Search PubMed⌕ Search

Biomedical subjects

F C Luft

Publications and source records attributed to F C Luft.

At least 307 records · Page 17Linked to original sources
PubMed1996

Effects of angiotensin converting enzyme inhibitor on renal haemodynamics during mental stress.

OBJECTIVE: To examine the effects of angiotensin converting enzyme (ACE) inhibition on renal and systemic haemodynamics as well as on humoral regulators, under resting conditions and during mental stress in 20 normotensive and 20 mildly hypertensive subjects. METHODS: All of the subjects received either 25 mg cilazapril or placebo once a day, in a randomized, double-blind, cross-over trial for 1 week, followed by a 2-week washout period before the alternative regimen was given. We measured renal blood flow with para-aminohippuran, glomerular filtration rate with inulin, cardiac output by impedance cardiography and blood pressure and heart rate by an oscillometric method. We also monitored effects on plasma renin activity, aldosterone, catecholamines and atrial natriuretic peptide. Mental stress consisted of a long-lasting, time-reaction device, thereby provoking activation of the sympathetic nervous system. RESULTS: At rest ACE inhibition lowered mean arterial pressure (92 +/- 10 versus 98 +/- 9 mmHg), increased renal blood flow (803 +/- 109 versus 707 +/- 93 ml/min) and the renal fraction of cardiac output (25.9 +/- 2.5 versus 23.5 +/- 2.5%) and decreased the filtration fraction (17.9 +/- 2.5 versus 19.8 +/- 2.7%) in hypertensive but not in normotensive subjects. Sympathetic activation by mental stress leading to a transient increase in blood pressure did not alter significantly the effects of ACE inhibition on renal and systemic haemodynamics, in normotensive or in hypertensive subjects, although a tendency towards attenuation of the rise in glomerular filtration rate was noted in hypertensives (7.2 +/- 1.0 versus 5.1 +/- 0.8%). ACE inhibition led to increased plasma noradrenaline at rest but not during mental stress in hypertensive patients. CONCLUSION: ACE inhibition in patients with mild hypertension increased selectively renal perfusion, which is conserved during mental stress without persistent effects on the sympathetic nervous system. Thus, mental stress as a correlate of daily life stress appeared not to confound the selective renal vasodilatory effect of ACE inhibitors.

Adult↗
PubMed1996

High permeation of L-type Ca2+ channels at physiological [Ca2+]: homogeneity and dependence on the alpha 1-subunit.

Molecular cloning has identified multiple isoforms of dihydropyridine-sensitive C-class L-type Ca2+ channels. We tested the hypotheses that L-type (C-class) channels exhibit homogeneous high permeation properties at physiological Ca2+ concentrations and membrane potentials. We measured unitary currents through single dihydropyridine-sensitive omega-conotoxin-insensitive endocrine and smooth muscle L-type Ca2+ channels in rat pituitary GH3 and rat aortic A7r5 cell lines. We also measured unitary currents through smooth muscle (Cb) Ca2+ channel alpha 1-subunits in Chinese hamster ovary (CHO) cells. Our results show that single channel conductances of all three L-type (C-class) channels are uniform with high Ba2+ concentrations, e.g., approximately 23 pS with 110 mM Ba2+. The single channel conductances were reduced to similar values when the Ba2+ concentration was lowered to near-physiological values: 11.1, 9.3, and 8.4 pS in GH3, A7r5, and CHO cells at 2 mM Ba2+, respectively. The single channel conductances were not significantly different with near-physiological Ca2+ concentrations: 5.5, 5.9, and 4.9 pS in GH3, A7r5, and CHO cells at 2 mM Ca2+, respectively. The data suggest that L-type (C-class) channels are homogeneous in terms of Ca2+ permeation at physiological charge carrier concentrations and membrane potentials. Furthermore, the data indicate that the relatively high Ca2+ permeation under physiological conditions is determined by the intrinsic properties of the pore-forming Ca2+ channel alpha 1-subunit.

