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Biomedical subjects

F C Luft

Publications and source records attributed to F C Luft.

At least 199 records · Page 11Linked to original sources
PubMed1998

Angiotensin-converting enzyme and angiotensinogen gene polymorphisms and heart rate variability in twins.

Decreased heart rate variability (HRV) is associated with congestive heart failure, post-myocardial infarction, ventricular arrhythmias, sudden cardiac death, and advancing age. A deletion/insertion polymorphism in the angiotensin-converting enzyme (ACE) gene and a substitution (M235T) in the angiotensinogen gene have been associated with risk for heart disease. The aim of this study was to determine the heritability of HRV and related parameters in monozygotic and dizygotic twins and to assess the influence of ACE and angiotensinogen polymorphisms. We studied 95 MZ pairs and 46 DZ pairs. We measured HRV and related parameters, ACE and angiotensinogen levels, plasma norepinephrine, ACE, and angiotensinogen genotypes. We found that HRV and related parameters were significantly influenced by genetic variability, although nonshared genetic effects were also important. Angiotensinogen and plasma norepinephrine were generally correlated with decreased HRV, whereas ACE was correlated with perturbances of normal rhythmic HRV. Nevertheless, the DD ACE genotype was associated with increased HRV (p <0.05), whereas angiotensinogen polymorphisms had no effect. We conclude that HRV and related parameters are in part heritable. Interestingly, the DD ACE genotype is associated with increased HRV.

Adult↗
PubMed1998

Effects of naloxone on hemodynamic and sympathetic nerve responses to pain in normotensive vs. borderline hypertensive men.

Pain sensitivity decreases with increasing resting blood pressure. This blood pressure-pain interaction may be mediated by endogenous opioids which have been shown to affect both blood pressure and nociception. To test this hypothesis, we measured mean arterial blood pressure (MAP), central venous pressure (CVP), heart rate (HR), muscle sympathetic nerve activity (MSNA), serum catecholamines, and individual pain rating scales during 2 min periods of noxious mechanostimulation (skin fold pinching) in nine young (26 +/- 2 year), male normotensive (NT) subjects and in 12 age and weight matched males with borderline hypertension (BHT). Measurements were performed before and after the i.v. administration of naloxone (0.15 mg/kg) and placebo in a randomized double-blind cross-over trial. In the pre-naloxone trials, pain led to similar changes in MAP, CVP, MSNA and plasma catecholamines in the two groups except for a higher increase in HR in the BHT group as compared to the NT group (3 +/- 1 vs. 1 +/- 1 bpm; P < 0.005). Opioid blockade with naloxone increased MSNA responses to pain in the NT group (from 5 +/- 1 to 9 +/- 1 bursts/min, and, from 100 +/- 23 to 204 +/- 36 units/min, respectively; P < 0.05) but did not significantly affect the MSNA response to pain in the BHT group. Pain induced responses of MAP, CVP, and catecholamines were not altered by naloxone in either group. Overall, there was a highly significant inverse correlation between pain perception and resting blood pressure which was not significantly affected by naloxone. The BHT subjects exhibited a lower pain perception compared to the NT subjects (P < 0.005). Naloxone increased pain rating in the NT group (from 194 +/- 9 to 218 +/- 13; P < 0.005) but not in the borderline hypertensive group (160 +/- 8 vs. 168 +/- 10; P = 0.36). Except for a decreased HR response in the BHT group, placebo had no effect on the responses to pain. Our data do not indicate a major role of the endogenous opioid system for the blood pressure-pain interaction in man. Endogenous opioids affect pain perception and sympathetic nerve activity responses to pain in normotensive men but their activity seems to be attenuated in borderline hypertensive subjects. Therefore, the lower pain sensitivity in human essential hypertension is probably mediated by non-opioid mechanisms.

Adult↗
PubMed1998

Integrin-induced protein kinase Calpha and Cepsilon translocation to focal adhesions mediates vascular smooth muscle cell spreading.

The extracellular matrix influences the cellular spreading of vascular smooth muscle cells (VSMCs) via integrin receptors. However, the intracellular signaling mechanisms are still incompletely understood. We investigated the hypothesis that VSMCs binding to fibronectin activates the protein kinase C (PKC) pathway, causes differential intracellular PKC isoform translocation, and mediates cell spreading. VSMCs binding to poly-L-lysine or preincubated with Arg-Gly-Asp (RGD) peptides were used as controls. Diacylglycerol (DAG) and phospholipase D (PLD) activity were measured by thin-layer chromatography. Intracellular distribution of PKC isoforms was assessed by confocal microscopy. VSMCs binding to fibronectin induced focal adhesions and cell spreading within 30 minutes. Fibronectin induced a rapid increase in DAG content, peaking at 10 minutes with a sustained response for <1 hour. In contrast, PLD activity was not influenced by specific binding to fibronectin. PKC isoforms alpha, delta, epsilon, and zeta were assessed by confocal microscopy. Fibronectin induced a PKC isoform translocation to the cell nucleus and to focal adhesions within minutes. The nuclear PKCalpha immunoreactivity was transiently increased. PKC isoforms a and epsilon were both translocated to focal adhesions. The intracellular distributions of other PKC isoforms were not influenced by fibronectin. The effects of fibronectin on DAG generation, the translocation of PKCalpha and PKCepsilon, and cell spreading were all abolished by the incubation with RGD peptides. Downregulation of PKC isoforms alpha and epsilon with specific antisense oligodinucleotides resulted in a significant inhibition of cell spreading. Our results show that integrins induce intracellular signaling in VSMCs via DAG and PKC. PKC isoform a is translocated to the nucleus, whereas PKC isoforms alpha and epsilon are translocated to focal adhesions. Both isoforms seem to play a role in inside-out integrin signaling and cell spreading.

