Temporary threshold shift after noise exposure in hypobaric hypoxia at high altitude: results of the ADEMED expedition 2011.

OBJECTIVES: To evaluate whether there is an increased risk for noise-induced hearing loss at high altitude rsp. in hypobaric hypoxia. METHODS: Thirteen volunteers got standard audiometry at 125, 250, 500, 750, 1000, 1500, 2000, 3000, 4000, 6000, and 8000 Hz before and after 10 min of white noise at 90 dB. The system was calibrated for the respective altitude. Measurements were performed at Kathmandu (1400 m) and at Gorak Shep (5300 m) (Solo Khumbu/Nepal) after 10 days of acclimatization while on trek. Temporary threshold shift (TTS) was analyzed by descriptive statistics and by factor analysis. RESULTS: TTS is significantly more pronounced at high altitudes. Acclimatization does not provide any protection of the inner ear, although it increases arterial oxygen saturation. CONCLUSION: The thresholds beyond which noise protection is recommended (> 80 dB) or necessary (> 85 dB) are not sufficient at high altitudes. We suggest providing protective devices above an altitude of 1500 m ("ear threshold altitude") when noise level is higher than 75 dB and using them definitively above 80 dB. This takes the individual reaction on hypobaric hypoxia at high altitude into account.

[Interventional treatment of high blood pressure-Current state]. / Interventionelle Therapien bei Hypertonie ­ aktueller Stand.

Arterial hypertension is a real global burden with a very high prevalence. In the last decades, many pharmaceutical approaches have been successfully developed for treating hypertension. Currently, novel medications for influencing blood pressure are not in sight. In recent years alternatives, such as interventional procedures for reducing blood pressure, have been developed and tested. Ablation of the renal sympathetic nerves (renal denervation, RDN), which are wrapped around the renal arteries in particular, has been intensively investigated as a procedure. After the first RDN studies a clear influence on the blood pressure could be shown; however, in the first sham-controlled studies the reduction in blood pressure by RDN could no longer consistently be shown. In very systematic sham-controlled, blinded studies in patients with hypertension but without medication a robust blood pressure reducing effect of RDN could be shown, which corresponded to the effect of a blood pressure-reducing drug. It is obvious that larger studies and also long-term studies have to sustainably confirm this effect. In recent years, active and passive stimulation of the baroreceptors could also be established as a blood pressure reducing principle, at least in studies but the evidence is still very low.

Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

[Baroreceptor activation therapy for therapy-resistant hypertension: indications and patient selection : Recommendations of the BAT consensus group 2017]. / Barorezeptorakivierungstherapie bei therapierefraktärer Hypertonie: Indikation und Patientenselektion : Empfehlungen der BAT-Konsensusgruppe 2017.

Baroreceptor activation therapy (BAT) has been available for several years for treatment of therapy-refractory hypertension (trHTN). This procedure is currently being carried out in a limited number of centers in Germany, also with the aim of offering a high level of expertise through sufficient experience; however, a growing number of patients who are treated with BAT experience problems that treating physicians are confronted with in routine medical practice. In order to address these problems, a consensus conference was held with experts in the field of trHTN in November 2016, which summarizes the current evidence and experience as well as the problem areas in handling BAT patients.

Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3.

Endothelial nitric oxide synthase (eNOS) plays a crucial role in vascular homeostasis. Lysophospholipid interaction with sphingosine 1-phosphat (S1P) receptors results in eNOS activation in different cells. In endothelial cells, eNOS activation via S1P1 or S1P3 was shown controversially. The aim of this study is to investigate the meaning of both S1P receptors for eNOS activation in human endothelial cells. Therefore, several S1P1 and S1P3 agonists in combination with antagonists and specific RNAi approach were used. eNOS activation was measured in human umbilical vein endothelial cells (HUVEC) via DAF2-DA-based fluorescence microscopy. For investigation of the signaling pathway, agonists/antagonist studies, RNAi approach, Luminex™ multiplex, and Western Blot were used. In HUVEC, both the S1P1 agonist AUY954 as well as the S1P1,3 agonist FTY720P induced eNOS activation in a time- and dose-dependent manner. Other S1P1 agonists activated eNOS to a lesser extent. The AUY954-induced eNOS activation was blocked by the S1P1 antagonist W146, the combination of W146 and the S1P3 antagonist CAY10444 and the S1P1,3 antagonist VPC23019, but not by CAY10444 indicating the meaning of S1P1 for the AUY954-induced eNOS activation. The FTY720P-induced eNOS activation was blocked only by the combination of W146 and CAY10444 and the combined S1P1,3 antagonist VPC23019, but not by W146 or CAY10444 indicating the importance of both S1P1 and S1P3 for FTY720-induced eNOS activation. These results were confirmed using specific siRNA against S1P1 and S1P3. The S1P1,3 activation results in Akt phosphorylation and subsequent activation of eNOS via phosphorylation at serine(1177) and dephosphorylation at threonine(495). Beside former investigations with rather unspecific S1P receptor activation these data show potent selective S1P1 activation by using AUY954 and with selective S1P receptor inhibition evidence was provided that both S1P1 and S1P3 lead to downstream activation of eNOS in HUVEC in the same experimental setting. Inhibition or knockdown of one of these receptor subtypes did not abolish the eNOS activation and subsequent NO production.

