Biomedical subjects

Michael Wolzt

Publications and source records attributed to Michael Wolzt.

At least 37 records · Page 2Linked to original sources

PubMed2005

Naloxone does not influence cardiovascular responses to mild mental stress in postmenopausal women.

The interaction between central opioid activity, sex hormones, and the cardiovascular reactivity to stress is unknown. Twenty-eight healthy postmenopausal women, 16 without, and 12 with hormone replacement therapy (HRT) participated in this randomized, double-blind, cross-over study. The opioid receptor antagonist naloxone or placebo was administered intravenously on 2 different days and mild mental stress was induced by the Stroop Color-Word Test. Cardiovascular responses were assessed noninvasively by impedance cardiography. Stress significantly increased stroke volume, cardiac output, blood pressure, and heart rate, which was not influenced by opioid receptor blockade. Whereas naloxone increased cortisol plasma concentrations irrespective of HRT status, luteinizing hormone concentrations, which were higher in non-HRT compared with HRT women, were increased by naloxone in women with HRT only. These data suggest that the opioidergic tone of the hypothalamus-pituitary-adrenal axis persists in postmenopausal women, irrespective of HRT use, while the opioidergic tone on the hypothalamus-pituitary-gonadal axis seems to depend on an estrogenic milieu. Naloxone does not alter cardiovascular mental stress reactions in postmenopausal women independent of their hormone substitution status.

Blood Pressure↗

PubMed2005

Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction.

Acute inflammation causes endothelial dysfunction, which is partly mediated by oxidant stress and inactivation of nitric oxide. The contribution of depletion of tetrahydrobiopterin (BH(4)), the cofactor required for nitric oxide generation, is unclear. In this randomized, double-blind, three-way crossover study, forearm blood flow (FBF) responses to ACh and glyceryltrinitrate (GTN) were measured before and 3.5 h after infusion of Escherichia coli endotoxin (LPS, 20 IU/kg iv) in eight healthy men. The effect of intra-arterial BH(4) (500 microg/min), placebo, or vitamin C (24 mg/min) was studied on separate days 3.5 h after LPS infusion. In addition, human umbilical vein endothelial cells were incubated for 24 h with vitamin C and LPS. ACh and GTN caused dose-dependent forearm vasodilation. The FBF response to ACh, which was decreased by 23 +/- 17% (P < 0.05) by LPS infusion, was restored to baseline reactivity by BH(4) and vitamin C. FBF responses to GTN were not affected by BH(4) or vitamin C. LPS increased leukocyte count, high-sensitivity C-reactive protein, IL-6, IL-1beta, IFN-gamma, monocyte chemoattractant protein-1, pulse rate, and body temperature and decreased platelet count and vitamin C concentration. Vitamin C increased forearm plasma concentration of BH(4) by 32% (P < 0.02). Incubation with LPS and vitamin C, but not LPS alone, increased intracellular BH(4) concentration in human umbilical vein endothelial cells. Impaired endothelial function during acute inflammation can be restored by BH(4) or vitamin C. Vitamin C may exert some of its salutary effects by increasing BH(4) concentration.

Acetylcholine↗

PubMed2005

PGE1 analog alprostadil induces VEGF and eNOS expression in endothelial cells.

Endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor 1-alpha (HIF-1alpha) are important regulators of endothelial function, which plays a role in the pathophysiology of heart failure (HF). PGE1 analog treatment in patients with HF elicits beneficial hemodynamic effects, but the precise mechanisms have not been investigated. We have investigated the effects of the PGE1 analog alprostadil on eNOS, VEGF, and HIF-1alpha expression in human umbilical vein endothelial cells (HUVEC) using RT-PCR and immunoblotting under normoxic and hypoxic conditions. In addition, we studied protein expression by immunohistochemical staining in explanted hearts from patients with end-stage HF, treated or untreated with systemic alprostadil. Alprostadil causes an upregulation of eNOS and VEGF protein and mRNA expression in HUVEC and decreases HIF-1alpha. Hypoxia potently increased eNOS, VEGF, and HIF-1alpha synthesis. The alprostadil-induced upregulation of eNOS and VEGF was prevented by inhibition of MAPKs with PD-98056 or U-0126. Consistently, the expression of eNOS and VEGF was increased, and HIF-1alpha was reduced in failing hearts treated with alprostadil. The potent effects of alprostadil on endothelial VEGF and eNOS synthesis may be useful for patients with HF where endothelial dysfunction is involved in the disease process.

