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Biomedical subjects

F C Luft

Publications and source records attributed to F C Luft.

At least 55 records · Page 3Linked to original sources
PubMed2001

Recent clinical trial highlights in hypertension.

Clinical trials continue to guide patient management. However, the hypotheses generally come from observational studies. Studies on women continue to be too little and too few, particularly in light of the fact that most elderly hypertensive patients are likely to be women. Attention has been drawn to the possibility that hypertension per se may engender symptoms such as headache for example, in addition to harder endpoints such as death. The MICROHOPE study, which was not a blood pressure-lowering study, showed that angiotensin converting enzyme inhibition with ramipril in diabetic patients provided the same beneficial effects previously published for the HOPE study. The doxazosin arm of the ALLHAT study was terminated by the data monitoring and safety board because the doxazosin-treated patients developed congestive heart failure at a greater rate than diuretic-treated patients. Two extensive studies testing two different classes of calcium antagonists against primarily diuretic-based treatment showed that the calcium antagonists were no less effective in terms of preventing hard endpoints. A small, but impressive cross-over study testing the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin, against placebo showed that statin treatment lowers blood pressure in hypercholesterolemic patients with hypertension. Meta- analyses emphasized the value of blood pressure reduction in the elderly and added to the controversy and confusion about the role of calcium antagonists in the first-line treatment of hypertension. The point may be moot since with the current recommendations few hypertensive patients will be adequately treated with a single agent.

Antihypertensive Agents↗
PubMed2001

Angiotensin, inflammation, hypertension, and cardiovascular disease.

We are used to thinking of angiotensin (Ang) II as a regulatory hormone that stimulates constriction of vascular smooth muscle cells, aldosterone release from the adrenal gland, and sodium reabsorption in the renal tubule. We have also become accustomed to understanding that Ang II may be formed and may act locally as a chemokine that induces tyrosine phosphorylation, cell growth, hypertrophy, and differentiation. Viewing Ang II as an inflammatory molecule is stranger still. Nevertheless, recent evidence shows that Ang II is important in stimulating the production of reactive oxygen species and the activation of ancient inflammatory mechanisms. The nuclear factor kappaB (NF-kappaB) is pivotal to these processes. Activation of NF-kappaB stimulates the expression of a gene menagerie that is important to chemoattraction, expression of surface adhesion molecules, coagulation, and inflammation. In addition, Ang II has been shown to regulate cellular immune responses. It stimulates the proliferation of lymphocytes and contributes to their activation via calcineurin-related pathways. Knowledge of these mechanisms may provide additional therapeutic avenues.

Angiotensin II↗
PubMed2001

Modulating angiotensin II-induced inflammation by HMG Co-A reductase inhibition.

Angiotensin (Ang) II is capable of producing inflammatory changes by signals through its AT1 receptor. Reactive oxygen species production, adhesion molecule expression, chemokines, and other mediators are involved. Nuclear factor-kappaB (NK-kappaB) and activator protein 1 (AP-1) are two of the transcription factors activating the responsible genes. We have studied Ang II-independent modulating effects in a double transgenic rat model harboring the human renin and angiotensinogen genes. We have recently focused on the protective effects of HMG-CoA reductase inhibition and review these data here. We found that cerivastatin decreased mortality, lowered blood pressure, preserved renal function, decreased cardiac hypertrophy, and inhibited the entire chain of inflammatory events. Furthermore, NF-kappaB and AP-1 activation was sharply attenuated. We also observed that cerivastatin blocked ERK1/2 phosphorylation in vivo and in vitro. Cerivastatin also inhibited phorbol ester-transmitted events in vascular smooth muscle cells. Because Rho, a member of the Ras protein superfamily is important to Ang II-dependent and -independent vascular smooth muscle signaling events, we suggest that cerivastatin may act by inhibiting the prenylation, membrane anchoring, and subsequent activation of Ras proteins. These data may in part explain cholesterol-independent, HMG-CoA reductase-related, protective effects.