In vivo TLR9 inhibition attenuates CpG-induced myocardial dysfunction.

The involvement of toll-like receptor 9 (TLR9), a receptor for bacterial DNA, in septic cardiac depression has not been clarified in vivo. Thus, the aim of the study was to test possible TLR9 inhibitors (H154-thioate, IRS954-thioate, and chloroquine) for their ability to protect the cardiovascular system in a murine model of CpG oligodeoxynucleotide- (ODN-) dependent systemic inflammation. Sepsis was induced by i.p. application of the TLR9 agonist 1668-thioate in C57BL/6 wild type (WT) and TLR9-deficient (TLR9-D) mice. Thirty minutes after stimulation TLR9 antagonists were applied i.v. Survival was monitored up to 18 h after stimulation. Cardiac mRNA expression of inflammatory mediators was analyzed 2 h and 6 h after stimulation with 1668-thioate and hemodynamic parameters were monitored at the later time point. Stimulation with 1668-thioate induced a severe sepsis-like state with significant drop of body temperature and significantly increased mortality in WT animals. Additionally, there was a time-dependent increase of inflammatory mediators in the heart accompanied by development of septic heart failure. These effects were not observed in TLR9-D mice. Inhibition of TLR9 by the suppressive ODN H154-thioate significantly ameliorated cardiac inflammation, preserved cardiac function, and improved survival. This suppressive ODN was the most efficient inhibitor of the tested substances.

Etoposide Upregulates Survival Favoring Sphingosine-1-Phosphate in Etoposide-Resistant Retinoblastoma Cells.

Improved knowledge of retinoblastoma chemotherapy resistance is needed to raise treatment efficiency. The objective of this study was to test whether etoposide alters glucosyl-ceramide, ceramide, sphingosine, and sphingosine-1-phosphate (sphingosine-1-P) levels in parental retinoblastoma cells (WERI Rb1) or their etoposide-resistant subclones (WERI EtoR). WERI Rb1 and WERI EtoR were incubated with 400 ng/ml etoposide for 24 h. Levels of glucosyl-ceramides, ceramides, sphingosine, sphingosine-1-P were detected by Q-TOF mass spectrometry. Statistical analysis was done by ANOVA followed by Tukey post-hoc test (p < 0.05). The mRNA expression of sphingolipid pathways enzymes in WERI Rb1, WERI EtoR and four human retinoblastoma tissue samples was analyzed by quantitative real-time PCR. Pathways enzymes mRNA expression confirmed similarities of human sphingolipid metabolism in both cell lines and tissue samples, but different relative expression. Significant up-regulation of sphingosine was seen in both cell lines (p < 0.001). Only sphingosine-1-P up-regulation was significantly increased in WERI EtoR (p < 0.01), but not in WERI Rb1 (p > 0.2). Both cell lines upregulate pro-apoptotic sphingosine after etoposide incubation, but only WERI EtoR produces additional survival favorable sphingosine-1-P. These data may suggest a role of sphingosine-1-P in retinoblastoma chemotherapy resistance, although this seems not to be the only resistance mechanism.

Oxidative stress markers in young hemodialysis patients - a pilot study.

AIMS: Studies in young hemodialysis patients without significant comorbidities might increase the understanding of incipient vascular pathology in uremia. We investigated whether a specific pattern of oxidative stress markers with potential prognostic significance could be identified in this population. MATERIAL AND METHODS: We performed a cross-sectional matched case control study of 25 young hemodialysis patients (age 18 - 40 years) without known comorbidity factors. Patients were matched pairwise to healthy controls, and markers of oxidative stress were analyzed for associations with surrogate parameters of vascular structure and function. RESULTS: Oxidized low-density lipoproteins (OxLDL) were similar in patients and controls whereas conjugated dienes were increased in the very low-density lipoproteins (VLDL) fraction (20 +/- 6 vs. 12 +/- 5 micromol/l, p < 0.0001), but not in the low-density lipoproteins (LDL) fraction (16 +/- 6 vs. 18 +/- 6 micromol/l). Superoxide dismutase (SOD) activity was diminished in patients (1,117 +/- 151 vs. 1,299 +/- 88 U/g Hb, p < 0.0001), but there was no difference in glutathione peroxidase (GPx) activity. Oxidative stress expressed as the ratio of oxidized and reduced glutathione (GSSG/GSH) was increased in patients (0.25 +/- 0.18 vs. 0.13 +/- 0.04, p = 0.0048). Intima-media thickness (IMT) of the common carotid artery (0.70 +/- 0.12 vs. 0.62 +/- 0.08 mm, p = 0.0007) was significantly increased, and postischemic peak flow (PIPF) by venous occlusion plethysmography was severely diminished in patients (632 +/- 319 vs. 1,057 +/- 543% of basal flow, p < 0.0001). None of the markers of oxidative stress was independently associated with IMT or PIPF or a significant discriminator between patients and controls by multivariate regression. CONCLUSIONS: In this pilot study of exclusively young patients on hemodialysis, oxidative stress markers were of limited clinical value in identifying young patients at risk for vascular complications.

