Biomedical subjects

Frank Pistrosch

Publications and source records attributed to Frank Pistrosch.

11 recordsLinked to original sources

PubMed2005

Reduced agonist-induced endothelium-dependent vasodilation in uremia is attributable to an impairment of vascular nitric oxide.

Current concepts for the explanation of endothelial dysfunction and accelerated atherosclerosis in uremia propose a reduced vascular bioavailability of nitric oxide (NO). The aim of the present study was to test the contributions of NO and NO/prostacyclin (PGI(2))-independent mechanisms to both baseline vascular tone and agonist-induced endothelium-dependent vasodilation in patients on hemodialysis (HD). In 10 HD patients and eight matched healthy control subjects, forearm blood flow (FBF) was measured at rest and during intrabrachial infusions of norepinephrine (NE; endothelium-independent vasoconstrictor, 60, 120, and 240 pmol/min) and N-monomethyl-L-arginine (blocker of NO synthases, 16 micromol/min). After inhibition of cyclo-oxygenase by ibuprofen (1200 mg orally), endothelium-dependent and -independent vasodilation was assessed by infusion of acetylcholine (ACh; 1, 5, 10, 50, 100, and 300 nmol/min) and sodium-nitroprusside (2.5, 5, and 10 microg/min). NO/PGI(2)-independent vasodilation was tested by equal infusions of ACh during NO clamp. N-monomethyl-L-arginine reduced resting FBF to a comparable degree in both groups. Vascular responses to ACh were reduced in HD (P = 0.003 versus control by ANOVA), whereas those to sodium nitroprusside were mainly at control level. Infusion of ACh during NO clamp caused a similar increment of FBF in both groups. NO-mediated vasodilation as calculated by the difference between ACh-induced responses without and with NO clamp was substantially impaired in HD (P < 0.001) compared with control. In HD patients, baseline NO-mediated arteriolar tone is at control level. This study provides first evidence that endothelial dysfunction of uremic patients as shown by reduced agonist-induced endothelium-dependent vasodilation is attributable to reduced stimulation of NO, whereas the NO/PGI(2)-resistant portion of ACh-mediated vasodilation is unaffected.

Acetylcholine↗

PubMed2005

PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells.

OBJECTIVE: Endothelial progenitor cells (EPC) are involved in the process of endothelial maintenance and angiogenesis and might be related to endothelial function. EPC function was shown to be impaired in type 2 diabetic patients. Since endothelial dysfunction of type 2 diabetic patients can be ameliorated by treatment with thiazolidinediones we asked whether this treatment might also influence number and function of EPC. METHODS AND RESULTS: We investigated 10 recently diagnosed type 2 diabetic patients and 10 age and sex matched healthy control subjects. After baseline examination of metabolic parameters and EPC, patients received 4 mg rosiglitazone b.i.d. for 12 weeks. We measured EPC number and migratory activity after 3 and 12 weeks of treatment. Migratory activity of EPCs obtained from type 2 diabetic patients at baseline was 40% lower compared to control (P<0.05). There was no significant difference of EPC number between patients (323+/-19) and controls (358+/-25) at baseline. Treatment of patients with rosiglitazone normalized impaired migratory activity of EPC and increased EPC number (464+/-33, P<0.01). In addition treatment improved glycemic control and insulin sensitivity. CONCLUSIONS: Twelve-week treatment with rosiglitazone improved EPC number and migratory activity of type 2 diabetic patients. The latter mechanism may contribute to the recently observed improvement of endothelial function by rosiglitazone in type 2 diabetes.

AC133 Antigen↗

PubMed2005

Nitric oxide in chronic renal failure.

Endothelium-derived nitric oxide (NO) is critically involved in the regulation of a wide variety of vascular functions. It had been hypothesized that a deficiency of vascular NO might be involved in the accelerated atherosclerosis and dramatic cardiovascular mortality observed in patients with chronic renal failure. At present it is difficult to measure authentic NO in vivo. An alternative is to study NO by its effect on vascular tone by using the forearm blood flow technique. In this way, studies demonstrated an unimpaired availability of NO under baseline conditions but a profound reduction of agonist-induced endothelium-dependent vasodilatation in uremic patients. Further investigation showed that the latter phenomenon is mainly attributable to a reduced availability of vascular NO upon agonist stimulation, while the NO-independent mechanism(s) appear(s) to be intact in this setting. Explanations for this finding include an uncoupling of NO synthase induced by cofactor deficiency, and/or a reduced NO availability caused by high levels of oxidative stress. Recent data suggest only a minor role for cytochrome-P450 2C9-dependent pathways in this context. Future studies have to show which mechanisms are most relevant, and whether they are sensitive to therapeutic intervention.

