Aims Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. The interactions of ET with the mediators of the sympathetic nervous system and the renin-angiotensin-system in humans are unclear. Methods We studied the effects of the ET A -selective antagonist BQ-123 and the ET Bselective antagonist BQ-788 (both 10 induced vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers using laser Doppler¯owmetry and double injection technique.Results BQ-123 caused a dose-dependent vasodilatation (maximum effect:+949t84 AUC-PU, P<0.001), whereas BQ-788 induced mild vasoconstriction (maximum effect: x388t96 AUC-PU, P<0.01). In the presence of BQ-123, but not BQ-788, ET-1, AT and NA caused markedly less vasoconstriction at any tested agonist dose; the effect was most pronounced on ET-1 (maximum effect at 10AUC-PU vs ET alone, P<0.001), followed by noradrenaline (maximim effect at 10 x16 M:+580t107 AUC-PU vs NA alone, P<0.01) and angiotensin II (maximim effect at 10 x14 M:+493t111 AUC-PU vs AT alone, P<0.001). Conclusions ET A -selective antagonism inhibits vasoconstriction to AT and NA in vivo in healthy subjects. This bene®cial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic agents and inhibitors of the renin-angiotensin system.

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We investigated prospectively the efficacy of ezetimibe in addition to statin therapy in stable renal transplant patients in whom hypercholesterolemia was not sufficiently treated. Eighteen renal transplant patients received 10 mg ezetimibe once daily in addition to high-dose statin therapy for uncontrolled hypercholesterolemia. Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, Tacrolimus (Tac)-and Cyclosporine A (CsA) blood levels, creatinine, urea, liver enzymes, electrolytes and creatinkinase (CK) were measured before initiation of ezetimibe therapy, after 7 days, 6 weeks and 3 months. Cholesterol concentrations decreased significantly (p < 0.005) from 264 ± 46 mg/dL at baseline to 205 ± 48 mg/dL after 1 week to 202 ± 48 mg/dL after 6 weeks and 212 ± 40 mg/dL after 3 months (reduction after 3 months 21 ± 10%). LDL-concentrations decreased significantly (p < 0.005) from 178 ± 41 mg/dL at baseline to 129 ± 35 mg/dL after 1 week to 123 ± 25 after 6 weeks and to 117 ± 40 mg/dL after 3 months (reduction after 3 months 37 ± 14%). Two patients stopped ezetimibe therapy due to nausea and muscle pain without CK elevation. Significant changes of CsA and Tac blood levels, liver and muscle enzymes were not observed. Ezetimibe seems to be an effective therapy for uncontrolled hypercholesterolemia in renal transplant patients when combined with high-dose statin therapy.

Since the identification of the new human virus, GB virus C (GBV-C)/hepatitis G-virus (HGV), in 1995/1996, reverse transcription polymerase chain reaction remained the sole available diagnostic tool for GBV-C/HGV infection. Recently, a serologic test based on the detection of antibodies to the putative envelope protein 2 (anti-E2) has been introduced. We used this assay for a seroepidemiological survey including 3,314 healthy individuals from different parts of the world, 123 patients from Germany who were suspected to have an increased risk of acquiring GBV-C/HGV infection, 128 multiple organ donors, and 90 GBV-C/HGV RNA positive persons. In European countries, anti-E2 seropositivity ranged from 10.9% (Germany) to 15.3% (Austria). In South Africa (20.3%) and Brazil (19.5%), even higher anti-E2 prevalence rates were recorded. In Asian countries like Bhutan (3.9%), Malaysia (6.3%), and the Philippines (2.7%), anti-E2 positivity was significantly lower. GBV-C/HGV anti-E2 prevalence in potential "risk groups," i.e., patients on hemodialysis and renal transplant recipients, did not vary significantly from anti-E2 seroprevalence in German blood donors. Anti-E2 and GBV-C/HGV RNA were found to be mutually exclusive, confirming the notion that anti-E2 has to be considered as a marker of past infection.

