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Biomedical subjects

Friedrich C Luft

Publications and source records attributed to Friedrich C Luft.

At least 109 records · Page 6Linked to original sources
PubMed2004

Regulation of the nitric oxide system in human adipose tissue.

Nitric oxide (NO) is involved in adipose tissue biology by influencing adipogenesis, insulin-stimulated glucose uptake, and lipolysis. The enzymes responsible for NO formation in adipose cells are endothelial NO synthase (eNOS) and inducible NO synthase (iNOS), whereas neuronal NO synthase (bNOS) is not expressed in adipocytes. We characterized the expression pattern and the influence of adipogenesis, obesity, and weight loss on genes belonging to the NO system in human subcutaneous adipose cells by combining in vivo and in vitro studies. Expression of most of the genes known to belong to the NO system (eNOS, iNOS, subunits of the soluble guanylate cyclase, and both genes encoding cGMP-dependent protein kinases) in human adipose tissue and isolated human adipocytes was detected. In vitro adipogenic differentiation increased the expression level of iNOS significantly, whereas eNOS expression levels were not influenced. The genes encoding eNOS, iNOS, and cGMP-dependent protein kinase 1 were expressed at higher levels in obese women. Expression of these genes, however, was not influenced by 5% weight loss. Insulin and angiotensin II (Ang II) increased NO production by human preadipocytes in vitro. Increased eNOS and iNOS expression in adipocytes and local effects of insulin and Ang II may increase adipose tissue production of NO in obesity.

Adipocytes↗
PubMed2004

Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells.

BACKGROUND: In a double-transgenic human renin and human angiotensinogen rat model, we found that mineralocorticoid receptor (MR) blockade ameliorated angiotensin II (Ang II)-induced renal and cardiac damage. How Ang II and aldosterone (Ald) might interact is ill defined. METHODS AND RESULTS: We investigated the effects of Ang II (10(-7) mol/L) and Ald (10(-7) mol/L) on extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling in vascular smooth muscle cells (VSMCs) with Western blotting and confocal microscopy. Ang II induced ERK 1/2 and JNK phosphorylation by 2 minutes. Ald achieved the same at 10 minutes. Ang II+Ald had a potentiating effect by 2 minutes. Two oxygen radical scavengers and the epidermal growth factor receptor (EGFR) antagonist AG1478 reduced Ang II-, Ald-, and combination-induced ERK1/2 phosphorylation. Preincubating the cells with the MR blocker spironolactone (10(-6) mol/L) abolished Ang II-induced ROS generation, EGFR transactivation, and ERK1/2 phosphorylation. CONCLUSIONS: Ald potentiates Ang II-induced ERK-1/2 and JNK phosphorylation. Oxygen radicals, the MR, and the EGFR play a role in early signaling induced by Ang II and Ald in VSMCs. These in vitro data may help explain the effects of MR blockade on Ang II-induced end-organ damage in vivo.

Aldosterone↗
PubMed2004

Clonidine improves spontaneous baroreflex sensitivity in conscious mice through parasympathetic activation.

Alpha-2 adrenoceptors are important in baroreflex regulation. We tested the impact of alpha-2 adrenoceptors on heart rate variability (HRV) and spontaneous baroreflex sensitivity (BRS) in conscious mice with telemetry (TA11PA-C20). Baseline beat-to-beat measurements (2 hours between 8:00 am to 12:00 pm) were compared with measurements after intraperitoneal alpha-2 adrenoceptor blockade (yohimbine 2 mg/kg) and alpha-2 adrenoceptor stimulation (clonidine 1, 10, and 50 mg/kg). Blood pressure (BP) was 128+/-6/87+/-6 mm Hg and heart rate (HR) was 548+/-18 bpm at baseline. BRS, calculated with the cross-spectral method, was 1.2+/-0.1 ms/mm Hg at baseline. BP increased 20+/-2/13+/-2 mm Hg with yohimbine. HR increased by 158+/-23 bpm. BRS did not change. BP decreased 16+/-7/5+/-4 mm Hg with 1 mg/kg of clonidine and did not change with a higher dose. HR decreased with clonidine (176+/-28, 351+/-21, 310+/-29 bpm during 1, 10, and 50 mg/kg of clonidine, P<0.01). HRV (total power=4629+/-465, 7002+/-440, and 6452+/-341 ms2 during 1, 10, and 50 mg/kg of clonidine, P<0.01) and BRS were profoundly increased with clonidine (14+/-1, 13+/-1, and 10+/-1 ms/mm Hg, P<0.01). The effects of clonidine were abolished with atropine (2 mg/kg plus 50 mg/kg of clonidine) but not with metoprolol (4 mg/kg plus 50 mg/kg of clonidine). These data suggest that alpha-2 adrenoceptors exert a regulatory influence on autonomic cardiovascular control and baroreflex function. The effect of clonidine on baroreflex HR regulation is mediated by the parasympathetic nervous system. These murine data fit well with recent human observations regarding parasympathetic activation via alpha-2 adrenoceptors.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2004

Haplotypes and SNPs in 13 lipid-relevant genes explain most of the genetic variance in high-density lipoprotein and low-density lipoprotein cholesterol.

