phosphorylation sites, Ki-67-antigen as a proliferation marker and nick end labeling (TUNEL) to detect apoptosis. All samples contained cytokeratin-positive VSMC but diverse phosphorylation patterns. The C-terminal serine 431 of cytokeratin 8 (CK8Ser-431) was phosphorylated in the vast majority of CK-expressing VSMC of coronary artery lesions. Only a subset of these cells demonstrated phosphorylation of CK18Ser-33 or, to an even lesser extent, CK8Ser-73. DNA fragmentation occurred predominantly in samples containing cells with phosphorylated CK8Ser-431 domains. In contrast, occluded peripheral lesions exhibited little or no phosphorylation. Neonatal VSMC in umbilical cord vessels contain abundant phosphorylated CK domains, again predominantly CK8Ser-431, but also CK18Ser-33. Again, only single cells were found to be proliferating or to contain DNA fragmentation. Thus, abundant CK phosphorylation in VSMC of atherosclerotic lesions suggests a specific functional response to cell stress and a possible relation to apoptosis.

Aorta↗
PubMed2001

Increased activity of membrane-associated nucleoside diphosphate kinase and inhibition of cAMP synthesis in failing human myocardium.

OBJECTIVE: Chronic heart failure is associated with a decreased responsiveness of the heart to beta-adrenergic receptor agonists. We recently demonstrated a receptor-independent activation of G proteins and modulation of cardiac adenylyl cyclase activity by sarcolemmal membrane-associated nucleoside diphosphate kinase. We wondered whether changes in the activity of nucleoside diphosphate kinase occur in heart failure and contribute to or compensate for the impairment in myocardial receptor-mediated cAMP generation. METHODS: Sarcolemmal membranes were purified from non-failing and failing human left ventricular myocardium. The protein level and activity of nucleoside diphosphate kinase were quantified. The influence of nucleoside diphosphate kinase on adenylyl cyclase activity was determined by measuring the effect of GDP on adenylyl cyclase activity in the absence and presence of nucleoside diphosphate kinase inhibitors. RESULTS: The amount and activity of nucleoside diphosphate kinase in sarcolemmal membranes from failing hearts (n=13) were increased 3- to 4-fold compared to levels in membranes from non-failing myocardium (n=5). This increase in sarcolemmal nucleoside diphosphate kinase activity resulted in a 50% inhibition of adenylyl cyclase activity over a range of GDP and ATP concentrations. CONCLUSION: The amount and activity of nucleoside diphosphate kinase are increased in sarcolemmal membranes of failing human myocardium, resulting in a substantial receptor-independent inhibition of adenylyl cyclase activity.

5'-Nucleotidase↗
PubMed2001

Risk stratification in middle-aged patients with congestive heart failure: prospective comparison of the Heart Failure Survival Score (HFSS) and a simplified two-variable model.

AIMS: The performance of a US-American scoring system (Heart Failure Survival Score, HFSS) was prospectively evaluated in a sample of ambulatory patients with congestive heart failure (CHF). Additionally, it was investigated whether the HFSS might be simplified by assessment of the distance ambulated during a 6-min walk test (6'WT) instead of determination of peak oxygen uptake (peak VO(2)). METHODS AND RESULTS: In 208 middle-aged CHF patients (age 54+/-10 years, 82% male, NYHA class 2.3+/-0.7; follow-up 28+/-14 months) the seven variables of the HFSS: CHF aetiology; heart rate; mean arterial pressure; serum sodium concentration; intraventricular conduction time; left ventricular ejection fraction (LVEF); and peak VO(2), were determined. Additionally, a 6'WT was performed. The HFSS allowed discrimination between patients at low, medium and high risk, with mortality rates of 16, 39 and 50%, respectively. However, the prognostic power of the HFSS was not superior to a two-variable model consisting only of LVEF and peak VO(2). The areas under the receiver operating curves (AUC) for prediction of 1-year survival were even higher for the two-variable model (0.84 vs. 0.74, P<0.05). Replacing peak VO(2) with 6'WT resulted in a similar AUC (0.83). CONCLUSION: The HFSS continued to predict survival when applied to this patient sample. However, the HFSS was inferior to a two-variable model containing only LVEF and either peak VO(2) or 6'WT. As the 6'WT requires no sophisticated equipment, a simplified two-variable model containing only LVEF and 6'WT may be more widely applicable, and is therefore recommended.