Animals↗

PubMed2005

Nitric oxide- and EDHF-mediated arteriolar tone in uremia is unaffected by selective inhibition of vascular cytochrome P450 2C9.

BACKGROUND: Uremia is a state of endothelial dysfunction as demonstrated by a reduced agonist-induced endothelium-dependent vasodilatation. Recent studies suggest that an endothelial cytochrome P450 (CYP) epoxygenase (CYP 2C9) can modulate endothelium-dependent vasodilatation in two different ways: (1) by the production of epoxyeicosatrienoic acids (EETs), which elicit hyperpolarization and relaxation; and (2) by the release of oxygen-derived free radicals, which compromise the bioavailability of nitric oxide. We therefore determined whether one of these pathways is involved in endothelial dysfunction of uremia. METHODS: Using venous occlusion plethysmography, we measured forearm blood flow (FBF) in response to the intrabrachial infusion of acetylcholine (ACh; endothelium-dependent vasodilator; 1, 5, 10, 50, 100, and 300 nmol/min) and sodium nitroprusside (SNP; endothelium-independent vasodilator; 2.5, 5 and 10 microg/min) in 10 stable patients on hemodialysis (HD) and 9 healthy control subjects. In HD patients, ACh infusions were repeated together with sulfaphenazole (SPZ, 6 mg/min), a highly selective inhibitor of CYP 2C9 with and without concomitant blockade of the nitric oxide synthase (NOS) by N(omega)monomethyl L-arginine (L-NMMA, 16 microumol/min). RESULTS: Endothelium-dependent vasodilatation to ACh was reduced in HD compared to control subjects (P= 0.002), indicating endothelial dysfunction in the patients examined. Endothelium-independent vascular responses to SNP were attenuated in HD, but not significantly different to control. SPZ failed to modulate both baseline FBF and Ach-induced vasodilatation in HD. Furthermore, SPZ had no effect on baseline FBF and ACh-mediated vasodilatation in the presence of L-NMMA in HD. CONCLUSION: Our results do not support a major role for CYP 2C9-derived products in the regulation of arteriolar tone in early endothelial dysfunction of uremic subjects.

Acetylcholine↗

PubMed2005

Rosiglitazone improves glomerular hyperfiltration, renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy in patients.

Microalbuminuria, an early feature of diabetic nephropathy, indicates intrarenal endothelial damage. In type 2 diabetes, microalbuminuria is strongly related to insulin resistance. We therefore investigated whether rosiglitazone, an insulin-sensitizing drug that is known to improve endothelial dysfunction, was able to improve intrarenal endothelial dysfunction and microalbuminuria. Nineteen type 2 diabetic patients participated in this double-blind cross-over trial. Nine patients with newly diagnosed disease without microalbuminuria were randomized to a treatment with rosiglitazone or nateglinide, each for 12 weeks. Ten patients with microalbuminuria were randomized to rosiglitazone or placebo, each for 12 weeks in addition to their previous antidiabetic medication. After each treatment, glomerular filtration rate (GFR), renal plasma flow, and filtration fraction were measured before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-L-arginine-acetate (L-NMMA). Ten healthy subjects served as control subjects. Type 2 diabetic patients at baseline showed glomerular hyperfiltration compared with healthy control subjects. Rosiglitazone reduced elevated GFR and filtration fraction toward control primarily in patients with microalbuminuria (GFR: 133.4 +/- 9.8 vs. 119.6 +/- 8.7 ml/min; filtration fraction: 23.2 +/- 1.7 vs. 20.5 +/- 1.6% before and after rosiglitazone, respectively; control subjects: GFR 111.7 +/- 8.6 ml/min, filtration fraction 20.4 +/- 1.5%). Rosiglitazone improved intrarenal NO bioavailability in type 2 diabetes toward control as shown by infusion of L-NMMA. Rosiglitazone reduced albumin excretion in type 2 diabetes with microalbuminuria from 116.5 +/- 31 to 40.4 +/- 12 mg/day. Rosiglitazone ameliorated glomerular hyperfiltration in early type 2 diabetes, improved NO bioavailability, and lessened renal end-organ damage in type 2 diabetes with microalbuminuria.

Aged↗

PubMed2004

Hyperkalaemia: again.

Explore the source record for details and available documents.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2004

Reduced endothelin-1- and nitric oxide-mediated arteriolar tone in hypertensive renal transplant recipients.

