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Biomedical subjects

M Tepel

Publications and source records attributed to M Tepel.

At least 73 records · Page 4Linked to original sources
PubMed1998

Decreased membrane Mg2+ concentrations in a subgroup of hypertensives: membrane model for the pathogenesis of primary hypertension.

Intracellular Mg2+ measurements were performed in erythrocyte membranes of 18 untreated normotensive and 19 untreated essential hypertensive patients. Mg2+ concentrations were determined by atomic absorption spectroscopy using a Video 12 apparatus. The results show that in patients with essential hypertension total Mg2+ content in erythrocyte membranes was significantly decreased as compared with the control group (0.28 +/-0.05 v 0.52+/-0.15 mmol/g membrane protein; mean+/-SD, P < .001). Additionally, plasma and free intracellular Mg2+ content of lymphocytes and platelets showed no significant difference in normotensives and hypertensives. Lowered total membrane Mg2+ concentrations in a subgroup of primary hypertensives may contribute to the development of this disorder, perhaps due to different buffering or membrane transport systems.

Adult↗
PubMed1998

Sodium-dependent Cl-/HCO3- exchange in patients with chronic renal failure: correlation with renal function.

To investigate the effects of uremia on cellular function the activity of the sodium-dependent chloride-bicarbonate exchanger (sodium-dependent Cl-/HCO3- exchanger) and the sodium-independent chloride-bicarbonate exchanger (sodium-independent Cl-/HCO3- exchanger) were examined in lymphocytes from 25 patients with mild chronic renal failure, 9 patients with end-stage chronic renal failure on regular hemodialysis, and from 25 age-matched healthy control subjects. Cytosolic pH (pHi) and the activity of the sodium-dependent Cl-/HCO3- exchanger and the sodium-independent Cl-/HCO3- exchanger were measured spectrophotometrically using the pH-sensitive fluorescent dye 2'7'-bis-carboxyethyl-5 [6]-carboxyfluorescein acetoxy-methylester (BCECF-AM). The activation of the sodium-dependent Cl-/HCO3- exchanger by removal of extracellular chloride was prevented in the presence of 500 micromol/liter 4,4' diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) or in the absence of extracellular sodium, but was not affected by the specific inhibitor of the sodium/proton exchanger, ethyl isopropyl amiloride (EIPA). The sodium-dependent Cl-/HCO3- exchangers were significantly different in lymphocytes from healthy control subjects, patients with mild chronic renal failure, and patients with end-stage chronic renal failure (X2 = 6.43, P = 0.040 by Kruskal-Wallis-test). The sodium-dependent Cl-/HCO3- exchanger was significantly lower in patients with end-stage chronic renal failure compared to patients with mild chronic renal failure or compared to healthy control subjects (each P < 0.05). In patients with chronic renal failure a significantly negative correlation between sodium-dependent Cl-/HCO3- exchanger and the serum creatinine concentration (r = -0.507; P = 0.0022) could be observed. On the other hand, resting pHi in lymphocytes and sodium-independent Cl-/HCO3- exchanger were not significantly different in lymphocytes from healthy control subjects, patients with mild chronic renal failure or patients with end-stage chronic renal failure. The present study suggests that the activity of the sodium-dependent Cl-/HCO3- exchanger is progressively impaired in chronic renal failure.

Adult↗
PubMed1998

Influence of end-stage renal failure and hemodialysis on event-related potentials.

Chronic renal failure frequently causes uremic encephalopathy with impairment of different cognitive functions, but the pathophysiology of uremic encephalopathy is still unknown. We measured visually evoked event-related potentials (ERPs) in 33 neurologically asymptomatic patients before and after they underwent hemodialysis and compared their data with those of a strictly age-matched healthy control group. Before hemodialysis, the patients' P3 latency was significantly increased and P3 amplitude was significantly decreased as compared with that of the healthy control group. After hemodialysis, P3 latency of the patients showed a significant decrease (457+/-56 before and 438+/-54 ms after hemodialysis) and the P3 latency habituation during the ERP measurement was also significantly decreased. Patients with higher levels of blood urea nitrogen (BUN), creatinine, and uric acid performed better in ERP measurement than did patients with lower levels. Hemoglobin did not influence ERP latencies and amplitudes. Our data suggest that impaired cognitive processing can be disclosed by ERP even in neurologically asymptomatic chronic renal disease. Removal of uremic toxins by hemodialysis leads to an improvement in cognitive processing.