Alprostadil↗

PubMed2005

Asymmetrical dimethylarginine plasma concentrations are related to basal nitric oxide release but not endothelium-dependent vasodilation of resistance arteries in peritoneal dialysis patients.

Vascular dysfunction in chronic renal failure may be linked to reduced nitric oxide (NO) bioactivity and increased circulating concentrations of the endogenous NO synthase inhibitor asymmetrical dimethyl L-arginine (ADMA). The association between ADMA and basal endothelial NO release and endothelium-dependent vasodilation in resistance arteries of chronic renal failure patients is unknown. Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine, the endothelium-independent vasodilator nitroglycerine, and the endothelium-dependent vasoconstrictor N(G)-monomethyl-L-arginine (L-NMMA) were assessed in 37 peritoneal dialysis patients. L-arginine and ADMA plasma concentrations were measured by HPLC. ADMA (mean +/- SEM: 0.68 +/- 0.02 micromol/L) was associated with basal forearm blood flow (r = -0.33; P < 0.05) and L-NMMA induced vasoconstriction (r = -0.55; P < 0.0005), but not with dilator effects of acetylcholine or nitroglycerine. L-arginine (68 +/- 3 micromol/L) tended to correlate with acetylcholine-induced vasodilation (r = 0.32; P = 0.05) but was not associated with other parameters. ADMA is related to basal but not to acetylcholine-stimulated NO bioactivity in patients on peritoneal dialysis. Impaired endothelium-dependent vasodilation found in chronic renal failure is not explained by elevated circulating NO synthase inhibitors in renal failure.

Arginine↗

PubMed2005

Simvastatin blunts endotoxin-induced tissue factor in vivo.

BACKGROUND: Beyond lipid lowering, various antiinflammatory properties have been ascribed to statins. Moreover, in vitro studies have suggested the presence of anticoagulant effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, as lipopolysaccharide (LPS)-induced monocyte tissue factor (TF) was suppressed. In this study, we examined the role of statins in experimental endotoxemia on inflammatory and procoagulant responses in vivo. METHODS AND RESULTS: In this double-blind, placebo-controlled, parallel-group study, 20 healthy, male subjects were randomized to receive either simvastatin (80 mg/d) or placebo for 4 days before intravenous administration of LPS (20 IU/kg IV). Plasma high-sensitive C-reactive protein (hsCRP), monocyte chemoattractant protein (MCP-1), sCD40L, sCD40, and prothrombin fragment F1+2 (F1.2) were determined by ELISAs at baseline and at 4 and 8 hours after LPS administration. Monocyte TF expression and monocyte-platelet aggregates were measured by whole-blood flow cytometry over the same time course. The increases in hsCRP and MCP-1, both known inducers of TF, were significantly suppressed by statin treatment after LPS challenge. Statin premedication blunted the increase of monocyte TF expression in response to LPS. In parallel, endotoxin-induced formation of F1.2 was significantly reduced by simvastatin after 4 and 8 hours. LPS infusion affected neither the formation and activation of monocyte-platelet aggregates nor plasma levels of sCD40 and sCD40L. CONCLUSIONS: Simvastatin suppresses the inflammatory response to endotoxin and blunts monocyte TF expression but does not affect platelet activation.

Adult↗

PubMed2005

Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease.

OBJECTIVE: As regular physical exercise improves endothelial dysfunction and promotes cardiovascular health, we investigated the effect of training on angiogenesis by measuring the number of circulating endothelial progenitor cells (EPC), the level of EPC-mobilizing growth factors and tested vascular function by flow-mediated dilation (FMD) in patients with coronary artery disease (CAD) and cardiovascular risk factors (CVRF). In addition, degradation products of the NO pathway (NOx) were determined. METHODS AND RESULTS: Twenty patients with documented CAD and/or CVRF joined a 12-week supervised running training. Circulating EPCs--defined by the surface markers CD34, KDR and CD133--were measured at baseline and after exercise training by flow cytometry. We found a significant increase in circulating EPCs (2.9+/-0.4-fold increase; P < .0001), which was positively correlated with both, the change of FMD (r = .81, P < .001) and the increase of NOx synthesis (r = .83, P < .001). Plasma VEGF and erythropoietin did not change in response to exercise. However, we observed a positive correlation between the number of EPCs and erythropoietin at baseline (r = .70, P < .01) and after training (r = .73, P < .01). CONCLUSIONS: Regular exercise training augments the number of circulating EPCs in patients with CVRF and CAD and is associated with improved vascular function and NO synthesis.

