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F C Luft

Publications and source records attributed to F C Luft.

At least 361 records · Page 20Linked to original sources
PubMed1994

Nuclear calcium signaling is initiated by cytosolic calcium surges in vascular smooth muscle cells.

Calcium is not only a second messenger in the cytoplasm but also may be involved in signaling within the nucleus itself. The regulation of the nuclear calcium signal is imperfectly defined. The purpose of our study was to further elucidate the relationship between cytosolic [Ca++]c and nuclear calcium concentration [Ca++]n in vascular smooth muscle cells and to test the hypothesis that components of the phospholipase C-induced signaling system are responsible for the hormone-induced increase in [Ca++]n. Cytosolic [Ca++]c and nuclear calcium concentration [Ca++]n were measured by confocal microscopy in primarily cultured vascular smooth muscle cells from rat aorta. Basal [Ca++]n was lower than the cytosolic calcium [Ca++]c concentration. Angiotensin II (10(-7) M) induced a rapid increase in [Ca++]c which was immediately followed by a surge in [Ca++]n. The high [Ca++]n was maintained for 20 to 30 seconds and returned to basal values thereafter. Increased transmembraneous calcium influx by KCl (80 mM) led to a rapid rise in [Ca++]n. Treatment of vascular smooth muscle cells with ionomycin (10(-4) M) also induced an increase in [Ca++]c accompanied by an increase in [Ca++]n. The calcium channel agonist A 2386 led to a slower increase in both [Ca++]c and [Ca++]n. An increase in extracellular calcium to 6 mM under these conditions enhanced the surge of [Ca++]c but not [Ca++]n. Removal of extracellular calcium by EGTA decreased both the angiotensin II-induced increase in [Ca++]c and the increase in [Ca++]n. Nitrendipine (10(-7) M) had the same effect as EGTA. Inhibition of the intracellular release by preincubating vascular smooth muscle cells with thapsigargin (10(-5) M) also partially inhibited the effect of angiotensin II (Ang II) on [Ca++]n. However, combined EGTA and thapsigargin abolished both the rise in [Ca++]c and the surge in [Ca++]n. The protein kinase C inhibitors staurosporine (5 x 10(-8) M) and H7 (10(-7) M) had no effect on the Ang II-mediated increases in [Ca++]c and [Ca++]n. Our results demonstrate that the angiotensin II-induced increase in [Ca++]c is rapidly followed by a rise in [Ca++]n. This effect on [Ca++]n is not mediated by an angiotensin II-induced generation of IP3 or activation of protein kinases, but rather seems to depend on an increase in [Ca++]c.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Enhanced Na(+)-H+ exchanger activity and NHE-1 mRNA levels in human lymphocytes during metabolic acidosis.

It has recently been demonstrated that uremic metabolic acidosis and experimental metabolic acidosis caused by ingestion of ammonium chloride coincide with increased Na(+)-H+ exchanger (NHE-1) activity in human blood cells. In the present study, we investigated whether an increased level of NHE-1 specific mRNA in human lymphocytes during the course of an experimental metabolic acidosis could explain the enhanced transport activity during metabolic acidosis. Six healthy individuals were studied before and after 5 days of taking 15 g of ammonium chloride daily. Plasma pH and bicarbonate decreased significantly, from 7.42 +/- 0.027 to 7.28 +/- 0.05 and from 26.7 +/- 2.0 to 15.6 +/- 2.9 mM, respectively. Basal cytosolic pH (pHi) and Na(+)-H+ exchange activity were measured in lymphocytes loaded with the fluorescent pHi indicator 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Basal pHi remained unchanged during metabolic acidosis (7.03 +/- 0.07 vs. 7.03 +/- 0.06). Ethylisopropylamiloride-sensitive pHi recovery increased from 0.046 +/- 0.007 to 0.076 +/- 0.012 dpHi/min (P < 0.0001). The transcript level of NHE-1 mRNA was measured by reverse-transcription polymerase chain reaction in comparison with a constitutively expressed reference gene (glyceraldehyde-3-phosphate dehydrogenase). NHE-1 mRNA in human lymphocytes increased 1.5-fold in metabolic acidosis. These data suggest that the increased Na(+)-H+ exchange activity in metabolic acidosis may be caused by de novo synthesis of antiport protein.

Acidosis↗
PubMed1994

Vascular angiotensin and the sympathetic nervous system: do they interact?

