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Biomedical subjects

M Christ

Publications and source records attributed to M Christ.

At least 37 records · Page 2Linked to original sources
PubMed2001

Acute effects of a single oral dose of carvedilol on cardiac sympathovagal balance in man.

Modulation of autonomic activity is considered to be a prognostic marker in patients with cardiovascular disease. The aim of the present study was to evaluate the modulation of sympathovagal balance after single-dose administration of carvedilol using various autonomic tests as challenges of sympathovagal balance. We conducted a randomized double-blind, placebo-controlled study in 18 male volunteers and applied a crossover design. While heart rate variability (HRV) remained unchanged in 24-hour measurements, modulatory effects on sympathovagal balance were demonstrated in controlled autonomic maneuvers at expected maximal drug levels of carvedilol: time-dependent HRV parameters indicative of vagal tone were increased during controlled breathing (15 cycles/min) in the supine body position by carvedilol. The percentage of successive normal RR intervals > 50 ms (pNN50) was increased to 39.8+/-5.1 vs. 32.7+/-4.7% in the placebo group (p < 0.05), root mean square successive differences (rMSSD) to 81.5+/-10.8 vs. 69.3+/-9.1 ms (p < 0.05 vs. placebo). In contrast, carvedilol versus placebo significantly reduced time- and frequency-domain parameters after an active standing-up procedure. This included rMSSD (26.5+/-2.8 ms vs. 34.9+/-3.8 ms), pNN50 (6.9+/-2.2% vs. 12.4+/-2.5%). total power (4329+/-592 ms2 vs. 6428+/-1158 ms2), low frequency (1472+/-179 ms2 vs. 2093+/-284 ms2) and high frequency power (251+/-42 ms2 vs. 353+/-92 ms2) of heart rate variability. Apparently, the effects of even small doses of carvedilol, too low to induce effects detectable in the 24-hour analysis of HRV testing, can be detected on controlled maneuvers of autonomic because of their ability to modulate autonomic balance. Under conditions of vagal stimulation, a potentially beneficial augmentation of HRV parameters indicative for this component is induced by carvedilol, while under conditions of sympathetic activation, carvedilol effects seem opposite. Interpretation of the latter results, in particular, requires further investigation.

Administration, Oral↗
PubMed2000

Striking increase of natriuresis by low-dose spironolactone in congestive heart failure only in combination with ACE inhibition: mechanistic evidence to support RALES.

BACKGROUND: A marked reduction of overall mortality in patients with severe congestive heart failure (CHF) has been demonstrated by addition of the mineralocorticoid receptor antagonist spironolactone to ACE inhibition. The aim of the present study was to examine a hypothesized interaction of spironolactone and ACE inhibitors in renal electrolyte and volume regulation. METHODS AND RESULTS: Wistar rats with extensive myocardial infarction or sham operation were treated with either placebo, the ACE inhibitor trandolapril, low-dose spironolactone, or a combination of the 2. Twelve weeks after infarction, rats were housed in metabolic cages. Urinary volume and sodium excretion were significantly increased in CHF rats on a combined treatment with spironolactone and trandolapril (21.2+/-2.6 mL/d, 2489+/-320 mmol/d, mean+/-SD; P<0.05 versus other experimental groups) versus placebo-treated rats (16.7+/-5.6 mL/d, 1431+/-458 mmol/d),whereas these parameters were not affected in rats on either spironolactone (16.1+/-6.6 mL/d, 1153+/-273 mmol/d) or trandolapril alone (15.9+/-4.2 mL/d, 1392+/-294 mmol/d). The effects on natriuresis coincided with a significant reduction of left ventricular end-diastolic pressure (LVEDP) in rats on trandolapril and spironolactone (10.8+/-8.2 mm Hg; P:<0.05 versus CHF placebo: 23.3+/-7.2 mm Hg; sham-operated rats: 5.1+/-0.9 mm Hg), whereas LVEDP remained elevated in rats treated with either compound alone. CONCLUSIONS: In the present study, we found an unexpected interaction of low-dose spironolactone and the ACE inhibitor trandolapril in experimental CHF leading to marked effects on renal electrolyte and volume regulation that were not apparent by treatment with either drug alone. These findings may explain the beneficial effects of spironolactone in CHF patients.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Effects of progestin-estrogen replacement therapy on QT-dispersion in postmenopausal women.