Animals↗
PubMed1996

Endothelial cell tyrosine kinase receptor and G protein-coupled receptor activation involves distinct protein kinase C isoforms.

Protein kinase C (PKC) is a family of serine/threonine protein kinase isoforms that is important to intracellular enzymes for both tyrosine kinase receptors and G protein coupled receptors. However, which isoforms are linked to which class of receptors in endothelial cell signaling is not known. Moreover, the PKC isoforms in endothelial cells have not been thoroughly characterized. We tested the hypothesis that specific PKC isoforms are involved in different signaling pathways. PKC isoform expression was assessed by using reverse transcription polymerase chain reaction and Western blotting. The spatial distribution of PKC after stimulation of the cells with basic fibroblast growth factor (bFGF) and thrombin was examined by using confocal microscopy. Expression of PKC alpha, delta, epsilon, theta, and zeta was detectable on both the mRNA and protein levels. In resting cells, PKC alpha and epsilon were mostly distributed in the cytosol, while PKC alpha and epsilon were also present in the nucleus. Nuclear immunoreactivity of PKC alpha and epsilon increased significantly between passages 1 and 3. The phorbol ester TPA induced a rearrangement of PKC delta and a translocation of PKC alpha and epsilon to the nucleus. Treatment of endothelial cells with TPA for 24 hours caused PKC alpha, delta, and epsilon to disappear, while PKC zeta was not influenced by TPA. bFGF induced a rapid assembly of PKC alpha along cytosolic structures, followed by a translocation of the isoform toward the perinuclear region and into the nucleus. bFGF had a smaller effect on PKC epsilon. In contrast, thrombin had a similar effect on nuclear translocation of PKC alpha, did not influence PKC epsilon, and induced a rapid nuclear translocation of PKC zeta. Thus, tyrosine kinase receptor activation via bFGF induced a rapid association of PKC alpha and epsilon with nuclear structures, while activation of the G protein-coupled thrombin receptor increased mostly nuclear PKC zeta. The translocation of PKC isoforms into the nucleus by growth-promoting factors may be important for the induction of endothelial cell growth.

Base Sequence↗
PubMed1996

Human renin-dependent hypertension in rats transgenic for human angiotensinogen.

To examine the utility of rats transgenic for human angiotensinogen in the study of human renin-induced hypertension, we first developed assays to measure both the human and rat renin-angiotensin systems in these rats. We used human and mouse renin, transgenic human angiotensinogen, and the human renin inhibitor Ro 42-5892 to determine human- and rat-specific plasma angiotensinogen concentrations, renin activity, and renin concentration. The assays were validated with rat and human plasma mixed in known amounts and with plasma from rats transgenic for human renin. We then tested the human angiotensinogen-transgenic rats by infusing recombinant human renin over 10 days (50 ng/h, n=4) with osmotic minipumps. High human angiotensinogen transgene expression was found in the liver, brain, kidney, gastrointestinal tract, and aorta, whereas rat angiotensinogen gene expression was detected in the liver and brain. During human renin infusion, blood pressure increased to >200/150 mm Hg. Before infusion, human angiotensinogen was 100-fold greater than rat angiotensinogen (141 +/- 73 versus 1.2 +/- 0.16 microg angiotensin l/mL); the relation was not changed by renin infusion. Plasma renin activity increased 300-fold; human plasma renin concentration increased to very high levels (449 +/- 262 ng of angiotensin I per mL per hour), whereas rat plasma renin concentration decreased to undetectable levels. Thus, chronic human renin infusion resulted in severe hypertension with extreme plasma renin activity and plasma renin concentration. However, even at these levels, human angiotensinogen was not rate limiting and angiotensin II was not a significant stimulus for angiotensinogen production. We conclude that these transgenic rats represent a novel model of human renin-dependent hypertension.

Angiotensinogen↗
PubMed1996

Acute and chronic neutral endopeptidase inhibition in rats with aortocaval shunt.