Adult↗
PubMed1998

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.

Adenosine Triphosphate↗
PubMed1998

HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs via decreased production of phosphoinositide-derived second messengers 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate.

We demonstrate that physiological concentrations of HDL3 inhibit the thrombin-induced platelet fibrinogen binding and aggregation in a time- and concentration-dependent fashion. The underlying mechanism includes HDL3-mediated inhibition of phosphatidylinositol 4,5-bis-phosphate turnover, 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate formation, and intracellular calcium mobilization. The inhibitory effects of HDL3 on inositol 1,4,5-tris-phosphate formation and intracellular calcium mobilization were abolished after covalent modification of HDL3 with dimethylsuberimidate. Furthermore, they could be blocked by calphostin C and bis-indolylmaleimide, 2 highly selective and structurally unrelated protein kinase C inhibitors. However, the inhibitory effects of HDL3 were not blocked by H89, a protein kinase A inhibitor. In addition, HDL3 failed to induce cAMP formation but stimulated the phosphorylation of the protein kinase C 40- to 47-kD major protein substrate. We observed a close temporal relationship between the HDL3-mediated inhibition of thrombin-induced inositol 1,4,5-tris-phosphate formation, intracellular calcium mobilization, and fibrinogen binding and the phosphorylation of the protein kinase C 40- to 47-kD major protein substrate. Taken together, these findings indicate that the HDL3-mediated inhibition of thrombin-induced fibrinogen binding and aggregation occurs via inhibition of phosphatidylinositol 4,5-bis-phosphate turnover and formation of 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. Protein kinase C may be involved in this process.

Adult↗
PubMed1998

Characterization of dimethylguanosine, phenylethylamine, and phenylacetic acid as inhibitors of Ca2+ ATPase in end-stage renal failure.

The activity of the plasma membrane Ca2+ ATPase of chronic renal failure patients is decreased by circulating inhibitors yet to be characterized. In this study, inhibitors of Ca2+ ATPase were isolated from ultrafiltrate of patients with end-stage renal failure. They were identified as dimethylguanosine, phenylethylamine, and phenylacetic acid by chromatography and mass spectrometry. Ca2+ ATPase activity was measured spectrophotometrically as the difference in hydrolysis of ATP in the presence and absence of Ca2+ with different concentrations of ATP and the isolated substances. All of the identified compounds are sufficiently lipophilic to penetrate the blood-brain barrier and to accumulate in cerebral tissue. The inhibitory effects of these agents were additive. The apparent K(m) values for ATP and Ca2+ were not altered by these substances, suggesting a noncompetitive mechanism of inhibition. In plasma of healthy subjects, the substances were not detectable. The Ca2+ ATPase inhibitors identified may play a role in the pathophysiology of end-stage renal failure and, potentially, in monitoring toxic effects on cellular Ca2+ metabolism in renal failure.

Adult↗
PubMed1998

Hypertensive crisis: pathophysiology, treatment and handling of complications.

Hypertensive crisis is a potentially life-threatening complication of nearly all forms of hypertension. Vascular damage causing end-organ failure and direct complications such as intracerebral hemorrhage determine the outcome of hypertensive crisis. In the case of apparent end-organ damage immediate and effective lowering of blood pressure is necessary. In addition to drugs used traditionally in hypertensive crisis, a number of alternative antihypertensives such as urapidil or enalaprilat have been recently introduced for treatment of hypertensive crisis.

Adolescent↗
PubMed1998

Identification of oxidized low-density lipoprotein in human serum by NMR spectroscopy.