Female gender is considered to be a risk factor for ventricular arrhythmias. Furthermore, experimental studies have shown that estrogen has an impact on the electrophysiological properties of the heart. Thus, the effects of estrogen- (ERT) and progestin-estrogen- (PERT) replacement therapy on QT-interval length and dipersion as indicators of ventricular repolarisation have been examined in the present study. Twenty-two postmenopausal women without hormone replacement therapy and 16 postmenopausal women on ERT and 22 on PERT (age 48-71 years) were included. QT intervals were measured in five subsequent cycles of at least 10 leads of standard ECG. QT-dispersion was calculated as the difference between maximal and minimal QT-interval. QT-intervals and -dispersions were rate (QT(c)) and linear (QT(lc)) corrected. PERT significantly reduced ventricular QT-dispersion (QT-, QT(c)- and QT(lc)-dispersion) compared to the control group (QT(c)-dispersion (ms): 32+/-13 vs. 48+/-14; P<0.05), while ERT significantly prolonged QT-intervals (QT(c) mean (ms): 423+/-28 vs. 398+/-31; P<0.05) without affecting QT-dispersion. These findings support the hypothesis that sex hormones may directly modulate ventricular repolarisation in vivo. Above all, the progestin component of replacement therapy is suggested to homogenize spatial heterogeneity of ventricular repolarisation.

Aged↗
PubMed2000

Modulation of the inflammatory properties and hepatotoxicity of recombinant adenovirus vectors by the viral E4 gene products.

Liver toxicity and inflammation were assessed in C57BL/6, CBA, and BALB/c mice injected intravenously with a series of recombinant adenoviruses deleted simultaneously in E1/E3, in E1/E3/E2A, or in E1/E3/E4. All vectors were either devoid of transgenes or carried in E1 the human CFTR cDNA under the control of the CMV promoter. Injection of the E1/E3-deleted vector induced a significant liver dystrophy and inflammatory responses that were accompanied by an increased serum transaminase concentration. The vector toxicity remained elevated on additional deletion of the E2A gene and was further enhanced when hCFTR was expressed. In contrast, additional deletion of E4 led to a reduction in hepatotoxicity, suggesting an active role of E4 gene products in liver injury. However, deletion of E4 also led to a loss of transgene expression. To identify the individual E4 product(s) involved in liver toxicity and in the regulation of transgene expression, a series of isogenic E1/E3-deleted vectors, with or without the hCFTR transgene, and containing various combinations of functional E4 open reading frames (ORFs), were evaluated in vitro and in vivo. We demonstrate that liver injury was markedly reduced with vectors containing either ORF3 alone or ORF3,4 while vectors containing ORF4, ORF6,7 or ORF3,6,7 still displayed elevated hepatotoxicity and inflammatory responses. Moreover, transgene expression was restored when ORF3,4 or ORF3,6,7 was retained in the vector. These results highlight the importance of the E4 gene products in the design of improved in vivo gene transfer vectors.

Adenoviridae↗
PubMed2000

Rapid, nongenomic steroid actions: A new age?

In the traditional theory of steroid action, steroids bind to intracellular receptors and modulate nuclear transcription after translocation of steroid-receptor complexes into the nucleus. Due to similarities of molecular structure, specific receptors for steroids, vitamin D(3) derivatives, and thyroid hormone are considered to represent a superfamily of steroid receptors. While genomic steroid effects characterized by their delayed onset of action and their sensitivity to blockers of transcription and protein synthesis have been known for several decades, rapid actions of steroids have been more widely recognized and characterized in detail only recently. Rapid effects of steroids, thyroid hormones, and the steroid hormone metabolite of vitamin D(3), 1alpha, 25-dihydroxyvitamin D(3), on cellular signaling and function may be transmitted by specific membrane receptors. Binding sites in membranes have been characterized, exposing binding features compatible with an involvement in rapid steroid signaling. Characteristics of putative membrane receptors are completely distinct from intracellular steroid receptors, a fact which is further supported by the inability of classic steroid receptor antagonists to block nongenomic steroid actions. A putative progesterone membrane receptor has been cloned and functionally expressed with regard to progesterone binding. Development of drugs that specifically affect nongenomic action alone or even both modes of action may find applications in various, areas such as in the cardiovascular and central nervous systems and treatment of preterm labor, infertility, and electrolyte abnormalities.

Animals↗
PubMed2000

Association of KM genotype with bullous pemphigoid.