In heart failure, sodium and water retention develop despite elevated plasma levels of atrial natriuretic peptide. Atrial natriuretic peptide is degraded in part by a neutral endopeptidase. Whether neutral endopeptidase inhibition improves sodium and water excretion in heart failure is unknown. We determined the effect of neutral endopeptidase inhibition on plasma levels of atrial natriuretic peptide and the renal response to acute volume expansion in rats with aortocaval shunts and in sham-operated controls. Acute endopeptidase inhibition with SQ 28,603 (30 mg/kg) elevated atrial natriuretic peptide plasma levels in both shunted rats (523 +/- 54 to 1258 +/- 330 pmol/L, P<.05) and controls (184 +/- 28 to 514 +/- 107 pmol/L, P<.05). Urinary cGMP excretion, which reflects renal action, increased in parallel. However, the diuretic and natriuretic responses to acute volume expansion were enhanced only in control rats and not in shunted rats. In contrast to the acute effects, chronic neutral endopeptidase inhibition with SCH 34826 (30 mg/kg twice daily) in shunted rats did not change atrial natriuretic peptide plasma levels or cGMP excretion. Nevertheless, the diuretic and natriuretic responses to acute volume load were increased by chronic endopeptidase inhibition in shunted rats (1789 +/- 154 to 2674 +/- 577 microL/80 min and 99 +/- 31 to 352 +/- 96 micromol/80 min, respectively; P<.05). Chronic endopeptidase inhibition attenuated the cardiac hypertrophic response to aortocaval shunt without changing arterial blood pressure. Our data show that the renal effects of neutral endopeptidase inhibition are not necessarily dependent on changes in atrial natriuretic peptide plasma levels but instead may be mediated by local inhibition of the neutral endopeptidase in the kidney. In addition, chronic endopeptidase inhibition may attenuate heart failure-induced cardiac hypertrophy independent of hemodynamic effects.

Alanine↗
PubMed1996

Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension.

We examined a Turkish kindred with a unique form of autosomal dominant hypertension that cosegregates 100% with brachydactyly and maps to chromosome 12p. Affected adults were 10 to 15 cm shorter than unaffected people; however, their body mass index (27 kg/m2) was not different. Blood pressure increased steeply with age in the affected people so that by age 40 years, they had a mean blood pressure of 140 mm Hg, compared with 92 mm Hg in unaffected individuals. Complete clinical, roentgenographic, and laboratory evaluation was performed in 6 subjects, including 24-hour blood pressure measurements and humoral determinations before and after volume expansion with 2 L normal saline over 4 hours followed by volume contraction on the following day with a 20-mmol sodium diet and 40 mg furosemide at 8 AM, noon, and 4 PM. Two affected men aged 46 and 31 years; 3 affected women aged 40, 31, and 30 years; and 1 unaffected man aged 29 years were studied. Systolic pressures ranged from 170 to 250 mm Hg, and diastolic pressures ranged from 100 to 150 mm Hg in affected people; the unaffected man had a blood pressure of 120/70 mm Hg. Thyroid, adrenal, and renal functions were normal; electrolyte and acid-base statuses were normal. Calcium and phosphate homeostasis was normal. Day-night circadian blood pressure rhythm was preserved. The subjects were not salt sensitive; renin, aldosterone, and catecholamine values reacted appropriately to volume expansion and contraction. Affected people had mild cardiac hypertrophy and increased radial artery wall thickness. Fibroblasts from affected people grew more rapidly in culture than from unaffected people. We conclude that this novel form of inherited hypertension resembles essential hypertension.

Adult↗
PubMed1996

K+ currents in human coronary artery vascular smooth muscle cells.