We tested the hypothesis that local vascular formation of angiotensin (ANG) II and the sympathetic nervous system potentiate each other. Isolated rat hindquarters were perfused with an artificial medium, and ANG I and II release was measured by high-performance liquid chromatography and radioimmunoassay. Electrical stimulation of the lumbar sympathetic chain (0.5, 2, and 8 Hz) did not affect vascular ANG release in Sprague-Dawley (SD) rats. Hypertensive, ren-2 transgenic (TG+) rat hindquarters released significantly more ANG I (110 +/- 19 vs. 65 +/- 21 fmol/30 min in SD rats) and ANG II (235 +/- 22 vs. 140 +/- 30 fmol/30 min); however, nerve stimulation did not alter ANG release in TG+ rats. Captopril inhibited vascular ANG II release by 90%, but neither captopril nor ANG II receptor blockade by losartan affected the pressor response to nerve stimulation in SD and TG+ rats. Isoproterenol failed to increase either vascular ANG release or pressor response to nerve stimulation in SD or spontaneously hypertensive rat hindquarters. Exogenous renin, which increased vascular ANG release approximately 100-fold, prolonged the pressor responses to nerve stimulation. We conclude that the vascular renin-ANG system does not interact with the sympathetic nervous system locally. However, high concentrations of ANG II, which can be induced by circulation-derived renin, may prolong the duration of sympathetic nerve-induced vasoconstriction.

Adrenergic beta-Agonists↗
PubMed1994

Renal effects of captopril and nitrendipine in transgenic rats with an extra renin gene.

We investigated the acute effects of captopril and nitrendipine on renal function and sodium excretion in hypertensive, male, heterozygous transgenic rats harboring a mouse renin gene [TGR (mRen-2)27]. Both drugs reduced blood pressure dose dependently in conscious transgenic rats. The oral ED20 for captopril was 0.5 mg/kg and 2.7 mg/kg for nitrendipine. In orally salt-loaded (20 mL/kg saline) transgenic rats captopril (0.3 to 3.0 mg/kg) reduced sodium excretion by approximately 90% in the 6 hours after administration, whereas equally antihypertensive doses of nitrendipine increased sodium excretion by approximately 100%. The antinatriuretic effect of captopril was accompanied by a reduction in creatinine clearance and a decrease in the excretion of cyclic GMP. In orally water-loaded (20 mL/kg water) transgenic rats captopril also reduced sodium excretion by more than 90%, and nitrendipine slightly increased sodium excretion. In control Sprague-Dawley rats the effects were opposite; namely, captopril tended to increase natriuresis, and nitrendipine caused a small but distinct decrease in sodium excretion. Intravenous captopril in anesthetized transgenic rats caused an antinatriuresis with a decrease in inulin clearance but not in Sprague-Dawley rats. To control for non-renin-related effects of captopril, we gave transgenic rats oral losartan. Losartan also decreased urinary sodium excretion. The results suggest a role for the renin-angiotensin system in the maintenance of glomerular filtration rate and sodium excretion in transgenic TGR (mRen-2)27 rats.

Animals↗
PubMed1994

Platelet-derived growth factor and angiotensin II induce different spatial distribution of protein kinase C-alpha and -beta in vascular smooth muscle cells.

Protein kinase C is an important second-messenger system that is translocated from the cytosol to the cell membrane on cell stimulation. We used confocal microscopy to study the spatial distribution of protein kinase C isoforms after stimulation of cultured vascular smooth muscle cells with platelet-derived growth factor and angiotensin II (Ang II). Monoclonal antibodies for the isoforms alpha and beta were used. Translocation was also assessed by Western blot. Isoform alpha was evenly distributed in the cytosol, whereas the beta isoform formed coarse granules in the perinuclear region. Both isoforms shifted from the cytosolic to the membrane fraction after exposure to Ang II (10(-7) mol/L) and platelet-derived growth factor (100 ng/mL at 6, 12, and 20 minutes). Confocal microscopy showed a rapid assembly of isoform alpha along cytosolic fibers at 6 minutes followed by a translocation toward the nucleus at 12 minutes with Ang II. Platelet-derived growth factor engendered a similar response; however, a cytoskeletal distribution was not observed. The beta isoform was rapidly translocated by both inducers to the perinuclear region and the nucleus. Our results show that inducers cause a translocation of protein kinase C isoforms not only into the cell membrane but also into the cell nucleus. We suggest that protein kinase C may also be important for nuclear signaling.

Angiotensin II↗
PubMed1994

Sympathetic baroreceptor responses after chronic NG-nitro-L-arginine methyl ester treatment in conscious rats.

