Claus Spieker

Effect of long-term hemodialysis on arterial compliance in end-stage renal failure.

To assess the influence of long-term hemodialysis on arterial compliance, the elastic vessel wall properties of the common carotid artery were determined in 20 normotensive renal transplant recipients (age 44.7 +/- 4.1 years) 8-12 weeks after first transplantation and in 10 healthy controls (age 45.9 +/- 5.2 years). Arterial distension was measured by using a multigate pulsed Doppler system, blood pressure curve was recorded by finger-plethysmography. 10 patients with a prior long-term hemodialysis of 51 +/- 11 months were compared to 10 patients with a prior short hemodialysis of 18 +/- 7 months. The patients and controls had been matched in respect of age, sex and blood pressure. In the long and short-term hemodialysis group, the proportion of patients (n = 10) with a history of mild hypertension was similar--mild hypertension for 25 +/- 10 months (n = 5) and for 27 +/- 9 months (n = 5). In the group with long-term hemodialysis, the cross-sectional compliance and the distensibility coefficient was significantly reduced in comparison to the group with short-term hemodialysis (p < 0.005) and to the control group (p < 0.001). A significant inverse correlation between the hemodialysis period and the distensibility coefficient (r = -0.59; p < 0.005) showed a decrease in arterial compliance with the length of hemodialysis treatment. The results demonstrate that vessel wall elasticity decreases with the length of hemodialysis treatment and is reduced by hemodialysis-dependent factors, which are detached from sustained arterial hypertension. As cause of reduced arterial compliance in long-term hemodialysis hypervolemia, hypercirculation and disturbed calcium-phosphate metabolism is suggested.(ABSTRACT TRUNCATED AT 250 WORDS)

Different calcium storage pools in vascular smooth muscle cells from spontaneously hypertensive and normotensive Wistar-Kyoto rats.

Objective To evaluate whether the distribution of intracellular free calcium may be impaired in primary hypertension. Design Cytosolic free calcium and stored calcium were investigated in cultured vascular smooth muscle cells from spontaneously hypertensive rats (SHR). Methods The concentrations of intracellular and stored calcium were investigated in cultured vascular smooth muscle cells from spontaneously hypertensive rats aged 6 months from the Münster strain (SHR) and from age-matched normotensive Wistar-Kyoto (WKY) rats. Vascular smooth muscle cells were grown on coverslips, and fluorescence measurements of the intracellular calcium concentration were performed using fura-2. The different effects of thapsigargin, a selective Ca-ATPase inhibitor, and of angiotensin II (Ang II) on the calcium storage pools were investigated. Results In the absence of external calcium thapsigargin produced a dose-dependent transient increase in the concentration of intracellular calcium in vascular smooth muscle cells. The thapsigargin-induced maximum peak increase in the concentration of intracellular calcium was not significantly different in SHR and WKY rats. After depletion of the thapsigargin-sensitive calcium pools the addition of 100nmol/l Ang II produced a rise in the concentration of intracellular calcium in vascular smooth muscle cells from SHR and WKY rats. Using vascular smooth muscle cells from the SHR the Ang II-induced increase in the concentration of intracellular calcium was not significantly different in the presence and absence of thapsigargin, indicating that the calcium pools depleted by thapsigargin and Ang II do not overlap significantly in vascular smooth muscle cells from SHR. In contrast, in the WKY rats the response to Ang II was significantly diminished after depletion of the thapsigargin-sensitive pool. When Ang II and thapsigargin were administered in the reverse order, i.e. Ang II before thapsigargin, the thapsigargin response was diminished in the WKY rats but not in the SHR. Conclusion SHR differ from WKY rats in having vascular smooth muscle cells that contain thapsigargin-sensitive calcium storage pools that are distinct from the Ang II-sensitive calcium pools.

Coenzyme A Glutathione Disulfide A Potent Vasoconstrictor Derived From the Adrenal Gland

The adrenal gland is involved in the regulation of vascular tone by secretion of vasoactive agents such as catecholamines, neuropeptide Y, or endogenous ouabain. A further potent vasoconstrictor is isolated from bovine adrenal glands and is identified by chromatography, mass spectrometry, UV spectroscopy, and enzymatic cleavage as coenzyme A glutathione disulfide (CoASSG). CoASSG is found in chromaffin granules of adrenal glands and is released from adrenal medulla slices by carbachol. At a concentration of 10(-12) mol/L CoASSG increases renal vascular resistance. Intra-aortic injection of 5 x 10(-10) mol CoASSG increases blood pressure in the intact animal. Besides its vasopressor properties, this substance potentiates the effects of angiotensin II on vascular tone. It is concluded that CoASSG could play a role in blood pressure regulation not only by direct effects but also by modulation of the action of angiotensin II.