Angiotensin II↗
PubMed2001

Inducible nitric oxide synthase in the myocard.

Recognition of significance of nitric oxide synthases (NOS) in cardiovascular regulations has led to intensive research and development of therapies focused on NOS as potential therapeutic targets. However, the NOS isoform profile of cardiac tissue and subcellular localization of NOS isoforms remain a matter of debate. The aim of this study was to investigate the localization of an inducible NOS isoform (NOS2) in cardiomyocytes. Employing a novel immunocytochemical technique of a catalyzed reporter deposition system with tyramide and electron microscopical immunocytochemistry complemented with Western blotting and RT-PCR, we detected NOS2 both in rat neonatal and adult cultured cardiomyocytes and in the normal myocard of adult rats as well as in the human myocard of patients with dilative cardiomyopathy. NOS2 was targeted predominantly to a particulate component of the cardiomyocyte--along contractile fibers, in the plasma membrane including T-tubules, as well as in the nuclear envelope, mitochondria and Golgi complex. Our results point to an involvement of NOS2 in maintaining cardiac homeostasis and contradict to the notion that NOS2 is expressed in cardiac tissue only in response to various physiological and pathogenic factors. NOS2 targeting to mitochondria and contractile fibers suggests a relationship of NO with contractile function and energy production in the cardiac muscle.

Animals↗
PubMed2001

Autonomic nervous system function in patients with monogenic hypertension and brachydactyly: a field study in north-eastern Turkey.

Laboratory studies in patients with autosomal-dominant hypertension and brachydactyly showed increased sensitivity to sympathetic stimuli and severe abnormalities in baroreflex buffering. To further elucidate the mechanisms by which impaired baroreflex sensitivity could influence blood pressure (BP), we conducted autonomic testing under field conditions. We studied 17 hypertensive affected (13 to 48 years, BMI 22.7 +/- 6.5 kg/m(2), 160 +/- 23/98 +/- 15 mm Hg) and 12 normotensive non-affected (9 to 60 years, BMI 24.0 +/- 4.7 kg/m(2), 120 +/- 16/70 +/- 10 mm Hg) family members. Pulse intervals and finger BP were measured using the Portapres device. Valsalva ratio, the blood pressure overshoot during phase IV of the Valsalva manoeuver, the Ewing coefficient (RR30/15 ratio), and heart rate and BP variability were similar in affected and non-affected family members. Overall, baroreflex sensitivity calculated using the cross-spectral (BRSLF, BRSHF) and sequence techniques (BRS+, BRS-) was not different between the groups. However, in younger family members, BRS+ was 12 +/- 3.7 and 22 +/- 13 msec/mm Hg in affected and in non-affected family members, respectively. The decline in BRS with age and with increasing blood pressure was absent in affected family members. We conclude that autonomic reflex testing conducted under field conditions is not impaired in patients with monogenic hypertension and brachydactyly. However, noninvasive testing showed impaired baroreflex control of heart rate at a young age. The reduced BRS in young family members with moderate arterial hypertension may suggest that the impaired baroreflex function is not secondary to the hypertension but rather a primary abnormality, which aggravates the progression of hypertension.

Adolescent↗
PubMed2001

Prolonged cold preservation augments vascular injury independent of renal transplant immunogenicity and function.