Adult↗

PubMed2005

Homocyst(e)ine-lowering therapy does not affect plasma asymmetrical dimethylarginine concentrations in patients with peripheral artery disease.

BACKGROUND: Elevated plasma asymmetrical dimethylarginine (ADMA) is suggested to contribute to hyperhomocyst(e)ine-related vascular dysfunction in patients with peripheral artery disease (PAD). The present trial investigated whether homocyst(e)ine (Hcy)-lowering therapy with vitamin-B (vit-B) and folic acid affects plasma concentrations of ADMA in patients with PAD and hyperhomocyst(e)inemia. SUBJECTS AND METHODS: Forty-nine subjects (15 women, 34 men) with PAD and fasting plasma total Hcy concentrations greater than 15 micromol/liter were randomized to receive either oral vit-B and folic acid therapy (n = 27) or placebo (n = 22) for 6 wk. Fasting venous blood samples were monitored for plasma total Hcy, vit-B12 and folate, ADMA, symmetric dimethylarginine, L-arginine, and high-sensitivity C-reactive protein. RESULTS: After 6 wk, plasma Hcy concentrations were decreased, and concentrations of vit-B12 and folate were elevated in patients with vitamin supplementation (all P < 0.05 vs. baseline) and unchanged in the placebo group. Dimethylarginine plasma concentrations were not affected by treatment. High-sensitivity C-reactive protein correlated with ADMA plasma concentrations (r = 0.29; P < 0.01). CONCLUSION: The lack of vit-B and folic acid therapy on plasma concentrations of ADMA renders a role of extracellular methylarginines unlikely to be involved in the pathophysiology of hyperhomocyst(e)inemia and its complications.

Aged↗

PubMed2005

Regular physical exercise normalizes elevated asymmetrical dimethylarginine concentrations in patients with type 1 diabetes mellitus.

INTRODUCTION: Levels of the endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) are elevated in patients with type 1 diabetes mellitus (DM1) and may contribute to vascular complications. In this study we tested the hypothesis that elevated ADMA in patients with DM1 can be reduced by regular physical exercise. METHODS: Plasma samples for analysis of L-arginine, ADMA, symmetrical dimethylarginine (SDMA) and metabolic parameters were obtained from 11 patients with DM1 who participated in a supervised aerobic exercise program for four months. Samples were collected before the training began, at two and four months after initiation, and eight months after cessation of regular training. Fifteen age- and sex-matched healthy persons who did not exercise regularly were examined once as controls and did not participate in the training program. RESULTS: The patients with DM1 had higher ADMA levels than the controls before the training program began (0.54 +/- 0.02 vs. 0.44 +/- 0.03 micromol/l; P < 0.05). After two and four months of exercise, ADMA concentrations in the patients decreased to those seen in healthy persons (0.42 +/- 0.02 and 0.43 +/- 0.03 micromol/l; P < 0.001 and P < 0.05 compared with ADMA levels before training began). Eight months after cessation of the exercise program, ADMA levels in the patients reverted to those observed before the start of training. The L-arginine-to-ADMA ratio increased slightly after two months; L-arginine, symmetrical dimethylarginine, blood lipids and HbA1c were not affected by the training program. CONCLUSIONS: Elevated ADMA levels in patients with DM1, who have a high risk for developing cardiovascular disease, can be lowered to those of healthy persons by regular physical exercise. This favorable effect on ADMA is not sustained when training is discontinued.

Adult↗

PubMed2005

History of cardiovascular disease is associated with endothelial progenitor cells in peritoneal dialysis patients.