Association of kappa light chain immunoglobulin allotypes with bullous pemphigoid was examined in 101 Caucasian patients. Km alleles were determined by polymerase chain reaction amplification followed by restriction enzyme digestion. The frequency of Km(3)/Km(1,2)kappa light-chain genotype was found to be significantly associated with the disease, while that of the Km(3)homozygous genotype was significantly higher in patients with both anti-BPAG1 and anti-BPAG2 autoantibodies.

Autoantigens↗
PubMed2000

[Insular carcinoma of the thyroid: a differentiated thyroid carcinoma with poor prognosis].

Insular carcinoma of the thyroid is a low differentiated type constituting about 5% of all thyroid cancers. Higher aggressiveness has been suggested as an important clinical feature. The value of preoperative fine-needle aspiration biopsy is not clearly proven for insular carcinoma. The criteria for histological diagnosis have been outlined by Carcangiu et al. Because of its aggressiveness, radical treatment at primary surgery appears advisable. Its clear distinction from undifferentiated (anaplastic) and medullary (C cell) cancers is important, as thyroglobulin is regularly synthesized by cancer cells. Enrichment of radioactive iodine makes such treatment feasible postoperatively and at relapse. Follow-up should be performed as in highly differentiated papillary and follicular thyroid cancer. A patient series of eight cases is presented. While all cancers were advanced at the initial diagnosis, the observed disease courses were in agreement with the assumption that insular carcinoma is a more aggressive form of differentiated thyroid cancer.

Adult↗
PubMed2000

Specific nongenomic actions of aldosterone.

BACKGROUND: According to the traditional model, steroid hormones modulate gene transcription and protein synthesis. The considerable latency of these genomic steroid effects is the consequence of these time-consuming steps of action. Over the years, it has become increasingly clear that rapid actions of steroids exist that are incompatible with this "classic" genomic model of action. These rapid, nongenomic effects, which recently have been shown for virtually all groups of steroids, are likely to be transmitted by specific membrane receptors. METHODS: A review of data mainly focusing on the nongenomic in vitro and in vivo effects of aldosterone is presented. RESULTS: For rapid aldosterone effects, a prominent example of a receptor/effector cascade for nongenomic steroid effects has been described in various cell types. Nonclassic membrane receptors with a high affinity for aldosterone, but not for cortisol, seem to be involved. As an important second messenger, [Ca2+]i is consistently increased within minutes after the addition of aldosterone. The effects are half maximal at physiological concentrations of free aldosterone (approximately 0.1 nmol/L), while the classic mineralocorticoid antagonist canrenone is ineffective in blocking the action of aldosterone. In addition, cortisol is active only at supramicromolar concentrations. Aldosterone rapidly acts on further cell signaling systems, for example, phosphoinositide hydrolysis and cAMP generation. CONCLUSIONS: For a better understanding of nongenomic aldosterone action even in a clinical context, future research will have to target the cloning of the first membrane receptor for aldosterone and the evaluation of the clinical relevance of rapid steroid effects in general.

Aldosterone↗
PubMed2000

Distribution of Borna disease virus in the brain of rats infected with an obesity-inducing virus strain.

Experimental infection of Lewis rats with Borna disease virus (BDV), a nonsegmented, single-stranded RNA virus, usually causes an immune-mediated biphasic neurobehavioral disorder. Such animals develop a persistent infection of the CNS with viral antigen expression in all brain regions and a disseminated nonpurulent meningoencephalitis. Interestingly, intracerebral infection of Lewis rats with a BDV-variant (BDV-ob) causes a rapid increase of body weight with the development of an obesity syndrome without obvious neurological signs. The obese phenotype is correlated with a characteristic distribution of inflammatory lesions and BDV-antigen in the rat brain. Infiltration with mononuclear immune cells and viral antigen expression are restricted to the septum, hippocampus, amygdala and ventromedian tuberal hypothalamus. Therefore, infection with the obesity-inducing BDV-ob results most likely in neuroendocrine dysregulations leading to the development of an obesity syndrome. This might be due to the restriction of viral antigen expression and inflammatory lesions to brain areas which are involved in the regulation of body weight and food intake. The BDV-induced obesity syndrome represents a model for the study of immune-mediated neuroendocrine disorders caused by viral infections of the CNS.

Animals↗
PubMed2000

Metabolic activity decreases as an adaptive response to low internal oxygen in growing potato tubers.