High-dose folinic acid with 5-fluorouracil (5-FU) is a novel combination chemotherapy used in the treatment of metastatic gastrointestinal cancer. One of the mechanisms of action of 5-FU is its conversion into fluorodeoxyuridylate (FdUMP), which inhibits thymidilate synthetase (TS). The rate of inhibition of TS is augmented by increasing concentrations of folinic acid. On the other hand, it is well known that treatment of animals with high doses of folinic acid results in acute renal failure due to tubular obstruction. In order to find out whether there are similar findings in the clinical setting, we investigated 8 patients (pts.) with metastatic gastrointestinal cancer who were treated with this chemotherapy. We used the following parameters: 1. excretion of four urinary enzymes (LDH, LAP, GGT, NAG); 2. creatinine clearance on days 1 and 5. Therapy consisted of folinic acid 200 mg/m2 i.v. on days 1-5 and 5-fluorouracil 400 mg/m2 on days 1-5. Each treatment cycle was repeated on day 28. We found a constant decrease in the excretion of all 4 enzymes from normal to subnormal values which was statistically significant (p less than .05) during the two treatment cycles. Creatinine clearance decreased about 50% in three patients from normal initial values. In conclusion, during therapy with high-dose folinic acid and 5-fluorouracil we found signs of tubular damage which are similar to those found in folate nephropathy.

T3 concentrations reflect renal graft function after renal transplantation. T3 is below normal in patients with delayed graft function (acute renal failure or acute rejection). The post-operative period (up to 3 days after renal transplantation) is associated with a low T3 syndrome. TSH does not return to pre-operative values even in patients with primary graft function. This might be due to the administration of prednisone. T3-sulphate is elevated before and after renal transplantation irrespective of graft function.

Genetic susceptibility contributes significantly to the risk of developing nephropathy in insulin-dependent diabetes mellitus (IDDM). The cellular substrate for this has remained enigmatic. We investigated whether afflicted IDDM patients display an enhanced activation of pertussis toxin (PTX)-sensitive G proteins, a phenomenon which has been demonstrated in patients with essential hypertension. We established immortalised B lymphoblast cell lines from 10 IDDM patients without nephropathy (DC) and 15 IDDM patients with nephropathy (DN). Nephropathy was defined as a persistent albumin excretion rate of more than 20 microg/min (DC 3.9 +/- 5.8, DN 562.3 +/- 539.0 microg/min, respectively). Subjects were matched with regard to age (DC 28.9 +/- 6.5, DN 35.9 +/- 9.9 years), diabetes duration (DC 19.3 +/- 6.9, DN 22.7 +/- 5.8 years) and HbA1c values (DC 8.5 +/- 1.4, DN 8.8 +/- 1.6%). Reactivity of PTX-sensitive G proteins was quantified by measuring platelet-activating factor (PAF)-induced Ca2+ mobilisation (fura 2 method) and by mastoparan-stimulated [35S]GTPgammaS binding. Expression of Galphai proteins was quantified by Western blot analysis. PAF-evoked Ca2+ increases above baseline averaged 77.0 +/- 52.5 nmol/l in DC and 150.7 +/- 61.5 nmol/l in DN (p = 0.005). PAF-evoked Ca2+ increases correlated with stimulated [35S]GTPgammaS binding (r2 = 0.42, p = 0.012). From Western blot analysis an overexpression of Galphai proteins could be excluded in DN. A consequence of the altered metabolic milieu in diabetes is the increased release of vasoactive and proliferative agonists which promote glomerular hyperfiltration, hypertrophy, enhanced matrix deposition, and, finally, glomerulosclerosis. Many of these auto- and paracrine agonists bind to G protein-coupled receptors. Therefore, their cellular effects are reinforced by the enhanced G protein reactivity and increase the propensity to nephropathy in IDDM.

Patients with renal failure treated with dialysis or subjected to renal transplantation are at increased risk of aquiring the GBV-C/HGV infection. Higher rates of the GBV-C/HGV RNA and a similar prevalence of anti-E2 in patients with renal failure as compared to donors suggest that the rate of GBV-C/HGV infection resolution in immunosuppressed patients with renal failure might be lower than in immunocompetent patients.