Effect of Na,K-ATPase inhibition on cytosolic free calcium ions in vascular smooth muscle cells of spontaneously hypertensive and normotensive rats

Objective To investigate the role of Na+-Ca2+ exchange in the regulation of cytosolic free Ca2+ and the pathogenesis of primary hypertension. Method: Cytosolic free Ca2+ ([Ca2+]i) in cultured vascular smooth muscle cells from normotensive and spontaneously hypertensive rats of the Münster strain was measured using the fluorescent dye fura-2 after inhibition of Na+,K+ ATPase by ouabain and after addition of angiotensin II. Results: [Ca2+]i showed a rapid increase together with a depolarization of membrane potential as measured by merocyanine 540. The ouabain-induced increase in [Ca2+]i was blocked in Ca2+-free medium and by nifedipine, but incubation with the inhibitor of the Na+-Ca2+ exchange, NiCl2, did not diminish the effect of ouabain. Likewise, in Na+-free medium the response to ouabain was not suppressed. The angiotensin II-induced changes in [Ca2+]i were diminished in Ca2+-free medium and by nifedipine, but enhanced by NiCl2. Conclusion: The increase in [Ca2+]i after Na+,K+ ATPase inhibition is not due to a modulation of Na+-Ca2+ exchange, but to a Ca2+ influx through Ca2+ channels. Changes in Na+-Ca2+ exchange caused by Na+,K+ ATPase inhibition may not play an important role in vascular smooth muscle cells of spontaneously hypertensive rats.

Ca2+ ATPase activity in essential and renal hypertension.

In 15 patients with essential hypertension, 16 patients with renal hypertension and in 12 healthy subjects Ca2+ ATPase activity was determined in red blood cells both in the basal state and after maximal stimulation with calmodulin. Normal subjects showed a basal and maximal activity of 7.1 +/- 3.6 and 16.0 +/- 2.3 pmol phosphate/min.10(6) RBC, respectively. Renal hypertensives had a similar basal Ca2+ ATPase activity (5.4 +/- 4.1 pmol phosphate/min.10(6) RBC) and a lowered maximal Ca2+ ATPase activity (9.8 +/- 5.4 pmol phosphate/min.10(6) RBC, p < 0.05). In essential hypertensives basal and maximal Ca2+ ATPase activity was 9.0 +/- 5.3 and 35.4 +/- 14.4 pmol phosphate/min.10(6) RBC, respectively, the latter being significantly increased (p < 0.01). This finding, which is in contrast to earlier results indicating a lowered Ca2+ ATPase activity in essential hypertension, may be explained as a consequence of an increased Ca2+ influx in essential hypertension. A lowered Ca2+ ATPase activity does not seem to be involved in the pathogenesis of essential hypertension.

Electron-probe X-ray microanalysis of sodium ion content in vascular smooth muscle cells from spontaneously hypertensive and normotensive rats.

In aortic smooth muscle cells from 12 spontaneously hypertensive rats (SHR) of the Münster strain and 11 normotensive Wistar-Kyoto rats (WKY), the intracellular Na+ content was measured by electron-probe microanalysis. Measurements were performed in aortic cryosections 3 microns thick; the Na+ content was 12.5 +/- 2.4 g/kg dry weight in SHR versus 6.96 +/- 1.1 g/kg dry weight in WKY (P less than 0.01). Thus, aortic smooth muscle cells from SHR are characterized by a markedly elevated intracellular Na+ content compared with normotensive cells. This may either be due to genetically determined disturbances in transmembrane Na+ transport or to a circulating factor affecting Na+ transport. Cellular Na+ handling may be disturbed in SHR aortic smooth muscle as it is in hypertensive blood cells.

Alteration in Mg2+ content of red blood cells from patients with diuretic therapy

Hypomagnesemia can cause ventricular tachycardia, cardiac necrosis, or torsades de pointes. Diuretic treatment can result in Mg2+ depletion, as many diuretics inhibit the reabsorption of filtered Mg2+ in the proximal or distal tubule. As plasma Mg2+ constitutes only about 3% of total body Mg2+ stores, intracellular Mg2+ determinations may be more useful for assessing total body Mg2+ content. Therefore we studied the effect of a thiazide diuretic (trichlormethiazide 4 mg/day), a combination of a thiazide and a potassium-sparing diuretic (trichlormethiazide and amiloride 2 mg/day each), and the loop diuretic piretanide (6 mg/day) on intracellular Mg2+ in patients with mild essential hypertension before and after 6 and 10 weeks of therapy. Mg2+ measurements were performed in blood plasma and in red blood cells by atomic absorption spectroscopy, using a Video 12 apparatus. There was a significant decrease in intracellular Mg2+ content under trichlormethiazide therapy (p<0.05). Furthermore, our results show that diuretic treatment with a combination of a thiazide and a potassium-sparing diuretic or with the loop diuretic piretanide may have the advantage of avoiding intracellular Mg2+ depletion.