Plants lack specialised organs and circulatory systems, and oxygen can fall to low concentrations in metabolically active, dense or bulky tissues. In animals that tolerate hypoxia or anoxia, low oxygen triggers an adaptive inhibition of respiration and metabolic activity. Growing potato tubers were used to investigate whether an analogous response exists in plants. Oxygen concentrations fall below 5% in the centre of growing potato tubers. This is accompanied by a decrease of the adenylate energy status, and alterations of metabolites that are indicative of a decreased rate of glycolysis. The response to low oxygen was investigated in more detail by incubating tissue discs from growing tubers for 2 hours at a range of oxygen concentrations. When oxygen was decreased in the range between 21% and 4% there was a partial inhibition of sucrose breakdown, glycolysis and respiration. The energy status of the adenine, guanine and uridine nucleotides decreased, but pyrophosphate levels remained high. The inhibition of sucrose breakdown and glycolysis was accompanied by a small increase of sucrose, fructose, glycerate-3-phosphate, phosphenolpyruvate, and pyruvate, a decrease of the acetyl-coenzymeA:coenzymeA ratio, and a small increase of isocitrate and 2-oxoglutarate. These results indicate that carbon fluxes are inhibited at several sites, but the primary site of action of low oxygen is probably in mitochondrial electron transport. Decreasing the oxygen concentration from 21% to 4% also resulted in a partial inhibition of sucrose uptake, a strong inhibition of amino acid synthesis, a decrease of the levels of cofactors including the adenine, guanine and uridine nucleotides and coenzymeA, and attenuated the wounding-induced increase of respiration and invertase and phenylalanine lyase activity in tissue discs. Starch synthesis was maintained at high rates in low oxygen. Anoxia led to a diametrically opposed response, in which glycolysis rose 2-fold to support fermentation, starch synthesis was strongly inhibited, and the level of lactate and the lactate:pyruvate ratio and the triose-phosphate:glycerate-3-phosphate ratio increased dramatically. It is concluded that low oxygen triggers (i) a partial inhibition of respiration leading to a decrease of the cellular energy status and (ii) a parallel inhibition of a wide range of energy-consuming metabolic processes. These results have general implications for understanding the regulation of glycolysis, starch synthesis and other biosynthetic pathways in plants, and reveal a potential role for pyrophosphate in conserving energy and decreasing oxygen consumption.

Adenine Nucleotides↗
PubMed2000

Aldosterone- and progesterone-membrane-binding proteins: new concepts of nongenomic steroid action.

n the classical theory of steroid action steroids penetrate into cells and bind to intracellular receptors resulting in modulation of nuclear transcription and protein synthesis within hours. In addition, rapid actions of steroids have been identified, which are incompatible with the classic model of steroid action. Specific binding sites for aldosterone and progesterone have been reported in membrane preparations of liver, vascular smooth muscle cells and kidney. These sites are discussed to be involved in rapid nongenomic steroid actions, such as the rapid activation of the Na(+)/H(+) exchanger and elevation of [Ca(2+)]i in vascular smooth muscle cells by aldosterone. In addition, rapid progesterone-induced increases of [Ca(2+)]i have been reported in spermatozoa. A high affinity progesterone-membrane binding protein from porcine liver has been identified and cloned. The derived amino acid sequence showed no significant identity with any functional protein suggesting a binding site completely different to classic progesterone receptors. These binding sites are possibly involved in rapidly induced meiotic maturation of amphibian oocytes and the spermatozoan acrosome reactions as evidenced by recent studies, where the progesterone induced acrosome reactions and calcium signaling was blocked by a specific antibody raised against the membrane binding site for progesterone. In addition to data on specific steroid binding and rapid steroid signaling in vitro, results of nongenomic steroid effects in vivo are presented and their physiological relevance are discussed in the review.

Aldosterone↗
PubMed2000

Multiple actions of steroid hormones--a focus on rapid, nongenomic effects.

According to the traditional model, steroid hormones bind to intracellular receptors and subsequently modulate transcription and protein synthesis, thus triggering genomic events finally responsible for delayed effects. Based upon similarities in molecular structure, specific receptors for steroids, vitamin D(3) derivatives, thyroid hormone, retinoids, and a variety of orphan receptors are considered to represent a superfamily of steroid receptors. In addition, very rapid effects of steroids mainly affecting intracellular signaling have been widely recognized that are clearly incompatible with the genomic model. These rapid, nongenomic steroid actions are likely to be transmitted via specific membrane receptors. Evidence for nongenomic steroid effects and distinct receptors involved is presented for all steroid groups including related compounds like vitamin D(3) and thyroid hormones. The physiological and clinical relevance of these rapid effects is still largely unclear, but their existence in vivo has been clearly shown in various settings including human studies. Drugs that specifically affect nongenomic steroid action may find applications in various clinical areas such as cardiovascular and central nervous disorders, electrolyte homeostasis, and infertility. In addition to a short description of genomic steroid action, this review pays particular attention to the current knowledge and important results on the mechanisms of nongenomic steroid action. The modes of action are discussed in relation to their potential physiological or pathophysiological relevance and with regard to a cross-talk between genomic and nongenomic responses.