BACKGROUND: The prevalence of hypertension is high in renal transplant recipients. It has been suggested that calcineurin inhibitors (CI) contribute to the development of post-transplant hypertension by stimulating endothelin (ET-1)-mediated and/or reducing nitric oxide (NO)-mediated vascular tone. METHODS: We tested this hypothesis using 2 groups of renal transplant recipients [normotensive patients without a need for antihypertensive medication (Normo-Tx), and hypertensive patients requiring antihypertensives (Hyper-Tx)] in the presence of CI-based immunosuppression. In addition, we studied matched control subjects (C). BQ 123 (ET-A receptor antagonist), BQ123 + BQ788 (ET-A/B-receptor antagonist), ET-1, L-NMMA (NO-synthase inhibitor), acetylcholine (ACH; endothelium-dependent vasodilator), glyceroltrinitrate (GTN, NO donor), and norepinephrine (NE, endothelium-independent vasoconstrictor) were infused into the brachial artery. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. RESULTS: Endothelium-independent vasomotion in response to GTN and NE was similar in all groups. Vascular responses to selective and combined blockade of ET receptors in both Normo-Tx and Hyper-Tx did not exceed those of C. In fact, we observed a significantly lower increase in FBF after BQ 123 (P= 0.03), as well as after BQ 123/788 (P= 0.03) in Hyper-Tx compared with Normo-Tx. This was associated with an increased vascular sensitivity to exogenous ET-1 in Hyper-Tx compared with Normo-Tx (P= 0.04). Vasoconstriction after L-NMMA was reduced in Hyper-Tx compared with Normo-Tx (P= 0.015), while the response to ACH was reduced in both groups of Tx patients to a similar degree (P= 0.005 vs. C). CONCLUSION: Our results do not support a major role for the vascular endothelin system in the hypertension of renal transplant recipients, whereas deficient baseline NO production may be a contributing factor.

Adult↗

PubMed2004

In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control.

OBJECTIVE: Insulin resistance is an independent risk factor for arteriosclerosis and cardiovascular mortality. However, the mechanism by which insulin resistance contributes to arteriosclerosis is unknown. Conceivably, endothelial dysfunction could be involved. Therefore, we asked whether therapy for insulin resistance ameliorates any endothelial dysfunction. RESEARCH DESIGN AND METHODS: We performed a double-blind cross-over trial of 12 patients with recently diagnosed type 2 diabetes. They received rosiglitazone 4 mg b.i.d. for 12 weeks and nateglinide 60 mg b.i.d. for the same number of weeks in random order. To assess the degree of endothelial dysfunction, we used venous occlusion plethysmography. We studied vasodilation in response to acetylcholine (ACh) with and without exogenous insulin. The agents were infused into the brachial artery. Furthermore, we determined insulin resistance by euglycemic clamp. RESULTS: Glycemic control was comparable under rosiglitazone and nateglinide. Rosiglitazone ameliorated insulin resistance by 60% compared with nateglinide. ACh response was significantly increased after rosiglitazone treatment (maximum forearm blood flow 12.8 +/- 1.3 vs. 8.8 +/- 1.3 ml/100 ml after rosiglitazone and nateglinide, respectively; P < 0.05) but did not attain the level of healthy control subjects (14.0 +/- 0.7 ml/100 ml). Coinfusion of exogenous insulin increased ACh response further in the rosiglitazone group. N-monomethyl-L-arginine-acetate (L-NMMA), an antagonist of nitric oxide synthase, largely prevented the increased vasodilation after rosiglitazone, regardless of the presence or absence of insulin. Insulin sensitivity and blood flow response were found to be correlated (P < 0.01). CONCLUSIONS: Insulin resistance is a major contributor toward endothelial dysfunction in type 2 diabetes. Both endothelial dysfunction and insulin resistance are amenable to treatment by rosiglitazone.

Acetylcholine↗

PubMed2004

Increased total number but impaired migratory activity and adhesion of endothelial progenitor cells in patients on long-term hemodialysis.