K+ channels and their currents are important in vascular tone regulation and are potential therapeutic targets; however, K+ channels in human coronary artery vascular smooth muscle cells (VSMCs) have received little attention. We examined K+ currents in freshly isolated VSMCs from human coronary arteries (n=368 from 32 human hearts) with conventional patch-clamp or perforated-patch techniques with nystatin. We detected four different K+ currents: (1) the delayed rectifier K+ current, IK(dr); (2) the Ca2+-activated K+ current, IK(Ca); (3) the nonrectifying noninactivating outward ATP-dependent K+ current, IK(ATP); and (4) the spontaneous transient outward K+ current, IK(STOC). K+ channels underlying spontaneous transient outward currents probably represent a single clustered population of Ca2+-activated K+ channels functionally associated with Ca2+ release channels in the sarcoplasmic reticulum. Inwardly rectifying K+ currents were not observed. K+ currents were unevenly distributed in that they were not uniformly exhibited by all cells. The most prominent K+ currents were IK(Ca) (100%) and IK(dr) (46%). IK(STOC)s, which have not been previously described in humans, were present in 67% of VSMCs. IK(ATP) was small under physiological conditions; however, IK(ATP) increased markedly after cell stimulation with exogenous or endogenous coronary vasodilators. Thus, IK(ATP) may be particularly relevant in ischemia and could be of special importance as a therapeutic target. We conclude that human coronary VSMCs have unique K+ currents that differ sufficiently from those of other species, thus making the investigation of human material clinically relevant. The findings suggest potential avenues for further therapeutic research.

Adenosine Triphosphate↗
PubMed1996

Effects of intracellular angiotensin II in vascular smooth muscle cells.

Angiotensin (Ang) II is present inside vascular smooth muscle cells (VSMCs); however, its intracellular functions, if any, are unknown. We tested the hypothesis that intracellular Ang II exerts effects on cytosolic Ca2+ ([Ca2+]i) in VSMCs. Ang II was administered via microinjection. Intracellular Ang II localization was demonstrated by fluorescein-labeled Ang II and electron microscopy. [Ca2+]i was monitored by confocal microscopy with fluo 3. Ang II was identified in endosomes and in the nucleus by both localizing techniques. Microinjection of Ang II (10(-10) mol/L) led to a rapid increase in [Ca2+]i in the cytosol and in the nucleus. The [Ca2+]i increase was due to the influx of extracellular Ca2+ ions. The intracellular Ang II effect was totally inhibited by the concomitant injection of the Ang II antagonist CV-11947. Desensitization of extracellular Ang II receptors, on the other hand, did not influence the intracellular effects, nor did extracellular CV-11947. The increase in [Ca2+]i was observed not only in the microinjected cell but also in directly adjacent VSMCs. In contrast to the microinjected cells, the [Ca2+]i increase in the adjacent cells was mostly due to release from intracellular stores. Pretreatment with thapsigargin abolished the Ang II response in adjacent cells. Microinjection of inositol tris-phosphate induced a [Ca2+]i response in adjacent cells that was similar to the Ang II-induced effects. Preincubation of VSMCs with the uncoupling substances dimethyl sulfoxide and heptanol did not decrease the Ang II response but instead prevented a [Ca2+]i surge in adjacent cells. We conclude that intracellular Ang II binds to intracellular Ang II receptors and elicits an increased [Ca2+]i in the injected cell and, thereafter, cells in the immediate neighborhood. Cell-cell contact is necessary for the Ang II-mediated effects. The data suggest that intracellular Ang II may stimulate a cluster of VSMCs from a single cell via the release of second messengers.

Angiotensin II↗
PubMed1996

Cardiovascular effects of beta-carbolines in conscious rats.