1. In this study we compared the 500 MHz 1H-NMRs from native and oxidized low-density lipoproteins. 2. The measurements revealed a characteristic pattern of three resonances in spectra from oxidized, but not from native low-density lipoprotein at 1.17 p.p.m., 1.18 p.p.m. and 1.20 p.p.m. (relative to 3-trimethylsilyl-[2,2,3, 3-2H4]-propionate).3.A quantitative comparison between these resonances in sera from patients with coronary heart disease and healthy control subjects revealed that the intensity was significantly higher in patients with coronary heart disease (1.17 p.p.m.: 0.026+/-0.014 versus 0.015+/-0.019; 1.18 p.p.m.: 0.032+/-0.011 versus 0.017+/-0.021; 1.20 p.p.m.: 0.030+/-0.066 versus 0.010+/-0.005; P<0.05 compared with healthy control subjects for each resonance).4.Fractionation of sera from patients with coronary heart disease revealed that the resonances equal to those obtained from experimentally oxidized low-density lipoprotein are indeed caused by the low-density lipoprotein fraction of the sera.5. When the NMRs from sera were calibrated with oxidized low-density lipoprotein prepared by Cu2+ oxidation, a concentration of 66.5+/-28.6 microgram/ml and 36.3+/-23.7 microgram/ml (P<0.05) was estimated in patients with coronary heart disease and healthy subjects respectively. Elevated levels of oxidized low-density lipoprotein also occurred in those patients with normal serum concentrations of total low-density lipoprotein.6. The study shows a simple method to measure oxidized low-density lipoprotein in human serum and may gain interest to assess the cardiovascular risk factor profiles more completely.

Case-Control Studies↗
PubMed1997

Phosphatidylcholine-specific phospholipase C regulates thapsigargin-induced calcium influx in human lymphocytes.

The involvement of phosphatidylcholine-specific phospholipase C (PC-PLC) and D (PC-PLD) in the regulation of the thapsigargin-induced Ca2+ increase was investigated. Pretreatment of human lymphocytes with the PC-PLC inhibitors D609 or U73122 enhanced the thapsigargin-induced Ca2+ influx. By contrast, no effect was observed in the presence of phospholipase D inhibitor butanol. Addition of exogenous PC-PLC but not PC-PLD to lymphocytes prestimulated with thapsigargin led to a decrease of intracellular Ca2+. In addition, thapsigargin was shown to release diacylglycerol (DAG) from cellular phosphatidylcholine pools. The thapsigargin-induced DAG formation was inhibited by U73122 and D609 but not by butanol. Moreover, no formation of the PC-PLD activity marker phosphatidylbutanol was detected. Thapsigargin-induced DAG formation was dependent on the Ca2+ entry, as it was abolished in the absence of extracellular Ca2+ or in the presence of Ni2+. Further investigations demonstrated that the inhibition of the cellular DAG target, protein kinase C (PKC), enhanced thapsigargin-induced Ca2+ increase, whereas direct PKC activation had an inhibitory effect. Taken together, our results reveal the involvement of PC-PLC in the regulation of the thapsigargin-induced Ca2+ increase and point to the existence of a physiologic feedback mechanism activated by Ca2+ influx and acting via consecutive activation of PC-PLC and PKC to limit the rise of intracellular Ca2+.

Bridged-Ring Compounds↗
PubMed1997

Low-density lipoproteins inhibit the Na+/H+ antiport in human platelets. A novel mechanism enhancing platelet activity in hypercholesterolemia.

BACKGROUND: LDL have been reported to augment platelet activation, and increased platelet reactivity has been observed in familial hypercholesterolemia. However, the underlying mechanisms of this putatively atherogenic effect is unknown. Because intracellular pH (pHi) may play an important role in platelet function, we examined the influence of LDL on pHi and Na+/H+ antiport activity in human platelets and compared it with the effect of [3-methylsulfonyl-4-piperidinobenzoyl] guanidine hydrochloride (HOE 694), a selective Na+/H+ antiport inhibitor. METHODS AND RESULTS: Using a fluorescent dye technique, we demonstrated that incubation of platelets with physiological concentrations of LDL or with HOE 694 decreased pHi. In addition, both LDL and HOE 694 inhibited the Na+/H+ antiport in platelets treated with sodium propionate or thrombin. The inhibitory effect of LDL was observed both in normal and in glycoprotein (GP)IIb/IIIa-as well as in GPIIIb (CD36)-deficient platelets and was not influenced by the covalent modification of apolipoprotein B lysine residues, suggesting that specific LDL binding sites were not involved. Thrombin-induced phosphoinositide breakdown, diacylglycerol formation, and Ca2+ mobilization, as well as platelet aggregation and granule secretion, were potentiated by both LDL and HOE 694. pHi and Na+/H+ antiport activity were significantly reduced in platelets from patients with familial hypercholesterolemia. Both parameters were normalized after normalization of LDL levels by apheresis treatment. CONCLUSIONS: LDL inhibits the Na+/H+ antiport most likely via receptor-independent mechanisms, thereby augmenting platelet reactivity. This novel mechanisms explains increased platelet reactivity in patients with familial hypercholesterolemia and may contribute to the atherogenic potential of LDL.