BACKGROUND: While prolonged cold ischemia has detrimental effects on graft survival, the mechanisms remain unclear. We tested whether or not cold preservation enhances intragraft inflammatory responses and vascular injury. METHODS: Rat renal grafts were cold preserved in University of Wisconsin solution for 2, 4, 6, 12, 24, and 48 hours, and then transplanted into syngeneic recipients and harvested after 24 hours. Frozen sections were examined histologically and stained for vascular cellular adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), major histocompatibility complex (MHC) class II, tissue factor, leukocyte function associated molecule-1 (LFA-1), very late antigen-4 (VLA-4), as well as for inflammatory cells. RESULTS: Function did not differ between isografts preserved for shorter (2 to 6 hours) or longer times (12 to 24 hours). Neutrophil influx and that of LFA-1-positive cells showed similar increases in all groups. Compared with short preservation groups, the long preserved grafts had more VLA-4-positive ED-1+ monocytic infiltrates adjacent to vessels expressing VCAM-1 (P < or = 0.001). Increased preservation duration had no effect on infiltration with recipient ED-2+ macrophages, MHC class II-positive cells, or dendritic cells. Decreased color intensity and continuity of PECAM-1 staining indicated loss of endothelial integrity in grafts preserved for longer than six hours. Intensity in VCAM-1 staining increased progressively in grafts preserved for more than six hours and was localized predominantly on the endothelium of elastic vessels. Endothelial cells, vascular smooth muscle cells, and monocytes expressed increasingly more tissue factor in grafts preserved for more than six hours, revealing enhanced intragraft procoagulant capacity. Furthermore, grafts with preservation times of more than six hours developed more severe vascular endothelial injury and worse tubular necrosis scores (P < or = 0.001) compared with grafts with shorter preservation times. CONCLUSIONS: Because of the prominent vascular injury, strategies for endothelial protection should be attempted in grafts with long preservation times in clinical renal transplantation.

Animals↗
PubMed2001

Left ventricular function in mice lacking the AT2 receptor.

OBJECTIVES: The role of the AT2 receptor in the heart is incompletely understood. We investigated left ventricular performance in AT2 receptor knockout mice, with and without deoxycorticosterone acetate (DOCA)-salt treatment. Given the putative opposing functions of the AT1 and AT2 receptor, we also analysed AT1 receptor expression in the left ventricle. METHODS: We used a miniaturized conductance-manometer system to measure pressure-volume loops for analysing left ventricular performance under baseline conditions and after increasing peripheral vascular resistance. We determined left ventricular AT1-receptor expression by RNase-protection assays. RESULTS: In AT2 receptor knockout mice, end-systolic and end-diastolic volumes were lower than in wild-type mice, so that pressure-volume loops were shifted leftward. Left ventricular systolic and diastolic kinetics were not different between the groups. AT2 receptor knockout mice and wild-type mice both stabilized their reduced stroke volume after laparatomy as peripheral resistance was increased. DOCA-salt treatment increased elastance in AT2 receptor knockout mice, compared to controls. Furthermore, AT2 receptor knockout mice had a steeper increase in dP/dtmax. Left ventricular AT1 receptor gene expression was increased in AT2 receptor knockout mice and was not down-regulated in response to DOCA-salt treatment. Finally, the hearts of AT2 receptor knockout mice were smaller than controls, but increased in size in response to DOCA-salt treatment. CONCLUSIONS: AT2 receptor knockout mice displayed no major changes in left ventricular function at baseline or in response to DOCA-salt treatment, compared to wild-type mice. The AT2 receptor may be important to AT1 receptor expression in response to DOCA-salt challenge and may have some influence on cardiac growth responses.

Animals↗
PubMed2001

Myocardial adrenergic dysfunction in rats with transgenic, human renin-dependent hypertension.