The beta-carbolines have a high affinity for the benzodiazepine receptor, where they demonstrate actions opposite to those of the benzodiazepines and elicit anxiogenic effects. We tested the acute cardiovascular effects of beta-carbolines in conscious unrestrained rats. Intravenous infusion of ethyl-beta-carboline-3-carboxylate (BCCE) or methyl-beta-carboline-3-carboxylate (BCCM) caused dose-related decreases in heart rate. Pretreatment with RO 15-1788 (10.0 mg/kg, i.v.), a benzodiazepine receptor antagonist, or atropine (1.0 mg/kg, i.v.) prevented the bradycardia elicited by BCCE (3.0 mg/kg, i.v.). In contrast, tetrahydro-beta-carboline (THBC; 3.0 mg/kg, i.v.) increased both heart rate and blood pressure significantly as compared with controls. However, larger doses of THBC failed to elicit further increases in heart rate or blood pressure. These experiments indicate that in conscious unrestrained rats, beta-carbolines given acutely do not routinely elicit the cardiovascular changes normally associated with stress or anxiety. We next extended our observations to rats given the beta-carboline noreleagnine, 2 mg/kg, or vehicle twice daily intraperitoneally for 4 weeks. The rats were fed either a high salt (8%) or a low salt (0.9%) diet. At 4 weeks, rats given noreleagnine and high salt had higher tail cuff pressures (146 +/- 4 vs. 134 +/- 4 mmHg) than those given noreleagnine and low salt. However, with direct arterial measurement, these differences disappeared. These data suggest that beta-carbolines do not provide a useful model for investigating the effects of chronic stress on cardiovascular function in rats.

Animals↗
PubMed1996

Lifelong angiotensin-converting enzyme inhibition, pressure natriuresis, and renin-angiotensin system gene expression in transgenic (mRen-2)27 rats.

The transgenic rat (TGR) (mRen-2)27 is said to have low circulating active renin values in plasma and little or no renin gene expression in the kidney. Nevertheless, intrarenal angiotensin II-related effects appear to be responsible for the rightward shift in pressure-natriuresis curves of TGR. To clarify the role of the intrarenal renin-angiotensin system in modulating TGR pressure-natriuresis, TGR were given lifelong lisinopril by treating TGR and their mothers before conception. Rat and mouse renin, AT1 receptor, and angiotensinogen gene expression in the kidneys were studied with in situ hybridization. Neural and endocrine regulatory differences between TGR and Sprague-Dawley Hannover (SDH) rats were eliminated by renal denervation and infusion of vasopressin, aldosterone, 17-OH corticosterone, and norepinephrine. TGR with lisinopril had blood pressures similar to SDH. In TGR with lisinopril, the pressure-natriuresis curve was shifted leftward but not quite to the values observed in SDH given lisinopril. The histology of lisinopril-treated TGR was indistinguishable from normal SDH. Lisinopril increased rat renin and angiotensinogen gene expression both in SDH and TGR, but it did not influence mouse renin gene expression in TGR. Discontinuing lisinopril increased blood pressure in TGR and shifted the pressure-natriuresis relationship rightward. Thus, the components of the endogenous renin-angiotensin system and the mouse renin transgene were present and expressed in kidneys of TGR. The rat gene components responded to lisinopril as expected, but the mouse renin transgene expression was not influenced. Lisinopril normalized TGR blood pressure; however, a detectable leftward shift in pressure-natriuresis remained. These studies underscore the role of angiotensin-mediated effects of the mouse renin transgene in terms of shifting pressure-natriuresis in TGR.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Circulating leukocyte integrin expression in Wegener's granulomatosis.

Leukocyte adhesion and infiltration are important in the pathogenesis of Wegener's granulomatosis (WG). We tested the hypothesis that the expression of the beta 1-chain integrin VLA-4 (CD49d/CD29) and the beta 2-chain integrins LFA-1 (CD11a/CD18), Mac-1 (CD11a/CD18), and gp150,95 (CD11c/CD18) is increased on leukocytes in patients with active WG. Fifteen patients with active WG as defined by positive antineutrophil cytoplasmic autoantibody (cANCA) titers and biopsy, 30 patients with WG in remission as defined by negative cANCA titers and/or immunosuppressive therapy, 25 normal control subjects, and 12 patients with other inflammatory renal and systemic diseases were studied. Surface expression of LFA-1, Mac-1, p150, 95, and VLA-4 on neutrophils, lymphocytes, and monocytes was measured by fluorescent antibody cell sorting with monoclonal antibodies against CD11a, CD11b, CD11c, CD18, CD49d, and CD29 respectively. Immunocytochemistry and confocal microscopy were also utilized. beta 1 (CD29) and beta 2 (CD18) integrin subunit expression on neutrophils, monocytes, and lymphocytes from patients with acute WG was significantly increased compared with healthy persons and compared with patients with treated vasculitis. Furthermore, the alpha-integrin subunit CD11b expression was increased on granulocytes and monocytes, but not on lymphocytes. Finally, the alpha-integrin subunit CD11a expression was increased on monocytes. Immunocytochemistry showed that the increased immunoreactivity on neutrophils was evenly distributed on the plasma membrane and in the cytosol. Immunosuppression resulted in decreased expression of the beta 1 and beta 2-integrin subunits. It was concluded that the integrin adhesion molecules, particularly Mac-1 (CD11b/CD18), are upregulated on leukocytes in active WG. This finding suggests a role for integrin expression in the pathogenesis of WG and a possible clue for treatment.