Adult↗
PubMed1997

Effect of diadenosine polyphosphates on Ca2+ ATPase activity.

Diadenosine tri-, tetra-, penta-, and hexaphosphate (Ap3A, Ap4A, Ap5A and Ap6A) have been described as having various effects on vascular tone depending on the number of phosphate groups. This study examined the effect of diadenosine polyphosphates on Ca2+ ATPase activity. The activity of the enzyme was measured spectrophotometrically as the difference in hydrolysis of ATP in the presence and absence of Ca2+ with various concentrations of ATP and diadenosine polyphosphates. The diadenosine polyphosphates increased the activity of the Ca2+ ATPase. The effect tended to be stronger with Ap5A and Ap6A than with Ap3A and Ap4A in the order of potency: Ap3A approximately AP4A < Ap5A approximately AP6A. The stimulatory effect of diadenosine polyphosphates was not competitive with that of ATP, suggesting an allosteric activation of Ca2+ ATPase by diadenosine polyphosphates. This effect may be physiologically relevant for limiting the increase in cytosolic free Ca2+ concentration elicited by diadenosine polyphosphates by receptor activation and modulating Ca2+ ATPase function under resting conditions.

Adenosine Triphosphate↗
PubMed1997

Diadenosine polyphosphates' action on calcium and vessel contraction.

The effects of the endogenous, platelet-derived vasoactive compounds, diadenosine tetraphosphate (AP4A), diadenosine pentaphosphate (AP5A), and diadenosine hexaphosphate (AP6A) on the vasoconstriction of isolated rat renal resistance vessels and rat aortic strips were measured using a vessel myograph. In addition, the effects of AP4A, AP5A, and AP6A on the cytosolic free calcium concentration ([Ca2+]i) were evaluated in cultured rat vascular smooth muscle cells (VSMC) using the fluorescent dye technique. Diadenosine polyphosphates dose-dependently increased the force of renal resistance vessels and isolated aortic strips. The administration of 10 mumol/L AP4A, AP5A, or AP6A significantly increased the force of isolated renal resistance vessels by 3.48+/-0.43 mN (n = 8), 2.14+/-0.40 mN (n = 12), or 2.70+/-0.31 mN (n = 11, each P < .01 compared with resting tension), respectively. The administration of 10 micromol/L AP4A, AP5A, or AP6A significantly increased the force of isolated aortic strips by 2.45+/-0.97 mNewton (n = 10), 2.70+/- 0.30 mN (n = 6), or 1.48+/-0.20 mN (each P < .01 compared with resting tension), respectively. The administration of 10 micromol/L AP4A, AP5A, or AP6A significantly increased [Ca2+]i in VSMC to a peak concentration of 314+/-60 nmol/L (n = 6), 247+/-25 nmol/L (n = 15), or 332+/-100 nmol/L (n = 5), respectively (each P < .01 compared with resting value). Both the diadenosine polyphosphate-induced vasoconstriction and [Ca2+]i increase was significantly reduced in the absence of extracellular calcium or after administration of a specific inhibitor of P2 purinoceptors. It is concluded that diadenosine polyphosphates increase [Ca2+]i and hence cause vessel constriction.

Animals↗
PubMed1997

Decreased cellular Mg2+ concentrations in a subgroup of hypertensives--cell models for the pathogenesis of primary hypertension.

A new method to determine total Mg2+ content in lymphocytes was developed, offering advantages for routine measurements as compared to fluorescence methods. Intracellular Mg2+ measurements were performed in lymphocytes of 18 untreated normotensive and 19 untreated essential hypertensive patients. Mg2+ content was referred to lymphocytic protein, which was determined according to Bradford's method. Mg2+ measurements were performed by atomic absorption spectroscopy using a Video 12 apparatus from Thermo Electron Instrumentation Laboratory, Andover, MA, USA. The results show that in patients with essential hypertension, total intralymphocytic Mg2+ content is significantly lower (0.07 +/- 0.05 mmol/g lymphocytic protein, mean +/- s.d.) as compared to controls (0.11 +/- 0.04 mmol/g lymphocytic protein, mean +/- s.d., P < 0.05). Free intracellular Mg2+ content was measured in lymphocytes by the fluorescent indicator mag-fura-II, showing no significant difference in normotensives and hypertensives (0.30 +/- 0.16 vs 0.38 +/- 0.17 mmol/l). In platelets free intracellular Mg2+ concentrations were not found of significant difference in normotensive and hypertensive patients (0.52 +/- 0.23 vs 0.47 +/- 0.27 mmol/l) using mag-fura-II. In plasma Mg2+ concentrations there was no significant difference in the normotensive and hypertensive group (0.92 +/- 0.07 vs 0.88 to 0.07 mmol/l). There was no correlation between plasma, free or total cellular magnesium concentrations in each group. Furthermore this method also seems suitable for routine measurements of total intracellular Mg2+ concentrations in even larger groups of patients in comparison with fluorescent indicator measurements like mag-fura-II. Lowered total intracellular Mg2+ concentrations in a subgroup of primary hypertension may contribute to the development of this disorder, perhaps due to different buffering systems.