Blood pressure elevations after nitric oxide inhibition may result in part from increased sympathetic tone. In this study arterial baroreceptor reflex control of heart rate, renal sympathetic nerve activity (RSNA), and adrenal sympathetic nerve activity (ASNA) were compared in rats given normal tap water or a 3.7 nmol/L (10 mg%) solution of NG-nitro-L-arginine methyl ester (L-NAME) for 1 or 5 weeks. L-NAME raised blood pressure after 5 weeks of treatment (153 +/- 3 versus 130 +/- 3 and 124 +/- 2 mm Hg, 5 weeks versus 1 week and control). The sensitivity of arterial baroreceptor reflex control of RSNA was reduced after both 1 and 5 weeks of treatment (-5.05 +/- 0.63% and -4.46 +/- 0.2% versus -6.43 +/- 0.39% baseline activity per millimeters of mercury). Set point gain of ASNA was attenuated after 5 weeks of treatment compared with controls (-1.7 +/- 3% versus -3.3 +/- 3% baseline activity per millimeters of mercury). Maximal inhibition of ASNA was attenuated in groups treated 1 and 5 weeks (60 +/- 3% and 66 +/- 3% versus 34 +/- 4% baseline activity). The maximal increase in both RSNA and ASNA was elevated in rats treated 5 weeks (RSNA: control, 263 +/- 19%; 1 week, 224 +/- 17%; 5 weeks, 324 +/- 20%; ASNA: control, 272 +/- 29%; 1 week, 252 +/- 31%; 5 weeks, 361 +/- 28% baseline activity). The data indicate that chronic L-NAME treatment alters arterial baroreceptor reflexes in part before the onset of hypertension.

Adrenal Glands↗
PubMed1994

Impaired cardiovascular reflexes precede deoxycorticosterone acetate-salt hypertension.

We hypothesized that impaired cardiopulmonary reflexes but not altered baroreceptor reflexes precede deoxycorticosterone acetate (DOCA)-salt hypertension. Uninephrectomized rats were given either DOCA and 0.9% NaCl as drinking water, 0.9% NaCl alone, or tap water. We measured mean blood pressure, heart rate, and renal sympathetic nerve activity. After 8 days, mean blood pressure was not different in DOCA-salt and control rats. Volume-sensitive cardiopulmonary reflexes were tested by intravenous volume loading with saline (10% body weight in 15 minutes), which decreased renal sympathetic nerve activity without changing mean blood pressure or heart rate. This response was blunted in DOCA-salt rats. Chemosensitive cardiopulmonary reflexes were tested by 15-minute infusions of the serotonin 5-HT3 agonist phenylbiguanide, which decreased renal sympathetic nerve activity without changing mean blood pressure or heart rate. Sustained decreases in renal sympathetic nerve activity occurred during phenylbiguanide infusion in controls but were blunted over time in DOCA-salt rats. The arterial baroreflex responses to graded infusions of methoxamine and nitroprusside were analyzed by sigmoidal curve fitting. There were no differences in gain of renal sympathetic nerve activity or heart rate between the groups. Thus, DOCA-salt rats exhibit impaired cardiopulmonary reflexes before the onset of hypertension; the volume-sensitive reflexes are more severely affected than chemosensitive reflexes. The arterial baroreceptor reflex is unaltered. The decreased sensitivity of cardiopulmonary reflexes may contribute to DOCA-salt hypertension.

Analysis of Variance↗
PubMed1994

Kidneys from pediatric donors: risk versus benefit.

We encountered four adult patients who received renal transplants from young children < 36 months of age, each of whom developed severe hypertension, heavy proteinuria, and progressive renal failure. Biopsies disclosed glomerular sclerosis with crescents in three patients and mesangial expansion in one. We thus analyzed our experience with 74 adults who received grafts from donors < or = 10 years of age and compared the results to those of 804 patients who were transplanted with kidneys from donors > 10 years of age. A Kaplan-Meier analysis revealed that graft survival was significantly worse in patients receiving grafts from younger, compared to older donors. This difference was apparent in patients treated either with or without cyclosporine. A subanalysis comparing patients with donor grafts aged < or = 5 or 6-10 years revealed a further adverse age-related effect. Renal artery thrombosis and recurrent or de novo biopsy-proven glomerulonephritis were more common in patients receiving grafts from younger donors, while graft failure from rejection actually appeared less common. We conclude that severe hypertension and resultant glomerular hyperperfusion promoted glomerulosclerosis and crescent formation in our patients. Our results have caused us to pursue a more conservative approach towards transplanting grafts from donors aged < or = 10 years into adult recipients.

Adult↗
PubMed1994

LDL increases (CA++)i in human endothelial cells and augments thrombin-induced cell signalling.