BACKGROUND: It is unknown whether traditional cardiovascular disease risk factors influence the number of endothelial progenitor cells (EPCs) and whether numbers of EPCs correlate with endothelial function in patients with end-stage renal disease. METHODS: In a cross-sectional study of 38 peritoneal dialysis patients, we examined numbers of circulating CD34+/KDR+/CD133+ cells, CD34+ hematopoietic stem cells, and EPCs cultured from peripheral blood. We also assessed conventional cardiovascular disease risk factors, such as history of vascular disease, diabetes, hypercholesterolemia, hypertension, and smoking. We determined endothelial function by measurement of endothelium-dependent and endothelium-independent reactivity of forearm resistance arteries by using strain-gauge plethysmography. RESULTS: Numbers of EPCs cultured from peripheral blood and forearm blood flow reactivity did not differ between erythropoietin-treated peritoneal dialysis patients and healthy individuals. A history of vascular disease was associated with number of cultured EPCs, but other cardiovascular disease risk factors showed no association. Furthermore, there was no association of endothelial-dependent and endothelial-independent forearm blood flow reactivity with EPCs in peritoneal dialysis patients. CONCLUSION: In this first study of EPCs in peritoneal dialysis patients, we found an association between history of vascular disease and EPCs, but no association of EPCs with endothelial function or other cardiovascular disease risk factors.

Aged↗

PubMed2005

Pharmacokinetics and pharmacodynamics of ximelagatran.

Oral anticoagulant therapy with vitamin K antagonists (VKAs) such as warfarin has proven benefits in the treatment and prevention of thromboembolic disorders but has important limitations that result in substantial underuse. In particular, the VKAs have variable and unpredictable pharmacokinetics and pharmacodynamics and a narrow separation between antithrombotic and hemorrhagic effects that necessitates careful dose adjustment based on frequent coagulation monitoring. In contrast, the oral direct thrombin inhibitor ximelagatran has a predictable and reproducible pharmacokinetic/pharmacodynamic profile that allows treatment using fixed-dose regimens without coagulation monitoring. The bioavailability of melagatran, the active form of ximelagatran, after oral administration of ximelagatran is approximately 20% with low inter- and intra-individual variability. Peak plasma melagatran concentrations are reached approximately 2 hours after oral dosing of ximelagatran to healthy volunteers, and melagatran is eliminated with a half-life of approximately 3 hours with clearance predominantly by renal excretion. Hence, a higher melagatran exposure is seen in patients with renal failure; ximelagatran is currently not recommended for patients with severe renal impairment (creatinine clearance of <30 mL/min) as these patients were not included in the clinical trial program. Exposure to melagatran increases linearly with the ximelagatran dose. The pharmacokinetic/pharmacodynamic profile is consistent across a broad range of different patient populations and is unaffected by gender, age, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Any differences in melagatran pharmacokinetics associated with these factors are attributable to differences in renal function.

Administration, Oral↗

PubMed2005

Low potential for interactions between melagatran/ximelagatran and other drugs, food, or alcohol.

Vitamin K antagonists including warfarin are associated with numerous interactions with other drugs and foods. In clinical practice, this complicates the task of maintaining plasma levels of warfarin within a narrow therapeutic window and so maximizing protection against thromboembolic events while minimizing the risk of complications, particularly bleeding. In contrast, ximelagatran has a low potential for pharmacokinetic drug:drug and food interactions. There is no significant metabolism of melagatran, and the main route of elimination of melagatran is renal excretion that appears to occur via glomerular filtration. Most importantly, cytochrome P450 isoenzymes that mediate many drug:drug interactions are not involved in the biotransformation of ximelagatran to melagatran. No significant pharmacokinetic interactions have been observed when oral ximelagatran is administered with a range of agents, including diclofenac, diazepam, nifedipine, digoxin, atorvastatin, or amiodarone. The low potential for drug:drug interactions with ximelagatran is also supported by an analysis of the pharmacokinetic data from clinical studies in patients with atrial fibrillation receiving long-term treatment with oral ximelagatran. Increases of mean melagatran area under the curve and maximum plasma concentration ( Cmax) of up to approximately 80% have been observed when ximelagatran is co-administered with the macrolide antibiotics erythromycin or azithromycin, and the mechanism for this interaction is currently under investigation. The bioavailability of melagatran is not altered by co-administration with food or alcohol. The melagatran-induced prolongation of activated partial thromboplastin time (APTT), an ex vivo coagulation time assay used as a measure of thrombin inhibition, is not altered by other drugs [including digoxin, atorvastatin, acetylsalicylic acid (ASA), and amiodarone], food, or alcohol. The effect of melagatran on capillary bleeding time, which is prolonged as a result of the inhibition of thrombin-induced platelet aggregation, is relatively low and additive to the platelet-inhibitory effect of ASA.

