W. Zidek

Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression

NO prevents atherogenesis and inflammation in vessel walls by inhibition of cell proliferation and cytokine-induced endothelial expression of adhesion molecules and proinflammatory cytokines. Reduced NO production due to inhibition of either eNOS or iNOS may therefore reinforce atherosclerosis. Patients with end-stage renal failure show markedly increased mortality due to atherosclerosis. In the present study we tested the hypothesis that uremic toxins are responsible for reduced iNOS expression. LPS-induced iNOS expression in mononuclear leukocytes was studied using real-time PCR. The iNOS expression was blocked by addition of plasma from patients with end-stage renal failure, whereas plasma from healthy controls had no effect. Hemofiltrate obtained from patients with end-stage renal failure was fractionated by chromatographic methods. The chromatographic procedures revealed a homogenous fraction that inhibits iNOS expression. Using gas chromatography/mass spectrometry, this inhibitor was identified as phenylacetic acid. Authentic phenylacetic acid inhibited iNOS expression in a dose-dependent manner. In healthy control subjects, plasma concentrations were below the detection level, whereas patients with end-stage renal failure had a phenylacetic acid concentration of 3.49 +/- 0.33 mmol/l (n = 41). It is concluded that accumulation of phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression. That mechanism may contribute to increased atherosclerosis and cardiovascular morbidity in patients with end-stage renal failure.

Adenosine(5') oligophospho-(5') guanosines and guanosine(5') oligophospho-(5') guanosines in human platelets.

We isolated and identified nucleoside(5) oligophospho-(5) nucleosides containing adenosine and guanosine (ApnG; n = 3-6) as well as diguanosine polyphosphates (GpnG; n = 3-6) in human platelets. For identification, UV spectrometry, matrix-assisted laser desorption/ionization, postsource decay matrix-assisted laser desorption/ionization mass spectrometry, and enzymatic cleavage experiments were used. The adenosine(5) oligophospho-(5) guanosines act as vasoconstrictors and growth factors. The diguanosine polyphosphates are potent modulators of growth in vascular smooth muscle cells, but do not affect vascular tone.

Tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome

BACKGROUNDnSteroid resistance and steroid dependence constitute a major problem in the treatment of minimal-change disease and focal segmental glomerulosclerosis (FSGS). Cyclophosphamide and cyclosporine are well-established alternative immunomodulating agents, whereas data on FK 506 (tacrolimus) are rare.nnnMETHODSnThe present work provides data from 10 patients of an open, monocentric, non-randomized, prospective trial. Five patients with steroid-dependent minimal-change nephrotic syndrome, 1 patient with steroid-refractory minimal-change disease and 4 patients with steroid-refractory FSGS were started on tacrolimus at trough levels of 5 10 microg/l. In case of steroid-dependence, prednisolone was tapered off in presence oftacrolimus within one month.nnnRESULTSnWithin 6 months, complete remission was achieved in 5 patients (50%) and partial remission in 4 patients (40%), yielding a final response rate of 90%. One patient was primarily resistent to tacrolimus (steroid-refractory minimal-change), another patient became secondarily resistant to tacrolimus after an initial remission (steroid-refractory FSGS). Average proteinuria significantly decreased by 77% from 9.5 +/- 1.4 - 2.2 +/- 1.1 g/day (p < 0.01). Serum protein significantly raised from 55.0 +/- 1.9 - 64.6 +/- 1.9 g/l (p < 0.01). Tacrolimus induced non-significant increases of blood glucose (4.9 +/- 0.1 - 5.1 +/- 0.2 mmol/l), systolic blood pressure (131.4 +/- 7.1 - 139.0 +/- 7.6 mmHg) and creatinine (93.2 +/- 13.9 103.2 +/- 15.3 mmol/l). Five patients have been tapered off tacrolimus so far, nephrotic syndrome relapsed in 4 of them (80%). Relapse occurred at tacrolimus levels between 2.6 and 6.9 ng/ml.nnnCONCLUSIONSnOur data suggest that tacrolimus may be a promising alternative to cyclosporine both in steroid-resistant and steroid-dependent nephrotic syndrome.