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.

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.

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) > or =60 years with systolic 24-h ambulatory blood pressure (ABP) > or =140 mm Hg and/or antihypertensive treatment were randomly assigned to sedentary activity or a heart-rate controlled 12-week treadmill exercise programme (lactate 2.0 mmol/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 (Delta systolic ABP 10.6+/-10.5 vs 10.6+/-8.8 mm Hg, Delta diastolic ABP 5.7+/-8.6 vs 5.8+/-4.0 mm 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.

Tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome.

BACKGROUND: Steroid 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. METHODS: The 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. RESULTS: Within 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. CONCLUSIONS: Our data suggest that tacrolimus may be a promising alternative to cyclosporine both in steroid-resistant and steroid-dependent nephrotic syndrome.

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

BACKGROUND: Mesangial 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. PATIENTS: A 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. FINDINGS: The 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. CONCLUSION: Our 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.

Dermatopathic lymphadenopathy: a differential diagnosis of enlarged lymph nodes in uremic pruritus.

BACKGROUND: In end-stage renal disease patients, the incidence of both infections and malignancies is increased leading to a higher incidence of peripheral lymphadenopathy. In the present work we describe a rare but probably underdiagnosed cause for enlarged lymph nodes in uremic patients. PATIENT: A 43-year-old male patient was admitted to our hospital with inguinal lymphadenopathy and pruritus. He turned out to be uremic due to focal segmental glomerulosclerosis (creatinine 4.5 mg/dl, MDRD creatinine clearance 12 ml/min). FINDINGS: Sonography revealed enlarged lymph nodes (up to 4 cm) with intact corticohilar border differentiation. After extirpation of an inguinal lymph node, histological examination established the diagnosis of dermatopathic lymphadenopathy. T cell lymphoma was excluded by PCR for T cell receptor-gamma rearrangements and subsequent GeneScan analysis. Intravenous fluid supplementation with subsequent decline of creatinine, UVB treatment, clemastine, and topical use of emollients led to a relief of the uremic pruritus and the lymph nodes' size normalized within 8 weeks. CONCLUSION: Dermatopathic lymphadenopathy refers to the reactive condition seen in lymph nodes that drain areas with disruption of the skin integrity, e.g. due to scratch marks. The present case report describes dermatopathic lymphadenopathy as a harmless cause of enlarged lymph nodes in uremic pruritus for the first time. This entity should be considered in the differential diagnosis of peripheral lymphadenopathy of unknown origin in patients with renal failure.

Central blood pressure assessment using oscillometry is feasible for everyday clinical practice.

The benefit of the central systolic blood pressure (cSBP) has already been recognized, but its general measurement in the everyday routine is still limited mainly because available established non-invasive assessment devices are not suitable for everyday use. In this study, we investigated the performance of an oscillometric device Tel-O-GRAPH for cSBP assessment in terms of suitability for everyday clinical use. One hundred and three patients were prospectively included. cSBP was computed by Tel-O-GRAPH compared with Sphygmocor using applanation tonometry. There was a good agreement between Tel-O-GRAPH and Sphygmocor for cSBP (mean difference±s.d.: -0.3±6.7 mm Hg; Pearson's R=0.95; P<0.0001). Recorded cSBP values in the supine vs seated position and for the experienced vs non-experienced user did not significantly differ (mean cSBPsupine 122.1±13.9 mm Hg vs cSBPseated 120.7±15.7 mmHg; cSBPnon-experienced 120.6±20.5 mm Hg and cSBPexperienced 119.2±19.9 mm Hg). The mean difference of cSBP between supine and seated positions was 1.5±6.8 and -1.4±5.0 mm Hg between experienced and non-experienced users. This study showed good accuracy in assessing cSBP with an oscillometric BP measurement device Tel-O-GRAPH compared with a Sphygmocor. Furthermore, the calculation of cSBP by Tel-O-GRAPH appears to be easy and can be done during the routine brachial BP measurement. Computed cSBP values seem to remain reliable independently of the patient body position and experience of the operator. Consequently, the easiness of utilization and reliability of the device may open the opportunity for its extended use in everyday clinical practice, as well as reliable alternative for clinical studies, making complex applanation tonometry dispensable.