Adult↗
PubMed1997

Cellular protective action of angiotensin converting enzyme inhibitors.

In several studies organ protective effects of ACE inhibitors independent from their antihypertensive action have been demonstrated. The mechanisms of the protective effects of angiotensin converting enzyme (ACE) inhibitors on vasculature and kidney are largely unknown. In the present study the modulatory action of captopril on the angiotensin II (AngII), arginine vasopressin (AVP), and platelet derived growth factor (PDGF)-induced increase of cytosolic free calcium concentration ([Ca2+]i) was investigated in cultured vascular smooth muscle cells (VSMC) and cultured glomerular mesangial cells (MC) from rats using the fluorescent dye technique. Resting [Ca2+]i in VSMC or MC was not significantly affected by captopril. The preincubation of VSMC with 1 mumol/l captopril significantly reduced the AngII-induced [Ca2+]i increase in VSMC from 90 +/- 10 nmol/l (n = 78; mean +/- SEM) to 51 +/- 16 nmol/l (n = 53; p < 0.05) and in MC from 102 +/- 42 nmol/l (n = 14) to 43 +/- 12 nmol/l (n = 7; p < 0.05). In the absence of extracellular calcium captopril produced no effect on AngII induced changes of [Ca2+]i. Captopril significantly attenuated the AVP-induced [Ca2+]i increase in VSMC and MC. The preincubation of MC with 1 mumol/l captopril for 40 min significantly reduced the PDGF-induced [Ca2+]i increase in MC from 127 +/- 31 nmol/l (n = 11) to 61 +/- 32 nmol/l (n = 5, p < 0.05). The present results may indicate that part of the protective effects of ACE inhibitors on vasculature and kidney may be promoted by inhibition of growth-factor induced changes of calcium homeostasis.

Angiotensin II↗
PubMed1997

Na+/H+ exchange during an oral glucose challenge in patients with essential hypertension.

To determine the effects of an oral glucose challenge on cellular Na+/H+ exchange in vivo we measured plasma glucose concentrations, plasma insulin concentrations, plasma C-peptide concentrations, arterial blood pressure, cytosolic pH (pHi) and cellular Na+/H+ exchange in 24 patients with essential hypertension (HT) and 41 age-matched healthy normotensive control subjects (NT) during a standardized oral glucose tolerance test. Under resting conditions, the plasma glucose concentrations, plasma insulin concentrations, plasma C-peptide concentrations and Na+/H+ exchange activity were significantly higher in HT compared with NT (P < 0.05 in each case). A significant increase in lymphocytic Na+/H+ exchange activity was only seen in NT (resting 0 h: (4.23 +/- 0.2) x 10(-3) pHi/s; mean +/- S.E.M.; 1 h after glucose administration: (6.00 +/- 0.56) x 10(-3) pHi/s; 2 h after glucose administration: (6.65 +/- 0.64) x 10(-3) pHi/s; P = 0.0003 by Friedman's two-way ANOVA), but not in HT (resting 0 h: (6.07 +/- 0.36) x 10(-3) pHi/s; 1 h after glucose administration: (6.72 +/- 1.02) x 10(-3) pHi/s; 2 h after glucose administration: (6.71 +/- 0.62) x 10(-3) pHi/s; P = 0.7470). During an oral glucose challenge the systolic (P < 0.0001) and diastolic (P < 0.0001) blood pressure significantly decreased in HT but not in NT. Essential hypertension shows abnormal in vivo regulation of Na+/H+ exchange and blood pressure following oral glucose intake.

Analysis of Variance↗