Beta-blockers do not impair the cardiovascular benefits of endurance training in hypertensives

Aerobic physical exercise is broadly recommended as a helpful adjunct to obtain blood pressure control in hypertension. Beta-blockade interacts with heart rate, sympathetic tone, maximal workload and local lactate production. In the present randomized-controlled study, we compared the cardiovascular effects of an endurance training programme in elderly hypertensives with or without beta-blockers and developed a first approach to determine a lactate-based training heart rate in presence of beta-blockade. Fifty-two patients (23 with beta-blocker, 29 without beta-blocker) ⩾60 years with systolic 24-h ambulatory blood pressure (ABP) ⩾140u2009mm Hg and/or antihypertensive treatment were randomly assigned to sedentary activity or a heart-rate controlled 12-week treadmill exercise programme (lactate 2.0u2009mmol/l). In the exercise group, the training significantly decreased systolic and diastolic 24-h ABP, blood pressure on exertion (100 W) and increased endothelium-dependent vasodilation (flow-mediated vasodilation, FMD) and physical performance both in the presence and absence of beta-blockade (P<0.05 each). The extent of ABP reduction did not significantly differ in the presence or absence of beta-blockade (Δ systolic ABP 10.6±10.5 vs 10.6±8.8u2009mm Hg, Δ diastolic ABP 5.7±8.6 vs 5.8±4.0u2009mm Hg). Mean training heart rate was significantly lower in the patients on beta-blockers (97.2±7.7 vs 118.3±7.5/min, P<0.001). Lactate-based aerobic endurance training evokes comparable cardiovascular benefits in the presence and absence of beta-blockade including a marked improvement of endothelial function. In the present study, target training heart rate with beta-blockers is about 18% lower than without.

Mediation of the vasoactive properties of diadenosine tetraphosphate via various purinoceptors.

Objective and methods The vasoactive properties of P1, P4-diadenosine tetraphosphate (Ap4A) were studied by measuring the effects of perfusion pressure of a rat isolated perfused kidney. Results The vasoconstrictive response to Ap4A was mediated to a large extent to a P2X receptor which could be shown by inhibition with pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid tetrasodium. The remaining vasoconstriction of Ap4A could be blocked by a 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A1 receptor antagonist. In raised tone preparation Ap4A evoked vasodilation when P2 receptors were blocked by suramin. The dilation was not mediated by a P2Y receptor as the effect could not be blocked by suramin. Conclusion Ap4A induces vasoconstriction via A1 and P2X receptors and vasodilatation via an unidentified receptor which is not a P2Y receptor. Ap4A may play an important role in kidney perfusion and, thus, in blood-pressure control.

Validation of the Stabil-O-Graph blood pressure self-measurement device

The present work describes the validation of the Stabil-O-Graph, an automated blood pressure device, according to the criteria of the British Hypertension Society (BHS) and the European Society of Hypertension (ESH). In the BHS, validation procedure leads to a final grade A/A for systolic and diastolic blood pressure. In the ESH procedure, the test device passed all phases and the devices measurements were considered to be very accurate and with no error of clinical relevance. Thus, the device met the accuracy requirements of both the BHS and the ESH standard and can be recommended for clinical use.

Mesangial iga deposition in minimal change nephrotic syndrome : coincidence of different entities or variant of minimal change disease?

BACKGROUNDnMesangial deposition of IgA (MCA) is a very rare finding in minimal change disease and has previously been considered a pure coincidence. In the U.S. and Europe only anecdotal case reports exist. To date, there has been no consensus on nomenclature and categorization of this entity. We describe 2 cases of MCA with analogue histological findings but relevant differences in clinical presentation, and we discuss the clinical implications of mesangial IgA deposition in minimal change nephrotic syndrome.nnnPATIENTSnA 47-year-old female was admitted to hospital with nephrotic syndrome, microscopic hematuria, arterial hypertension and slight impairment of renal function 3 weeks after an unspecific upper airway infection. A 42-year-old male presented with nephrotic syndrome, microscopic hematuria, normotension and normal renal function. Both of the nephrotic syndromes were steroid-responsive and steroid-dependent.nnnFINDINGSnThe clinical presentation of the male patient was consistent with the features of minimal change glomerulopathy, whereas the female patient combined signs of minimal change disease and IgA nephropathy. Light microscopy revealed mesangial IgA immune deposits and slight mesangial hypercellularity. Electron microscopic studies of MCA patients disclose diffuse effacement of glomerular foot processes.nnnCONCLUSIONnOur cases and a review of the literature indicate that the histological diagnosis of MCA may comprise different pathogenetic entities. From the clinical point of view, MCA has to be regarded as a minimal change nephrotic syndrome with symptomatic or asymptomatic mesangial IgA deposition. IgA deposition constitutes a risk factor for impairment of renal function and indicates a frequently relapsing course.