Anticoagulants↗

PubMed2005

Vasoconstrictor hyporeactivity can be reversed by antioxidants in patients with advanced alcoholic cirrhosis of the liver and ascites.

OBJECTIVE: Hyperdynamic circulation and systemic vasodilation complicate cirrhosis of the liver and are related to vasoconstrictor hyporeactivity. We investigated whether impaired vasoconstrictor responsiveness may be overcome by antioxidants in patients with decompensated alcoholic cirrhosis. DESIGN: Controlled clinical study. SETTING: University setting. PATIENTS: Nine patients with liver cirrhosis Child-Pugh grade C and nine healthy age-matched volunteers. INTERVENTIONS: Forearm blood flow responses to intra-arterial norepinephrine, angiotensin II, and the nitric oxide synthase inhibitor N-monomethyl-l-arginine were measured by strain-gauge plethysmography and compared between groups of patients. To assess the role of oxidative stress, the antioxidant vitamin C (24 mg/min) was administered locally into the brachial artery, and forearm blood flow responses were reassessed. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of vitamin C were lower in patients with cirrhosis (p < .05). In patients with cirrhosis, the reactivity to norepinephrine and angiotensin II was markedly reduced (p < .05 vs. controls). Coadministration of vitamin C completely restored the potency of vasoconstrictors to that in controls but had no effect in healthy subjects. No changes were observed in time-control experiments in cirrhosis patients (n = 3) employing vehicle coinfusion. The response to N-monomethyl-L-arginine was comparable between groups and not affected by vitamin C. CONCLUSIONS: Oxidative stress with consumption of antioxidants seems to play an important role in the development of vasoconstrictor hyporeactivity in patients with cirrhosis. Antioxidant therapy may be a promising clinical approach to restore vasoconstrictor hyporeactivity in these patients.

Angiotensin II↗

PubMed2005

Intravenous iron increases labile serum iron but does not impair forearm blood flow reactivity in dialysis patients.

BACKGROUND: There are concerns about adverse vascular effects of intravenous iron by inducing oxidative stress. We therefore examined the effect of a single high dose of intravenous iron on endothelial function and biochemical markers of iron homeostasis. METHODS: In a randomized, placebo-controlled, double-blind, parallel-group study, forearm blood flow (FBF) was assessed by strain-gauge plethysmography in 38 peritoneal dialysis patients before and after a single intravenous infusion of 300 mg iron sucrose. RESULTS: Iron infusion increased total (Delta 601 microg/100 mL, CI 507, 696) and non-transferrin-bound iron (Delta 237.2 micromol/L, CI 173.6, 300.8) approximately 10-fold, as well as redox-active iron nearly five-fold (Delta 0.76 micromol/L, CI 0.54, 0.98). After iron infusion basal FBF was 59% higher than after placebo. FBF response to acetylcholine before and after iron infusion was 263 +/- 32% and 310 +/- 33%, corresponding to 304 +/- 43% and 373 +/- 29% in the placebo group, respectively. Before and after iron or placebo infusion, glyceryl-trinitrate increased resting FBF to 232 +/- 22% and 258 +/- 21% in the iron group, and to 234 +/- 18% and 270 +/- 30% in the placebo group. L-N-monomethyl-arginine decreased FBF to 70 +/- 4% and 72 +/- 3% before and after iron, and to 74 +/- 4% and 73 +/- 4% before and after placebo infusions, respectively. Despite higher basal FBF after iron infusion, absolute and relative FBF changes in response to vasoactive substances were not significantly different between iron and placebo groups. CONCLUSION: Our data suggest that 300 mg intravenous iron sucrose has a vasodilatory effect, but does not impair vascular reactivity in dialysis patients, despite a significant increase in non-transferrin-bound and redox-active iron.