Follow-Up Studies↗
PubMed1996

Potential effect of metabolic acidosis on beta 2-microglobulin generation: in vivo and in vitro studies.

Beta 2-microglobulin (beta 2M) is responsible for dialysis-associated amyloidosis. Level of beta 2M in plasma increase during chronic renal failure; however, retention does not appear to be the sole mechanism responsible. The effect of metabolic acidosis on beta 2M production was examined. Thirty-six patients with stable chronic renal insufficiency, 12 uremic patients before their first dialysis, 8 hemodialysis patients who were assigned to acetate or bicarbonate dialysate and then crossed over to the alternative regimen, and 6 normal subjects given NH4Cl to initiate metabolic acidosis were studied. In vitro studies in the human myeloid cell line U 937 were also performed. beta 2M protein was measured with ELISA, beta 2M mRNA was measured with reverse transcription polymerase chain reaction, and the U 937 cells were studied at two pH levels with FACScan flow cytometry. The cells were exposed in vitro up to 60 min in a buffered incubation medium to either pH 5.10 or pH 7.34. An inverse correlation was found between beta 2M and bicarbonate concentrations in plasma in the stable chronic renal failure patients (r = -0.54; P < 0.05) and in the uremic patients before their first dialysis (r = -0.72; P < 0.05). In hemodialysis patients, blood pH and plasma bicarbonate values were lower (P < 0.05) and beta 2M concentrations in plasma were higher (P < 0.05) with acetate than with bicarbonate dialysate. In normal men, NH4Cl resulted in an increase (P < 0.05) in beta 2M mRNA expression in lymphocytes by an average factor of 1.5 (range, 1.1 to 1.8). In U 937 cells, the cell surface expression of beta 2M and HLA Class I heavy chain assembled with beta 2M decreased at low pH compared with normal pH. Concomitantly, an increase in beta 2M release into the supernatant was observed, possibly as the result of beta 2M dissociation from cell surface HLA Class I complex. The results suggest that metabolic acidosis may enhance cellular beta 2M generation and release.

Acidosis↗
PubMed1996

Substitution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year.

BACKGROUND: A new galenic form of cyclosporin A has been developed, based on microemulsion technology. The bioavailability of the compound is relatively independent of food intake and bile flow. It was the purpose of this prospective clinical trial to study the safety of the microemulsion form of cyclosporin A. METHODS: Three hundred and two renal transplant patients, stratified according to transplant age, were switched from the conventional to the new microemulsion formulation of cyclosporin A. A 1:1 conversion ration was used. Measurements included CsA levels, S-creatinine, liver enzymes, uric acid, and blood pressure. Measurements were performed at baseline and on days 4, 8, 15, 29 and months 3, 6 and 12 after conversion. Dose adjustments were performed to achieve through levels of 80-120 ng/ml. RESULTS: Within the 12-month observation period the cyclosporin dose was reduced by 14.7% (from 204 +/- 60 mg/day at baseline to 174 +/- 51 mg/day after conversion, P < 0.001). Acutely, i.e. by day 8, 1:1 dose conversion resulted in a modest increase of mean drug through levels (from 114 ng/ml at baseline to 120 ng/ml, P < 0.01). This increase was accompanied by an increase in serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in uric acid values (P < or = 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decrease (P < 0.05). After 1 month, drug through levels had decreased to baseline (112 ng/ml) and remained there until month 6. They were significantly lower after 12 months (102 +/- 33 ng/ml), P <0.001). Creatinine clearance values increased to above baseline at 6 and 12 months. Within the 1-year period there occurred 24 (= 8%) episodes of biopsy proven rejection and seven episodes of cyclosporin-attributed nephrotoxicity. CONCLUSIONS: The 1:1 conversion from conventional cyclosporin A to the microemulsion formulation s efficacious and safe, but an initial dose reduction of 10% is advised in patients with through levels in the high-normal range.