OBJECTIVES: We investigated cardiac function in rats transgenic for the human renin and angiotensinogen genes (TGR) to test the hypothesis that elevated local angiotensin II precipitates adrenergic dysfunction and abnormal contractile function. METHODS: Hearts from TGR and Sprague-Dawley control rats, aged 6 weeks, were studied using the Langendorff model and papillary muscle preparations (n = 6-10 per group). Incremental isoproterenol (1 - 1000 nmol/l) and external Ca2+-concentrations (0.75-6.0 mmol/l) were tested. Cardiac protein and mRNA expression levels were determined by Western blot and RNAase protection assay. RESULTS: TGR rats showed left ventricular hypertrophy (54%), higher blood pressures (76 mmHg), and elevated plasma renin activity (seven-fold) compared to controls (P < 0.01). The effect of isoproterenol on TGR rat systolic and diastolic left ventricular performance was decreased in both in-vitro models compared to controls (two- to threefold, P < 0.01). TGR rat papillary muscles showed impaired force generation with abnormal basal and Ca2+-dependent relaxation. Gialpha2 and Gialpha3 protein levels were increased (20-30%) and SERCA2a and adenylyl cyclase protein levels were decreased (23 and 37%, respectively) in TGR hearts compared to controls, while Gsalpha or beta1 and beta2-receptor levels were unchanged. Cardiac angiotensin converting enzyme and atrial natriuretic peptide mRNA levels were increased more than four-fold in TGR with no differences for the angiotensin type1 receptor, beta1-receptor, SERCA2a, phospholamban, adenylyl cyclase V and angiotensinogen genes. CONCLUSIONS: TGR rat hearts develop severe adrenergic dysfunction with decreased adenylyl cyclase and abnormal intracellular Ca2+-homeostasis. Our findings emphasize angiotensin II as a major risk factor promoting early functional decline in cardiac hypertrophy. The data may have implications for patients with activating polymorphisms of the renin-angiotensin system and support the need for an early therapeutic intervention.

Adrenergic beta-Agonists↗
PubMed2001

Determination of renal arterial stenosis severity: comparison of pressure gradient and vessel diameter.

PURPOSE: To determine the hemodynamic significance of arteriographically detected renal arterial stenosis by obtaining pressure gradients with a miniaturized pressure guide wire. MATERIALS AND METHODS: Forty-six renal arterial stenoses in 38 patients were assessed in terms of severity and then subjected to gradient determination before and after angioplasty. The patients (mean age, 63 years) had a mean serum creatinine value of 1.3 mg/dL +/- 0.4 (114.9 micromol/L +/- 35.4 [SD]) and required on average three medications for blood pressure control. The mean degree of stenosis diameter was 51% +/- 17 (range, 12%-85%). RESULTS: The systolic and mean arterial pressure gradients with and those without vasodilatation were highly correlated with stenosis severity, systolic blood pressure, and serum creatinine as a curvilinear fit (r = 0.9, P <.01). At 50% stenosis severity, the mean pressure gradient was 22 mm Hg. CONCLUSION: Patients with a pressure gradient greater than 20 mm Hg should be good candidates for renal arterial dilatation, and use of the pressure guide wire will facilitate interventional decisions.

Adult↗
PubMed2001

Localization of thiazide-sensitive Na(+)-Cl(-) cotransport and associated gene products in mouse DCT.

The mammalian distal nephron develops a complex assembly of specialized cell types to accomplish the fine adjustment of urinary electrolyte composition. The epithelia of the distal convoluted tubule (DCT), the connecting tubule (CNT), and the cortical collecting duct (CCD) show an axial structural heterogeneity that has been functionally elucidated by the localization of proteins involved in transepithelial ion transport. We compared the distribution of the thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC), basolateral Na(+)/Ca(2+) exchanger (Na/Ca), cytosolic calcium-binding proteins calbindin D(28K) and parvalbumin, and the key enzyme for selective aldosterone actions, 11 beta-hydroxysteroid-dehydrogenase 2 (11HSD2), in the distal convolutions of the mouse. In the mouse, as opposed to the rat, we found no clear subsegmentation of the DCT into a proximal (DCT1) and a distal (DCT2) portion. The TSC was expressed along the entire DCT. Na/Ca and calbindin D(28K) were similarly expressed along most of the DCT, with minor exceptions in the initial portion of the DCT. Both were also present in the CNT. Parvalbumin was found in the entire DCT, with an occasional absence from short end portions of the DCT, and was not present in CNT. 11HSD2 was predominantly located in the CNT and CCD. Short end portions of DCT only occasionally showed the 11HSD2 signal. We also observed an overlap of 11HSD2 immunoreactivity and mRNA staining. Our observations will have implications in understanding the physiological effects of gene disruption and targeting experiments in the mouse.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