Single nucleotide polymorphisms (SNPs) and derived haplotypes within multiple genes may explain genetic variance in complex traits; however, this hypothesis has not been rigorously tested. In an earlier study we analyzed six genes and have now expanded this investigation to include 13. We studied 250 families including 1054 individuals and measured lipid phenotypes. We focused on low-density cholesterol (LDL), high-density cholesterol (HDL) and their ratio (LDL/HDL). A component analysis of the phenotypic variance relying on a standard genetic model' showed that the genetic variance on LDL explained 26%, on HDL explained 38% and on LDL/HDL explained 28% of the total variance, respectively. Genotyping of 93 SNPs in 13 lipid-relevant genes generated 230 haplotypes. The association of haplotypes in all the genes tested explained a major fraction of the genetic phenotypic variance component. For LDL, the association with haplotypes explained 67% and for HDL 58% of the genetic variance relative to the polygenic background. We conclude that these haplotypes explain most of the genetic variance in LDL, HDL and LDL/HDL in these representative German families. An analysis of the contribution to the genetic variance at each locus showed that APOE (50%), CETP (28%), LIPC (9%), APOB (8%) and LDLR (5%) influenced variation in LDL. LIPC (53%), CETP (25%), ABCA1 (10%), LPL (6%) and LDLR (6%) influenced the HDL variance. The LDL/HDL ratio was primarily influenced by APOE (36%), CETP (27%) and LIPC (31%). This expanded analysis substantially increases the explanation of genetic variance on these complex traits.

Cholesterol, HDL↗
PubMed2004

Alpha-2 adrenergic transmission and human baroreflex regulation.

We observed earlier that central alpha-2 adrenoceptor stimulation in mice greatly augments parasympathetic tone. To test the effects in humans, we assessed autonomic vasomotor tone and baroreflex regulation in 9 normal young adults on 2 occasions, once with and once without clonidine. We determined heart rate (HR), beat-by-beat blood pressure (BP), and muscle sympathetic nerve activity. HR variability was analyzed in the time and frequency domain. Pharmacological baroreflex slopes were determined using incremental phenylephrine and nitroprusside infusions. Clonidine lowered resting BP (122+/-4/73+/-3 versus 100+/-7/55+/-3 mm Hg, P<0.01), muscle sympathetic nerve activity (18+/-3 versus 4+/-2 bursts/min, P<0.01), and HR (62+/-3 versus 56+/-3 bpm, P<0.05). The baroreflex heart rate curve was reset to much lower HR values and showed no saturation at low HR. HR variability profoundly increased during clonidine plus phenylephrine (total power: 3224+/-843 versus 8943+/-2329 ms2, P<0.05). High-frequency power was 1451+/-520 at baseline and 6720+/-2475 ms2 during baroreceptor loading (P<0.05). The low-frequency/high-frequency ratio decreased (1.94+/-0.41 versus 0.69+/-0.10, P<0.05). In contrast, clonidine reduced resting sympathetic vasomotor tone and shifted the operating point of the sympathetic baroreflex to a flat part of the sympathetic baroreflex curve. The shift decreased the ability of the baroreflex to withdraw sympathetic vasomotor tone during baroreflex loading. These baroreflex changes were associated with a moderate increase in phenylephrine responsiveness. We conclude that alpha-2 adrenoceptor stimulation has a differential effect on baroreflex HR and vasomotor regulation. alpha-2 Adrenoceptor stimulation greatly augments baroreflex-mediated bradycardia, most likely by parasympathetic activation.

Action Potentials↗
PubMed2004

Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function.

Norepinephrine transporter (NET) function has a central role in the regulation of synaptic norepinephrine concentrations. Clinical observations in orthostatic intolerance patients suggest a gender difference in NET function. We compared the cardiovascular response to selective NET inhibition with reboxetine between 12 healthy men and 12 age-matched women. Finger blood pressure, brachial blood pressure, and heart rate were measured. The subjects underwent cardiovascular autonomic reflex testing and a graded head-up tilt test. In a separate study, we applied incremental concentrations of tyramine and isoproterenol through subcutaneous microdialysis catheters in eight men and in eight women. NET inhibition elicited a threefold greater increase in supine blood pressure in men than women (P < 0.05). The pressor response was driven by an increased cardiac output. The orthostatic heart rate increase during NET inhibition was greater in men than women (56 +/- 5 beats/min in men, 42 +/- 4 beats/min in women, P < 0.001). In contrast, NET inhibition resulted in a similar suppression in the cold pressor and handgrip response, low-frequency blood pressure oscillations, and venous norepinephrine in the supine position. Men and women were similarly sensitive to the lipolytic effect of isoproterenol and tyramine. We conclude that NET inhibition results in more pronounced changes in cardiac regulation in men than women. Our observations suggest that the NET contribution to cardiac norepinephrine turnover may be decreased in women. The gender difference in NET function may not be expressed in tissues that are less NET dependent than the heart.

Abdomen↗