Low-density lipoproteins (LDLs) stimulate cytosolic calcium ([Ca++]i) in endothelial cells. To elucidate the mechanisms of this response, we compared the effects of low-density lipoprotein (LDL) with those of thrombin, a known endothelial cell agonist. [Ca++]i was measured in cultured endothelial cells from human umbilical veins. Both spectrofluorometry of single cells with fura-2 and confocal microscopy were used. LDL (100 micrograms/ml) led to a rapid increase in [Ca++]i (143 +/- 46 nmol/L to 426 +/- 69 nmd/L; p < 0.05) followed by a sustained plateau phase. Higher concentrations did not increase this response further. Removal of extracellular calcium resulted in a significant decrease of the plateau phase, which remained significantly elevated as compared with baseline values. On the other hand, the initial peak was only slightly altered. Incubation of endothelial cells with thapsigargin (10(-6) mol/L) reduced the initial calcium peak, while the incubation of the cells with pertussis toxin (10(-6) mol/L) for 24 hours abolished the LDL-induced [Ca++]i response together. Down-regulation of LDL receptors by exposing the endothelial cells to high LDL concentrations (500 micrograms/ml) for 24 hours abolished the LDL-induced calcium signal, while preincubation of the cells with acetylated LDL (500 micrograms/ml) did not alter the cellular response to LDL. Visualization of the calcium signal showed a rapid increase in [Ca++]i followed by an increase in the nuclear calcium concentration. The LDL calcium signalling was shorter than that observed with thrombin (0.1 U/ml). Administration of thrombin and LDL together resulted in an increased [Ca++]i response as compared with either substance alone. Our results show that (1) LDL leads to both a release of calcium from intracellular stores and a transmembranous calcium influx, (2) the effect of LDL is dependent on binding to a specific G-protein-coupled receptor, and (3) LDL enhances the activation induced by other agonists.

Calcium↗
PubMed1994

Angiotensin II infusions elevated blood pressure independently of platelet cytosolic calcium concentrations in humans.

A remarkably close correlation between platelet cytosolic calcium ([Ca2+i]) and arterial blood pressure has been identified in patients with essential hypertension. We tested the notion that a pharmacologically relevant infusion of angiotensin (Ang) II is associated with an increase in cytosolic calcium [Ca+2i]. Five normal volunteers received Ang II (5 ng/kg/min) for three hours or vehicle intravenously in random sequence respectively. The investigations were conducted at least 14 days apart. Plasma renin activity and blood pressure were measured every 20 minutes. [Ca+2i] was measured with the fluorescent indicator fura-2 before and at the end of the last hour of Ang II infusion. Mean arterial blood pressure increased by 10 mmHg during Ang II infusion (P < 0.05). Plasma renin activity decreased from 2.21 +/- 0.28 to 1.31 +/- 0.22 ng/ml/hour during the Ang II infusion (P < 0.05). On the other hand, [Ca+2i] was 131 +/- 13 nmol/l before and 129 +/- 13 nmol/l after the infusion (P = NS). The data suggest that agonists may increase blood pressure without an increase in platelet [Ca+2i]. Furthermore, Ang II may increase blood pressure independently of [Ca+2i].

Adolescent↗
PubMed1994

[Clinical aspects and differential therapy of mild hypertension in pregnancy].

Pregnant patients with increases in blood pressure are often treated with medication, in our view inappropriately. We examined 222 pregnant women who were referred because of two blood pressure determinations > 140/90 mm Hg. The women were primarily treated by nonpharmacological means. Only 44 required medications to maintain a blood pressure < 140/90 mm Hg. Twenty-six additional pregnant women referred for hypertension were taught to measure their blood pressures at home. Fourteen underwent 24-h ambulatory blood pressure monitoring. Home and 24-h blood pressure measurements were both significantly lower than those obtained in the office and did not significantly differ from each other. We conclude that most pregnant women without proteinuria, who show mild to moderate blood pressures > 140/90 mm Hg are best treated conservatively without drugs. Those in whom home or 24-h blood pressures exceed 140/90 mm Hg and who do not respond to nonpharmacologic methods require medication. Finally, "white coat" hypertension is common in pregnant women.

Arousal↗
PubMed1994

Sodium kinetics in white and black normotensive subjects: possible relevance to salt-sensitive hypertension.