Cardiovascular side effects after renal allograft rejection therapy with Orthoclone: prevention with nitrendipine.

Orthoclone (OKT-3), a monoclonal antibody, is an effective immunosuppressant in organ graft recipients. One of the reported side effects is serious pulmonary edema, heart failure, hyperdynamia, and elevation of blood pressure. It should be assessed whether patients treated with OKT-3 benefit from antihypertensive therapy with a calcium channel blocker before and during the allograft rejection therapy to prevent from cardiovascular side effects. To assess a preventive cardiovascular effect of therapy with nitrendipine before and during the OKT-3 rejection therapy, the patients studied (n = 28) were randomly allocated to two study groups. Group a without nitrendipine comprised 15 patients, and group b with 2 x 10 mg of nitrendipine daily comprised 13 patients. In study group a (without nitrendipine therapy), in 8 of 15 patients, there was a short-lasting increase in blood pressure during 3 h after the first injection of OKT-3 by 20.0 +/- 12.8 (systolic)/10.1 +/- 6.7 (diastolic) mm Hg. Whereas this initial rise of blood pressure on the first day was accompanied by an increase in heart rate by 24.1 +/- 10.8 beats/min, the longer-lasting increase in blood pressure at day 2 was not associated with significant changes in heart rate. In group b (patients receiving 2 x 10 mg of nitrendipine before OKT-3 therapy was started and during the whole treatment course), in 3 of 13 patients, a short increase in blood pressure (13.7 +/- 2.9/7.8 +/- 5.1 mm Hg) was recorded 5 h after the first dose of OKT-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma, Intracellular, and Membrane Mg2+ Concentrations in Normal Pregnancy and in Preeclampsia

Objective and Design: Decreased cellular Mg2+ concentrations seem to be involved in the pathogenesis of preeclampsia. To investigate the changes in Mg2+ metabolism in normal pregnancy and preeclampsia, plasma, intracellu-lar, and membrane Mg2+ concentrations were determined in a clinical study and compared to values of healthy nonpregnant subjects.Subjects and Methods: Twenty-five healthy female subjects (nonpregnant), 22 untreated healthy pregnant women, and 20 preeclamptic women were investigated. In each patient, plasma, erythrocyte, and membrane Mg2+ content were measured. In the preeclamptic group, plasma and erythrocyte Mg2+ content were determined before and after a Mg2+ supplementation and 4–7 days after delivery.Results: Plasma Mg2+ concentrations were significantly lowered in the healthy pregnant group and the preeclamptic group as compared to nonpregnant controls (P < 0.0001). In comparison with nonpregnant subjects, both healthy pregnant and preeclamptic women had significantly lowered intra-c...

Efficacy and safety of ramipril therapy in hypertension after renal transplantation

The efficacy of the new ACE-inhibitor ramipril in the treatment of hypertension is well established, but there is no experience with the use of ramipril in hypertensive renal recipients. In the present study, the efficacy and safety of the antihypertensive therapy with ramipril was examined in 10 untreated, hypertensive, renal transplant recipients with stable transplant function. For control, 10 age- an sex-matched renal transplant patients receiving conventional antihypertensive treatment with a Ca2+ channel blocker and/or diuretic were followed. Starting with 2.5 mg/day, the dose of Ramipril was increased to 5 mg and 10 mg at intervals of 5 days as long as diastolic blood pressure dropped below 90 mmHg. Twentyfour-hour blood pressure monitoring was performed before, 2 weeks, 6 weeks, and 12 weeks after ramipril therapy. Twentyfour-hour blood pressure was 155.8±7.1/96.1 ±3.0 mmHg before the Ramipril therapy and dropped to 147.6±3.73/87.5±3.1 mmHg after 2 weeks 140.6 ±5.4/84.5±2.4 mmHg after 6 weeks, and 138.5±5.7/83. 1±3.1 mmHg after 12 weeks of therapy. In the control group, the effect of antihypertensive treatment was not significantly different. The renal transplant function improved during the therapy with ramipril. The cyclosporin A level did not change significantly during the therapy, [cyclosporin A (HPLC) 101.4±15.9 g/l before, 98.3±15.7 g/l after 2 weeks, 94.8±13.1 g/l after 6 weeks, and 96.2±12.3 g/l after 12 weeks of ramipril therapy]. No anemia was induced by the therapy with ramipril. The potassium remained unchanged before, 2,6, and 12 weeks after the treatment with ramipril. The results show that ramipril is a safe and efficient drug for treating hypertension in renal transplant recipients.