Animals↗
PubMed1999

Rapid nongenomic effects of aldosterone in mineralocorticoid-receptor-knockout mice.

In addition to genomic effects of aldosterone, rapid nongenomic effects of steroids have been reported in various tissues that were clearly incompatible with a genomic action of aldosterone. Rapid effects of aldosterone involve second messengers such as calcium and cAMP. Specific high affinity binding sites for aldosterone have been characterized in membranes for different cells, which probably transmit those rapid steroid effects. To date, it is unclear if these binding sites are modified classical mineralocorticoid receptors (MR) or if they represent an unrelated receptor protein. The aim of the present study was to investigate whether rapid aldosterone action still occurs in the absence of the classical MR. For this purpose we used the model of MR knockout mice. Rapid effects were analyzed in skin cells, measuring intracellular calcium and cAMP levels after stimulation with aldosterone. We found that rapid effects are not only present in MR knockout mice, but that the effects are even larger than in wild-type mice cells. The results of the present study demonstrate that the classic MR is dispensable for rapid aldosterone action. The study, thus, proves that a receptor different from the classic intracellular receptor is involved in rapid aldosterone signaling.

Aldosterone↗
PubMed1999

Aldosterone, not estradiol, is the physiological agonist for rapid increases in cAMP in vascular smooth muscle cells.

BACKGROUND: Steroid-induced gene regulation in the endocrine tissues and vascular wall is achieved through the interaction of specific receptor proteins and promoters of target genes. In addition to these delayed steroid actions, rapid effects of steroids have been reported in various tissues that were clearly incompatible with the classic theory of genomic steroid action. METHODS AND RESULTS: Because high doses of 17beta-estradiol have been shown to modulate intracellular cAMP levels in vascular smooth muscle cells, steroid-induced stimulation of adenylate cyclase stimulation and phosphorylation of cAMP response element binding protein was investigated in porcine coronary artery vascular smooth muscle cells. Aldosterone induces a approximately 1.5- to 2.5-fold increase in intracellular cAMP levels (EC50 approximately 0.01 to 0.1 nmol/L) within 1 minute, whereas 17beta-estradiol and hydrocortisone act only at supraphysiological concentrations (10 micromol/L). Aldosterone-induced changes in intracellular cAMP are calcium dependent; they are not blocked by inhibitors of mineralocorticoid receptors, transcription, or protein synthesis. In addition, aldosterone induces a time-dependent phosphorylation of cAMP response element binding protein with potential transcriptional importance. CONCLUSIONS: A nongenomic modulation of vascular smooth muscle cells by aldosterone is consistent with the data that aldosterone, not estrogen, is the physiological stimulus for cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Nongenomic steroid actions: fact or fantasy?

In the common theory of steroid action, steroids bind to intracellular receptors and modulate nuclear transcription after translocation of steroid--receptor complexes into the nucleus. Due to homologies of molecular structure, specific receptors for steroids, vitamin D3, and thyroid hormone are considered to represent a superfamily of steroid receptors. While genomic steroid effects being characterized by their delayed onset of action and their sensitivity to blockers of transcription and protein synthesis have been known for several decades, very rapid actions of steroids have been more widely recognized and characterized in detail only recently. Rapid effects of steroids, vitamin D3, and thyroid hormones on cellular signaling and function may be transmitted by specific membrane receptors. Although no receptor of this kind has been cloned up to now, binding sites in membranes have been characterized exposing binding features compatible with an involvement in rapid steroid signaling. Characteristics of putative membrane receptors were completely different from those of intracellular steroid receptors, which was further supported by the inability of classic steroid receptor antagonists to inhibit nongenomic steroid actions. Development of drugs that specifically affect nongenomic action alone or even both modes of actions may find applications in various areas such as the cardiovascular and central nervous systems and treatment of preterm labor, infertility, and electrolyte homeostasis. To acquaint the reader with major aspects of nongenomic steroid actions, these effects on cellular function will be summarized, potentially related binding sites in membranes discussed, and the physiological or pathophysiological relevance of nonclassic actions exemplified.

Animals↗