Adult↗

PubMed2004

Simvastatin prevents vascular hyporeactivity during inflammation.

BACKGROUND: There is growing evidence that statins exert anti-inflammatory and antioxidative vascular actions that are independent of lipid lowering. We tested whether hyporeactivity to the endothelium-dependent vasodilator acetylcholine (ACh) and the vasoconstrictor norepinephrine (NE) during acute experimental inflammation could be prevented by simvastatin. METHODS AND RESULTS: In a randomized, placebo-controlled, parallel group study, forearm blood flow (FBF) responses to NE, ACh, and the endothelium-independent vasodilator nitroglycerin (NTG) were assessed at baseline, after 4 days of simvastatin 80 mg PO or placebo treatment, and during Escherichia coli endotoxin (lipopolysaccharide [LPS])-induced inflammation in 20 healthy volunteers. Additionally, markers of inflammation and neutrophil oxidative burst were assessed. Simvastatin and placebo had no effect on FBF or oxidative/inflammatory markers. LPS administration decreased the responses of FBF to NE by 43% (P<0.05) and decreased responses to ACh by 48% (P<0.05) but did not decrease FBF responses to NTG. Simvastatin completely preserved responses to NE and to ACh. The LPS-induced increases in neutrophil oxidative burst and plasma tumor necrosis factor-alpha concentrations were mitigated by simvastatin (P<0.05 versus placebo). CONCLUSIONS: This study demonstrates potent vasoprotective properties of high-dose simvastatin during endotoxemia that may be useful for patients with acute systemic inflammation and associated vascular hyporeactivity.

Acetylcholine↗

PubMed2004

Extracorporeal shockwave treatment is effective in calcific tendonitis of the shoulder. A randomized controlled trial.

BACKGROUND: Calcific tendonitis of the shoulder is often associated with chronic pain and impairment of function. Extracorporeal shockwave therapy (ESWT) is considered to be a treatment option. We compared the effects of two different ESWT regimens. METHODS: 43 patients (57 shoulders) with symptomatic calcific tendonitis of the shoulder for more than six months were included in a double-blinded study. Thirty-one shoulders were treated at the area of maximum pain with application of 2 x 2000 impulses of 0.28 mJ/mm2 at an interval of two weeks (treatment group) and 26 shoulders with 2 x 2000 impulses of < 0.07 mJ/mm2 at an interval of two weeks (control group), without pretreatment analgesia. Shoulder function (Constant score) and pain (visual analogue scale, VAS) were assessed before treatment and at one week, three months and seven months after treatment. Shoulder X-rays were performed at the 3- and 7-month follow-up visits. RESULTS: Improvement in Constant score was significantly higher in the treatment group at all follow-up visits (p < 0.05). Seven months post-treatment, calcifications dissolved completely in 19% of the treatment group and 8% of the control group, and a > 50% reduction was observed in 19% and 8% respectively. With regard to reduction of pain, there was significant improvement in the treatment group compared with the control group at the 1-week follow-up (p < 0.05). However, at the 3-month and 7-month visits, no significant between-group difference in pain could be detected. CONCLUSION: As applied, ESWT with an energy flux density of 0.28 mJ/mm2 led to a significantly greater improvement in shoulder function and a slightly higher, nonsignificant, rate of > 50% disintegration of calcific deposits compared with the control group. However, this did not result in reduction of pain.

Activities of Daily Living↗

PubMed2004

LPS-induced microvascular leukocytosis can be assessed by blue-field entoptic phenomenon.