The impact of pulse pressure on the accuracy of wrist blood pressure measurement

There is an increasing number of wrist blood pressure measurement devices that successfully passed the validation procedures of the British Hypertension Society (BHS) and the European Society of Hypertension (ESH). It remains unknown, however, whether pulse pressure as a marker of arterial stiffness and vascular ageing affects the accuracy of these devices. An ESH protocol validated wrist device was compared with the upper arm mercury sphygmomanometry in a study population (33 patients, 99 measurements) including a relevant number of subjects with pulse pressure >50u2009mmu2009Hg (84.8%) and isolated systolic hypertension (27.3%). Mean systolic bias was 10.2u2009mmu2009Hg with 95% limits of agreement of −13.1 and 33.6u2009mmu2009Hg, mean diastolic bias was 4.8u2009mmu2009Hg with limits of agreement of −11.0 and 20.7u2009mmu2009Hg. The impact of body mass index, age, systolic blood pressure and pulse pressure on the absolute value of blood pressure bias was tested by stepwise multiple regression analysis. The systolic bias significantly depended on pulse pressure, whereas there was no significant effect of the independent variables on the diastolic bias. Separate correlation analysis showed a significant correlation between pulse pressure and both absolute systolic bias (Pearson r=0.48, P<0.001) and relative systolic bias (systolic bias divided by systolic blood pressure, Pearson r=0.29, P=0.003). Even well-validated wrist blood pressure devices can show a clinically relevant bias in patients with elevated pulse pressure. Increased arterial stiffness may impair the accuracy of oscillometric blood pressure measurement at the wrist.

Inotropic Effects of Diadenosine Tetraphosphate in Isolated Canine Cardiac Preparations

We studied the effects of diadenosine tetraphosphate (AP4A) on the force of contraction in canine preparations. The force of contraction was measured in isolated electrically driven (1 Hz) atrial and ventricular cardiac trabeculae from adult dogs. AP4A (100 microM) alone and after prestimulation with 10 nM isoproterenol reduced force of contraction in atrial preparations by approximately 24%. Moreover, AP4A (100 microM) alone and after prestimulation with 10 nM isoproterenol reduced the force of contraction in ventricular preparations by 29 and 29%, respectively. The negative inotropic effects of AP4A were abolished by the A1-adenosine receptor antagonist 1,3-dipropyl-cyclopentyl-xanthine (DPCPX). In summary, in canine myocardium, AP4A alone and after prestimulation with a beta-adrenoceptor agonist exerts negative inotropic effects, which are probably mediated via A1-adenosine receptors.

Vasoactive diadenosine polyphosphates in human placenta: possible candidates in the pathophysiology of pre-eclampsia?

Background One hypothesis of the pathophysiology of pre-eclampsia is that placentally derived, yet unidentified, vasoactive factors are released into the maternal circulation, causing hypertension. Objective To determine if diadenosine polyphosphates, new potent vasoconstrictors, are present in human placenta. Methods and results Human placental tissue was homogenated and fractionated by size-exclusion chromatography, affinity chromatography, anion-exchange chromatography and reversed-phase chromatography. In fractions purified to homogeneity, diadenosine diphosphate, diadenosine triphosphate, diadenosine tetraphosphate, diadenosine pentaphosphate, diadenosine hexaphosphate and diadenosine heptaphosphate were identified by matrix-assisted laser desorption/ionization mass spectrometry, retention-time comparison and enzymatic cleavage analysis. Conclusions The presence of diadenosine polyphosphates in human placenta makes them possible candidates for involvement in the pathophysiology of pre-eclampsia. However, their contribution to the pathophysiology of eclampsia requires substantiation in further studies.