Adult↗
PubMed2001

Ecarin clotting time but not aPTT correlates with PEG-hirudin plasma activity.

BACKGROUND: Novel antithrombotic agents such as hirudin have shown promise in the therapy of acute coronary syndromes. PEG-hirudin (polyethyleneglycol conjugated hirudin) has been developed to provide a longer plasma half-life and more stable antithrombotic plasma levels. Privious trials indicated a narrow therapeutic window for hirudin and a number of aPTT (activated partial thromboplastin time)-monitored trials investigating hirudin in acute coronary syndromes had to be stopped because of intracranial bleeding complications. OBJECTIVES: The present study evaluates the ecarin clotting time (ECT), a parameter based on the conversion of prothrombin by the snake venom enzyme ecarin, for the monitoring of PEG-hirudin therapy. METHODS: Plasma from either healthy volunteers (n=20) or from patients (n=10) suffering from unstable angina pectoris (UAP) was spiked with increasing PEG-hirudin concentrations. In a prospective randomized clinical trial patients with UAP were treated with intravenous PEG-hirudin or heparin over 72 hours. Patients were randomized to the following treatment groups: (1) heparin control group, n=15; (2) PEG-hirudin low dose (0.1 mg/kg bolus, 0.01 mg/kg/h infusion), n=19; (3) intermediate dose (0.15 mg/kg and 0.015 mg/kg/h), n=17; 4) high-dose (0.2 mg/kg and 0.02 mg/kg/h), n=16. Spiked plasma samples and plasma from UAP patients treated with i.v. PEG-hirudin were analyzed for aPTT, ECT, and PEG-hirudin levels. RESULTS: A linear correlation up to the highest therapeutic concentrations could be observed between PEG-hirudin plasma concentrations and the ECT. This was true for both plasma samples spiked with PEG-hirudin in vitro as well as for samples taken from patients treated with i.v. PEG-hirudin (correlation coefficient 0.9, respect.) In contrast the aPTT did not show a reliable linear correlation to PEG-hirudin concentrations. CONCLUSION: Monitoring of PEG-hirudin therapy by ECT may help to avoid inadequate anticoagulation or overdosing. Thus, the safety and efficacy profile of PEG-hirudin therapy is likely to be enhanced by ECT monitoring.

Angina, Unstable↗
PubMed2001

Transfer of the human NaI symporter gene enhances iodide uptake in hepatoma cells.

UNLABELLED: The characteristic feature of thyroid cells of taking up iodide enables benign thyroid diseases and differentiated thyroid carcinoma to be successfully treated with radioiodide therapy. The transport of iodide across the cell membrane is mediated by the human NaI symporter (hNIS). We therefore investigated whether the accumulation of iodide may be induced by the retroviral transfer of the hNIS gene in nonthyroid tumor cells. METHODS: With use of a bicistronic retroviral vector for the transfer of the hNIS coding sequence and the hygromycin resistance gene, rat Morris hepatoma (MH3924A) cells were infected with retroviral particles and 32 hNIS-expressing cell lines were generated by hygromycin selection. After incubation of the genetically modified and wild-type hepatoma cells and the rat thyroid cell line FRTL5 with Na125I, the uptake and efflux of iodide were determined. In addition, the iodide distribution in rats bearing wild-type and genetically modified hepatomas was monitored. RESULTS: Genetically modified MH3924A cell lines accumulated up to 235 times more iodide than did noninfected hepatoma cells. The maximal iodide uptake in the cells was observed after 60 min incubation time. Competition experiments in the presence of sodium perchlorate revealed a dose-dependent decrease of iodide uptake (87%-92%). Moreover, carbonyl cyanide p-trifluoromethoxyphenylhydrazone led to a loss of accumulated I- (32%), whereas 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene increased the I- uptake into the cells (22%). However, a rapid efflux of the radioactivity (80%) was observed during the first 10 min after 125I(-)-containing medium had been replaced by nonradioactive medium. In rats, the hNIS-expressing tumors accumulated six times more iodide than did the contralateral wild-type tumor as monitored by scintigraphy. The ex vivo quantitation of the iodide content performed 1 h after tracer administration in 1 g of tumor tissue revealed a 17-fold higher iodide accumulation in the genetically modified tumors. In accordance with the in vitro data, we also observed a rapid efflux of radioactivity from the tumor in vivo. CONCLUSION: The transduction of the hNIS gene per se is sufficient to induce 125I transport in Morris hepatoma cells in vitro and in vivo. With regard to a therapeutic application, however, additional conditions need to be defined that inhibit the iodide efflux from the tumor cells.