Administration of low doses of Escherichia coli endotoxin [a lipopolysaccharide (LPS)] to humans enables the study of inflammatory mechanisms. The purpose of the present study was to investigate whether the blue-field entoptic technique may be used to quantify the increase in circulating leukocytes in the ocular microvasculature after LPS infusion. In addition, combined laser Doppler velocimetry and retinal vessel size measurement were used to study red blood cell movement. Twelve healthy male volunteers received 20 IU/kg iv LPS as a bolus infusion. Outcome parameters were measured at baseline and 4 h after LPS administration. In the first protocol (n = 6 subjects), ocular hemodynamic effects were assessed with the blue-field entoptic technique, the retinal vessel analyzer, and laser Doppler velocimetry. In the second protocol (n = 6 subjects), white blood cell (WBC) counts from peripheral blood samples and blue-field entoptic technique measurements were performed. LPS caused peripheral blood leukocytosis and increased WBC density in ocular microvessels (by 49%; P = 0.036) but did not change WBC velocity. In addition, retinal venous diameter was increased (by 9%; P = 0.008), but red blood cell velocity remained unchanged. The LPS-induced changes in retinal WBC density and leukocyte counts were significantly correlated (r = 0.87). The present study indicates that the blue-field entoptic technique can be used to assess microvascular leukocyte recruitment in vivo. In addition, our data indicate retinal venous dilation in response to endotoxin.

Adult↗

PubMed2004

Specific endothelin ET(A) receptor antagonism does not modulate insulin-induced hemodynamic effects in the human kidney, eye, or forearm.

There is evidence that hyperinsulinemia may stimulate endothelin-1 (ET-1) generation or release, which may affect diabetic vascular complications. BQ-123, a specific ET(A) receptor antagonist, was used to investigate if insulin-induced vascular effects are influenced by an acute ET-1 release. Two randomized, placebo-controlled, double-blind, cross-over studies were performed. In protocol 1, 12 healthy subjects received, on separate study days, infusions of BQ-123 (60 microg/min for 30 min) during placebo clamp conditions, BQ-123 during euglycemic hyperinsulinemia (3 mU/kg/min for 390 min), or placebo during euglycemic hyperinsulinemia. Fundus pulsation amplitude (FPA) was measured to assess pulsatile choroidal blood flow, and mean flow velocity (MFV) of the ophtalmic artery was measured by color Doppler imaging. In protocol 2, eight healthy subjects received, on separate study days, intra-arterial infusions of BQ-123 (32 microg/min for 120 min) during placebo or insulin clamp. Forearm blood flow was measured with bilateral plethysmography, expressing the ratio of responses in the intervention arm and in the control arm. Insulin alone increased FPA (+10%, p < 0.001) and forearm blood flow (+19%). BQ-123 increased FPA, MFV, and forearm blood flow ratio in the absence and presence of exogenous insulin, but this effect was not different between normo- and hyperinsulinemic conditions. ET-1 plasma concentrations were not affected by insulin. In conclusion, these data do not support the concept that hyperinsulinemia increases ET-1 generation in healthy subjects. Our results, however, cannot necessarily be extrapolated to diabetic and obese subjects.

Adult↗

PubMed2004

Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure.

AIM: In experimental studies, nonexcitatory electrical stimulation delivered at the time of absolute myocardial refractoriness resulted in cardiac contractility modulation (CCM) with improved systolic function. This study reports the initial experience with CCM in patients with chronic heart failure. METHODS AND RESULTS: Twenty-five patients, 23 males, with a mean age of 62+/-9 years and drug-refractory NYHA class III heart failure were assigned to CCM-generator implantation. The underlying heart disease was idiopathic dilated cardiomyopathy in 12 patients and coronary heart disease in 13 patients. Acute efficacy of CCM with 7.73-V stimuli delivered via two right ventricular leads was evaluated by measuring the time derivative of left ventricular pressure (dP/dt). After implantation, the CCM generator was activated for 3 h daily over 8 weeks. In 23/25 patients the CCM system was implanted successfully. Heart failure significantly improved from NYHA class III to class II in 15 patients and to class I in 4 patients (p < 0.000001), left ventricular ejection fraction improved from 22+/-7% to 28+/-8% (p = 0.0002), and the Minnesota Living with Heart Failure Score improved from 43+/-22 to 25+/-18 (p = 0.001). The 6-min walk test increased from 411+/-86 to 465+/-81 m (p= 0.02). Nine patients (39%) had intermittent sensations associated with CCM delivery. There were two (8%) non-device-related deaths during follow-up. CONCLUSIONS: These preliminary data indicate that CCM by delivery of intermittent nonexcitatory electrical stimuli is a promising technique for improving ventricular systolic function and symptoms in patients with drug-refractory NYHA class III heart failure.

Cardiomyopathy, Dilated↗