Isolation and characterization of coenzyme A glutathione disulfide as a parathyroid-derived vasoconstrictive factor.

BACKGROUND: Coenzyme A glutathione disulfide (CoA-SSG) was recently isolated from bovine adrenal glands and was shown to be a renal vasoconstrictor. The identification of CoA-SSG in human parathyroid glands and its action on cultured vascular smooth muscle cells (VSMCs) are described here. METHODS AND RESULTS: After purification to homogeneity by several chromatographic steps, CoA-SSG was identified by matrix-assisted laser desorption/ionization mass spectrometry and enzymatic analysis. The dose-dependent growth-stimulating effect of CoA-SSG on VSMCs, measured by the [(3)H]thymidine method, is characterized by a threshold of 10(-)(8) mol/L and a maximum effect of 10 micromol/L, increasing VSMC proliferation 254+/-21% above control. A dose of 10 micromol/L methylmalonyl-CoA and 10 micromol/L CoA increased the rate of proliferation of VSMCs only by 178+/-43% and 50+/-42% above control, respectively. Glutathione has no proliferative effect on VSMCs. The growth-stimulating effect of CoA-SSG (1 micromol/L) was decreased by the antagonists 3,7-dimethyl-1-propargylxanthine (DMPX; 11 micromol/L) (38% compared with CoA-SSG without antagonist) and pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid (PPADS; 10 micromol/L) (48% compared with CoA-SSG without antagonist; each P:<0. 05 versus control), indicating that the effect is mediated partly via A(2) and partly via P(2)Y(1) and/or P(2)Y(4) receptor. CONCLUSIONS: CoA-SSG may play a regulatory role in VSMC growth as a progression factor and thereby could play an important role in development of hypertension.

[New tendencies in combination antihypertensive therapy]. / Antihypertensive Therapie. Was gibt es Neues bei den Kombinationen?

In the management of hypertension, the constant lowering of target pressures ever more frequently requires combination treatment in order to achieve the goals set. A combination of amlodipine and perindopril effectively lowered the blood pressure, and significantly reduced overall mortality, cardiovascular mortality, cardiovascular events and stroke risk in comparison with atenolol/bendroflumethiazide. In combination with both ACE inhibitors and AT1 blockers, diuretics reduced blood pressure more effectively that the respective components used alone. Now, however, the long-term use of diuretics is suspected of increasing the risk of terminal kidney failure and diabetes. This also means an enhanced probability of a cardiovascular event. In the ASCOT study, the combination of beta blocker and diuretic proved inferior to treatment with a calcium antagonist and ACE inhibitor. For the long-term application of diuretics as antihypertensive monotherapy, therefore, further comparative studies involving the latest antihypertensives are mandatory.

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.

Effect of dexamethasone on the lymphocytic Na+/H+ antiporter activity.

OBJECTIVE: The effects of short-term administration of dexamethasone on sodium/proton antiporter (Na+/H+ antiporter) in human lymphocytes were investigated in vitro. METHODS: Cytosolic pHi in lymphocytes was measured spectrophotometrically using the pH-sensitive fluorescent dye 2'-7'-bis-carboxyethyl-5(6)-carboxyfluorescein at 530 nm with excitation wavelengths of 440 and 530 nm. The Na+/H+ antiporter activity was determined after intracellular acidification using 100 mmol/l propionic acid. RESULTS: The addition of 1 micromol/l dexamethasone significantly reduced cytosolic pHi from 7.44+/-0.03 to 7.25+/-0.05 (mean +/- SEM; P<0.01). Incubation with dexamethasone for 40 min significantly reduced the Na+/ H+ antiporter activity from (9.19+/-0.61)x10(-3) pHi/s (n = 22) to (7.23+/-0.49)x10(-3) pHi/s (n = 22; P<0.01). The effect of dexamethasone was time and concentration dependent The apparent affinity of the Na+/H+ antiporter was not significantly different in the absence or presence of dexamethasone. The inhibition of the Na+/H+ antiporter by dexamethasone was abolished in the presence of the glucocorticoid receptor blocker, mifepristone. CONCLUSION: Dexamethasone directly inhibits the Na+/H+ antiporter using a receptor-dependent pathway. This effect may be important for pharmacological side effects such as glucocorticoid-induced hypertension.