The hypothesis that sodium (Na) kinetics are not a first order process was tested. Twelve normotensive white and 12 normotensive black men were given 10, 200, and 400 mmol/d Na as the chloride salt for 7 days in random order. All urine made was collected. No effect of Na intake on blood pressure was identified in either whites or blacks. The half-life (T1/2) with decreasing Na intake to 10 mmol/d was 1.08 days in whites and 1.65 days in blacks (p = not significant [NS]). With increasing Na intake, T1/2 increased in both whites and blacks; at the 400 mmol/d intake, the T1/2 for whites was 2.88 days and for blacks was 5.81 days (p < 0.05). At that intake, whites accumulated 385 +/- 153 mmol compared with 909 +/- 153 mmol for blacks (p < 0.05). The data showed that T1/2 increases with increasing Na intake and is, therefore, dose-dependent or "zero" order. The effect of dose is more prominent in blacks than in whites; blacks accumulate more Na with increasing Na intake than whites. These data may have relevance for the pathogenesis of salt-sensitive hypertension in blacks.

Adult↗
PubMed1993

Usefulness of piretanide plus ramipril for systemic hypertension: a multicenter trial.

To test the dose responses of piretanide, ramipril, and their combination in patients with essential hypertension, a prospective, randomized, double-blind, placebo-controlled trial was conducted in 480 patients. Twelve separate groups were studied: placebo, piretanide 3 mg, piretanide 6 mg, ramipril 2.5 mg, ramipril 5 mg, ramipril 10 mg, and their combinations, as single daily morning doses. Patients were randomized after a 2-week run-in period without drugs; treatment was given for 6 weeks. A dose response compared with placebo was found for both drugs; the combination was more effective than either drug alone. Piretanide 6 mg, combined with ramipril 5 mg, provided optimal blood pressure reduction. Self-reported adverse effects of both drugs and their combinations did not exceed those reported for placebo. A surface analysis suggested that piretanide primarily reduced systolic blood pressure, whereas ramipril was more effective in reducing diastolic blood pressure. The data attest to a combined efficacy of piretanide and ramipril in decreasing arterial blood pressure.

Adult↗
PubMed1993

Prevalence and long-term outcome of glomerulonephritis in renal allografts.

We report long-term results over 10 years in patients developing glomerulonephritis after renal transplantation. The prevalence rate of glomerulonephritis was 6.2% in 785 renal transplants involving 697 patients with end-stage renal disease. This rate was 14% in patients undergoing biopsy of their grafts because of malfunction. The rate was 15% in patients diagnosed as having glomerulonephritis of any cause prior to transplantation. Membranous, focal sclerosing, and IgA glomerulonephritis were the most common histologic diagnoses. Documented histologic recurrence occurred in only 1% of patients with poor, biopsy-proven glomerulonephritis of their native kidneys. Patients with focal sclerosing glomerulonephritis had the greatest risk from recurrence. De novo glomerulonephritis was most likely to be membranous in character. The graft survival rate of patients with glomerulonephritis was not distinguishable from that of patients showing rejection; both were 45% at 60 months and 33% versus 11%, respectively, at 120 months (P = NS); the graft survival rate in patients without rejection was 76% at 120 months. Thus, glomerulonephritis is responsible for approximately 14% of renal graft malfunction. Glomerulonephritis has a prognosis similar to chronic rejection. Finally, glomerulonephritis as specific histologic recurrence is unusual. Patients with glomerulonephritis should not be discouraged from undergoing transplantation because of putative risks related to recurrence.

Adolescent↗
PubMed1993

Clinical correlates of functional status in patients with chronic renal insufficiency.

Patients with end-stage renal disease (ESRD) are known to have significantly reduced functional abilities, as measured by the Sickness Impact Profile (SIP). We investigated the clinical correlates with SIP scores in a cohort of patients with lesser degrees of renal dysfunction recruited from an academic general medicine practice (mean calculated creatinine clearance, 25 mL/min). Of 603 eligible patients with chronic renal insufficiency (CRI) defined as a serum creatinine greater than 1.5 mg/dL and a calculated creatinine clearance less than 50 mL/min on two occasions more than 6 months apart, 360 (60%) agreed to participate. These patients were primarily elderly (mean age, 69 years) black (83%), women (69.2%), with an average of 6 years of education and a household income of $400 to $800 per month; 92% had hypertension and 57% had diabetes. The SIP was administered in-home by trained interviewers. Independent variables included demographic data, education, income, and medications (via interviewers), vital signs taken by a renal nurse, and diagnostic test results and diagnoses from patient's computerized records. The total SIP score was the dependent variable, and its physical and psychosocial subscales were also investigated. Variables with univariate correlations with total SIP (P < 0.05) were included in a multiple regression analysis. All variables with a multivariable P value less than 0.10 were included in the final model. The mean SIP score was 24.5 +/- 15.6, higher than that found in patients on dialysis. Significant (P < 0.05) independent correlates with higher SIP scores (greater disability) were lower educational level and income, prior diagnoses of coronary artery disease and stroke, and lower serum albumin.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