BACKGROUND: Endothelial progenitor cells (EPCs), derived from bone marrow, contribute to vessel repair and neovascularization. Because uremia is a state of endothelial dysfunction associated with high cardiovascular mortality, as well as a state of reduced hematopoiesis, we studied the number and function of EPCs in patients on long-term hemodialysis (HD) therapy. METHODS: We counted the number of EPCs in 20 HD patients and 16 healthy volunteers. To assess EPC function, we measured migratory activity, adhesion to matrix proteins, and adhesion to endothelial cells. Furthermore, we measured blood levels of vascular endothelial growth factor (VEGF) and granulocyte-macrophage colony-stimulating factor, factors known to influence EPC kinetics. Circulating precursor cells (CD34+ , CD34+ /CD133+ , CD34+ /KDR+ cells) were counted by means of flow cytometric analysis. RESULTS: The number of EPCs in HD patients was significantly elevated compared with controls (459.7 +/- 92 versus 364.8 +/- 77.4 EPC/high-power field). However, migratory activity was markedly decreased in HD patients (47.5 +/- 27.7 versus 84.7 +/- 3.2 EPC/high-power field). EPCs of HD patients showed impaired adhesion to extracellular matrix and endothelial cells. VEGF blood levels in HD patients were 2-fold greater compared with controls. The number of circulating CD34+ and CD34+ /133+ cells was reduced in HD patients. There were no differences in total numbers of CD34+ /KDR+ cells. CONCLUSION: This study shows an elevated number, but pronounced functional impairment, of EPCs in patients on long-term HD therapy. The latter may result in limited endothelial repair, which, in turn, may contribute to endothelial dysfunction in this particular group of patients.

AC133 Antigen↗

PubMed2003

Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low disease activity.

OBJECTIVE: Cardiovascular mortality is excessive in patients with rheumatoid arthritis (RA). It has been proposed that the chronic inflammatory state of RA contributes to accelerated atherosclerosis. The aim of this study was to determine whether endothelial dysfunction, an early sign of arteriosclerosis, is present in young, long-term RA patients receiving standard methotrexate (MTX) therapy. Furthermore, we tested whether etanercept (ENC), a TNF-alpha receptor blocker, resulted in improved endothelial function compared to MTX in the same patients. METHODS: We studied eight RA patients twice: (1) on MTX and (2) after MTX washout and receiving ENC. Eight healthy volunteers matching for age, gender, height, weight and conventional cardiovascular risk factors served as control (C). All participants received intrabrachial infusions of increasing doses of acetylcholine (ACh, endothelium-dependent vasodilator) and glyceryl-trinitrate (GTN, endothelium-independent vasodilator). Forearm blood flow (FBF) was measured by bilateral venous occlusion plethysmography. RESULTS: Disease activity of RA was comparably low during both MTX and ENC (DAS 28 3.9+/-0.3 and 3.5+/-0.3). FBF in response to ACh was reduced in RA compared to C (P<0.01). Switching from MTX to ENC failed to improve vascular responsiveness to ACh. GTN comparably increased FBF in all groups. CONCLUSIONS: Our study for the first time demonstrates that long-term RA is associated with manifested endothelial dysfunction. Switching from MTX to ENC in stable RA patients has no beneficial effect on endothelial function.

Acetylcholine↗

PubMed2003

Baseline blood flow and bradykinin-induced vasodilator responses in the human forearm are insensitive to the cytochrome P450 2C9 (CYP2C9) inhibitor sulphaphenazole.

A substantial portion of the vasodilator response elicited by bradykinin in the human forearm is unaffected by the combined inhibition of nitric oxide (NO) synthases and cyclo-oxygenases. The cytochrome P450 (CYP) 2C9 inhibitor sulphaphenazole was recently identified as a potent inhibitor of NO- and prostacyclin (PGI2)-independent relaxation in porcine coronary arteries. The aim of the present study was to determine the effect of sulphaphenazole on basal and bradykinin-induced NO/PGI2-independent changes in the forearm blood flow (FBF) of healthy subjects. Eleven healthy male volunteers participated in this placebo-controlled study. Test agents were infused into the brachial artery and FBF was measured by bilateral venous occlusion plethysmography. Sulphaphenazole (0.02-2 mg/min) alone did not affect basal blood flow. Inhibition of the NO synthases by NG-monomethyl-L-arginine (L-NMMA; 4 micromol/min) and cyclo-oxygenases by ibuprofen (1200 mg, orally) reduced FBF to 48 +/- 7% in the absence and 50 +/- 8% in the presence of sulphaphenazole (2 mg/min; P=not significant). After pretreatment with L-NMMA (16 micromol/min) and ibuprofen (1200 mg, orally), sulphaphenazole (6 mg/min) did not substantially inhibit bradykinin-induced vasodilation. We conclude that CYP2C9-derived metabolites (i) are not involved in the regulation of baseline blood flow, and (ii) do not mediate bradykinin-induced NO/PGI2-independent vasorelaxation in the human forearm. However, determining the contribution of this enzyme to regulation of blood flow in pathological conditions associated with endothelial dysfunction requires further studies.

Adult↗