Animals↗
PubMed2001

Attenuation by fibrates of plasminogen activator inhibitor type-1 expression in human arterial smooth muscle cells.

Human atherosclerotic lesions exhibit increased expression of plasminogen activator inhibitor type-1 (PAI-1) that has been implicated in atherogenesis. Although vascular smooth muscle cells are a predominant source of PAI-1 expression potentially favorable modulation of PAI-1 expression by fibrates has not yet been characterized in these cells. Human aortic smooth muscle cells were exposed to selected growth factors. PAI-1 expression was stimulated most powerfully by TGF-beta (EC50 = 0.2 ng/ml, up to 12-fold increase). Gemfibrozil inhibited basal PAI-1 expression by 23% (p = ns) and TGF-beta-induced PAI-1 expression by 52% (p = 0.017) whereas t-PA and total protein synthesis was not affected. Changes in PAI-1 protein accumulation reflected PAI-1 gene expression attributable to modulation of half-life of PAI-1 mRNA by gemfibrozil. Inhibition by other fibrates was less. Gemfibrozil specifically attenuates TGF-beta-induced PAI-1 expression in human arterial smooth muscle cells. Thus, fibrates are promising agents for normalizing increased PAI-1 expression in arterial walls in patients in whom PAI-1 expression is increased.

Aorta↗
PubMed2000

Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis.

BACKGROUND: Tetrahydrobiopterin (BH4), an essential cofactor for the synthesis of NO, improves endothelial dysfunction after ischemia/reperfusion. Therefore, we hypothesized that reduction of BH4 is involved in the attenuation of endothelium-dependent vasodilation in atherosclerosis, and we investigated the effect of alterations of the BH4 level on the vasodilatory potential of coronary resistance vessels from humans and pigs with atherosclerosis. METHODS AND RESULTS: Coronary arterioles were obtained from patients undergoing CABG (atherosclerosis group) or valve replacement (control group) and from pigs fed either a standard diet (control group) or atherogenic diet (atherosclerosis group). After isolation, vessels were cannulated, pressurized, and placed on the stage of an inverted microscope. Dose-response curves were investigated in response to the endothelium-dependent agonists histamine, serotonin, and acetylcholine (for pigs, substance P) and to the endothelium-independent agonist sodium nitroprusside (SNP) under control conditions and before and after incubation of the vessels with sepiapterin (substrate for BH4 synthesis). In vessels from patients and from animals with atherosclerosis, compared with vessels from the control groups, there was a significant (P:<0.05) reduction of vasodilation to all tested endothelium-dependent agonists but not to SNP. After application of sepiapterin, the responses to the endothelium-dependent agonists but not to SNP were significantly improved in vessels from the atherosclerosis groups. Sepiapterin did not influence vascular reactivity in the control groups. CONCLUSIONS: Atherosclerosis severely compromises endothelial function of coronary resistance arteries. Administration of sepiapterin leads to a significant improvement of endothelium-dependent vasodilatation to different agonists in vessels from humans and pigs with atherosclerosis. Therefore, we conclude that a reduced availability of BH4 is involved in the development of endothelial dysfunction in atherosclerosis.

Acetylcholine↗