Administration, Oral↗
PubMed1996

Conversion to microemulsion cyclosporine in stable renal transplant patients: results after one year.

We switched 302 renal transplant patients from the conventional to a new microemulsion formulation of cyclosporine, to study the latter's safety and efficacy. We used a simple 1:1 conversion of the patient's total daily dose. We measured trough drug levels as well as serum creatinine, liver enzymes, uric acid, and blood pressure values at baseline and at days 4, 8, 15, 29, and months 3, 6 and 12 after drug substitution. Dose adjustments directed at trough levels 80-120 ng/ml were performed, starting at day 8. Within the 12-month observation period, the cyclosporine dose was reduced by 14.7% (204 +/- 60 mg/day baseline vs 174 +/- 51 mg/day after conversion, p < or = 0.001). By day 8, the 1:1 dosage conversion resulted in a modest mean increase in drug trough levels (114 ng/ml baseline vs 120 ng/ml, p < or = 0.01). This increase was accompanied by an increase in serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in uric acid values (p < or = 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decreased (p < or = 0.05). After one month, drug trough levels had decreased to baseline (112 ng/ml) and remained there until month 6. They were significantly lower after 12 months (102 +/- 33 ng/ml, p < or = 0.001). Plasma creatinine values decreased to below baseline by month 6 (p < or = 0.001) and month 12 (p < or = 0.001). Twenty-four (8%) biopsy proven rejection episodes and 7 cases of cyclosporine attributed nephrotoxicity occurred in these 302 patients within these 12 months. We conclude, that a 1:1 conversion from conventional to the microemulsion form of cyclosporine is efficacious and safe. However, we advise an initial 10% decrease in dose reduction in those patients whose trough levels are in the high-normal range.

Adult↗
PubMed1996

Nisoldipine and pressure-natriuresis curves in transgenic (mRen2)27 rats.

OBJECTIVES: The mechanism by which antihypertensive drugs influence pressure natriuresis gives insight into their mode of action. We tested the effects of nisoldipine on pressure natriuresis, glomerular filtration rate, and renal blood flow in transgenic (mRen2)27 rats and Sprague-Dawley Hannover control rats. METHODS: The rats were anaesthetized, uninephrectomized with denervation of the remaining kidney, administered noradrenaline, 17-hydroxycorticosterone, vasopressin, and aldosterone to 'clamp' these regulatory systems and nisoldipine (0.5 mg/kg bolus plus 0.017 mg/kg per min). The glomerular filtration rate and renal plasma flow were measured with inulin and PAH. Renal perfusion pressure was varied from approximately 100 to approximately 200 mmHg with clamps above and below the kidney. RESULTS: Nisoldipine shifted not only the pressure-diuresis and pressure-natriuresis curves but also the fractional sodium and water curves leftwards in transgenic (mRen2)27 rats, but not in Sprague-Dawley Hannover rats. Nisoldipine increased the glomerular filtration rate and renal blood flow in transgenic (mRen2)27 rats but not in Sprague-Dawley Hannover rats. CONCLUSIONS: Nisoldipine shifts the pressure-natriuresis curve in transgenic (mRen2)27 rats leftwards; sodium and water excretion is increased for any given perfusion pressure. This effect is intrinsic to the kidney and is associated with inhibition of tubular sodium and water reabsorption and with an increase in renal perfusion.

Animals↗