Animals↗
PubMed1998

Ostial renal artery stent placement for atherosclerotic renal artery stenosis in patients with coronary artery disease.

To test the utility of endoprosthetic treatment for ostial renal artery stenosis, and to examine blood pressure and its treatment, serum creatinine, and restenosis rate, 44 ostial renal stent placements were performed in 30 patients with concomitant coronary artery disease, arterial hypertension, and the indication for angiotensin converting enzyme (ACE) therapy. There was a marked decrease in systolic and diastolic blood pressure (163+/-30 to 145+/-17 and 93+/-18 to 83+/-10 mm Hg; P < 0.008) with a decrease in number of medication (3.2+/-0.9 to 2.8+/-1.0; P = 0.005). In 5 out of 8 patients not receiving an ACE inhibitor, this drug could be added. Serum creatinine changed from 1.46+/-0.7 mg/dl to 1.39+/-0.58 mg/dl (P = ns). Three patients showed restenosis (12.5%). Ostial stenting lowers blood pressure, decreases antihypertensive drugs and increases medication flexibility.

Adult↗
PubMed1998

The renin-angiotensin system in the vessel wall.

The behavior of the circulating renin-angiotensin system is well known; however, the actions of renin and the generation of angiotensin (ANG) II at the tissue level are less appreciated. We have used rat models to study this issue. We examined the cleavage of human angiotensinogen to ANG I by human renin and its inhibition by a human renin inhibitor in an isolated perfused hindlimb preparation from rats which express the human angiotensinogen gene. With this model, we were able to show that renin acts at the site of the vascular wall, rather than in the lumen, to generate ANG I, which is subsequently converted to ANG II. Furthermore, the cleavage is specifically dependent on renin and not on other lysosomal proteases. The renin gene is present in the vascular wall; however, whether or not renin is generated locally to act locally, or whether renin is taken up from the circulation to act locally was not clear. We used the same strain of transgenic rats to test this issue and showed that renin can be taken up by cardiac or coronary vasculature tissue and induces long-lasting local ANG II generation. Locally formed ANG I was converted to ANG II more effectively than infused ANG I. We did additional studies to examine the conversion step from ANG I to ANG II in the vessel wall. We perfused hindlimbs from Sprague-Dawley rats with ANG I and observed ANG II production, which was linear over a 10,000-fold concentration range of ANG I. However, when we increased angiotensin converting enzyme (ACE) gene expression in the vascular bed, which also increased ACE tissue concentrations, we were nevertheless able to demonstrate increased ANG II production with ACE upregulation. Taken together, these results demonstrate (1) the cleavage of local angiotensinogen to ANG I within the vascular wall by renin, (2) renin uptake from the circulation to evoke that local effect, and (3) a potential regulatory effect by vascular tissue ACE on ANG II production in the vessel wall. The findings support the notion of localized renin-angiotensin system-related effects on vascular function and structure.

Angiotensin I↗
PubMed1998

Angiotensin II acts intracellularly in vascular smooth muscle cells.

Angiotensin (ANG) II is present inside vascular smooth muscle cells (VSMC); however, its intracellular functions if any, are unknown. We tested the hypothesis that intracellular Ang II exerts effects on cytosolic calcium [Ca++]i in VSMC. ANG II was administered via microinjection. Microinjection of ANG II led to a rapid increase in [Ca++]i in the cytosol and in the nucleus. The [Ca++]i increase was due to the influx of extracellular Ca++ 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 [Ca++]i was not only observed in the microinjected cell, but also in directly adjacent VSMC. In contrast to the microinjected cells, the [Ca++]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 IP3 induced a [Ca++]i response in adjacent cells which was similar to the ANG II-induced effects. Preincubation of VSMC with the uncoupling substances DMSO and heptanol did not decrease the ANG II response, but instead prevented a [Ca++]i surge in adjacent cells. We conclude that intracellular ANG II binds to intracellular ANG II receptors and elicits an increased [Ca++]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 ANG II-related effects may be amplified by an intracellular action.

Angiotensin II↗
PubMed1998

Effects of multidisciplinary case management in patients with chronic renal insufficiency.

PURPOSE: Though case management has been recommended to improve the outcomes of patients with costly or morbid conditions, it has seldom been studied in controlled trials. We performed a randomized, controlled clinical trial of an intensive, multidisciplinary case management program for patients with chronic renal insufficiency and followed patients for 5 years. PATIENTS AND METHODS: We enrolled 437 primary-care patients (73% of those eligible) with chronic renal insufficiency (estimated creatinine clearance consistently < 50 mL/min with the last serum creatinine level > 1.4 mg/dL) who were attending an urban academic general internal medicine practice. The intensive case management, administered during the first 2 years after enrollment, consisted of mandatory repeated consultations in a nephrology case management clinic staffed by two nephrologists, a renal nurse, a renal dietitian, and a social worker. Control patients received usual care. Primary outcome measurements included serum creatinine level, estimated creatinine clearance, health services use, and mortality in the 5 years after enrollment. Secondary measures included use of renal sparing and potentially nephrotoxic drugs. RESULTS: There were no differences in renal function, health services use, or mortality in the first, second, or third through fifth years after enrollment. There were significantly more outpatient visits among intervention patients, mainly because of the added visits to the nephrology case management clinic. There were also no significant differences in the use of renal sparing or selected potentially nephrotoxic drugs. The annual direct costs of the intervention were $89,355 ($484 per intervention patient). CONCLUSION: This intensive, multidisciplinary case-management intervention had no effect on the outcomes of care among primary-care patients with established chronic renal insufficiency. Such expensive and intrusive interventions, despite representing state-of-the-art care, should be tested prospectively before being widely introduced into practice.

Aged↗