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Biomedical subjects

M Wehling

Publications and source records attributed to M Wehling.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1999

The new topical steroid ciclesonide is effective in the treatment of allergic rhinitis.

A randomized, placebo-controlled, double-blind crossover study was performed to investigate the efficacy of ciclesonide nasal spray in allergic rhinitis at the dose level of 200 micrograms per nostril. Twenty-four subjects (13 males, 11 females; median age: 28 years) with a history of allergic rhinitis but free of symptoms at screening entered the study. Ciclesonide and placebo were given for 7 days each with a washout period of at least 14 days in between. In both treatment periods, controlled intranasal allergen provocation with pollen extracts was performed on the 2 days before start of treatment (days -2 and -1) and on all treatment days (days 1 to 7) about 2 hours after administration of the study medication. At 5 and 30 minutes after each allergen provocation, rhinal airflow was measured by anterior rhinomanometry, and the subjective symptoms of obstruction, itching, and rhinorrhea were assessed by means of a standardized visual analog scale. Rhinal airflow improved significantly from day 5, while the subjective symptom of obstruction improved from day 2. Itching and rhinorrhea also improved significantly. The local and systemic tolerability of ciclesonide nasal spray was excellent. The results of this study clearly indicate that the new topical steroid ciclesonide is effective in the treatment of allergic rhinitis without producing local or systemic side effects.

Administration, Intranasal↗
PubMed1999

Specific progesterone binding to a membrane protein and related nongenomic effects on Ca2+-fluxes in sperm.

Rapid, nongenomic effects of steroids are supposed to be transmitted by membrane receptors unrelated to the classic intracellular steroid receptors. In this context, a putative progesterone membrane binding protein (mPR) has been identified, recently. Here we show that expression of mPR-cDNA in CHO cells leads to increased microsomal progesterone binding. This result is mirrored by effects of an antibody raised against the recombinant E. coli mPR which suppressed the rapid progesterone-initiated Ca2+ increase in sperm. Our results support the assumption that mPR represents the first steroid membrane receptor or a part of it involved in rapid, nongenomic steroid signalling.

Animals↗
PubMed1999

Short term cardiovascular effects of aldosterone in healthy male volunteers.

Clinical evidence of rapid, nongenomic aldosterone effects in the cardiovascular system has been provided by clinical studies; an increase in systemic vascular resistance (SVR) was shown by invasive techniques within 3 min after injection of aldosterone. Here, we study the dose dependency and the later course of the rapid aldosterone effects by noninvasive techniques. In 12 healthy male volunteers, SVR and heart rate variability were determined by impedance cardiography and digital electrocardiography, respectively, for 8 h after the injection of 0.05 or 0.5 mg aldosterone in a double blind, placebo-controlled, 3-fold cross-over study. No significant differences were observed for baseline values among the three treatments. The area under the curve of SVR during the first 45 min after injection was significantly different between the periods with the highest areas under the curve seen after the injection of 0.5 mg aldosterone (mean +/- SD, 40.4 +/- 12.8 vs. 36.8 +/- 10.3 for 0.05 mg aldosterone and 36.8 +/- 10.4 for placebo; P = 0.05). Individual comparisons showed significant differences at 6 and 30 min between placebo and the 0.5 mg aldosterone period (P < 0.05), with values for the 0.05 mg aldosterone period similar to those for the placebo period. From 330-390 min, opposite changes occurred; SVR was depressed during the 0.05 mg (P < 0.05) and 0.5 mg aldosterone periods compared with that during the placebo period. These delayed effects may reflect an increased vagal tone in the aldosterone groups, as demonstrated by higher values of the time domain parameter of heart rate variability pNN50. This study provides further evidence for clinically detectable rapid cardiovascular aldosterone effects in vivo obtained by noninvasive techniques. The data are consistent with the view of aldosterone as a rapid modulator of cardiovascular responses acting through nongenomic mechanisms.

Adult↗
PubMed1999

Rapid aldosterone effects on tyrosine phosphorylation in vascular smooth muscle cells.

Non-genomic aldosterone effects are characterized by their rapid onset, their specificity for mineralocorticoids and their insensitivity both to the mineralocorticoid type 1 receptor antagonist spironolactone and to the inhibitors of transcription and translation, cycloheximide and actinomycin D. The aim of the present study was to further characterize the second messenger system involved in the non-genomic pathway of aldosterone with particular emphasis on protein phosphorylation. The rapid increase of free intracellular calcium by aldosterone in VSMC is sensitive to genistein, so that tyrosine kinase activity appears likely to be involved in the signaling pathway. Here, the effect of 100 nmol/l aldosterone (10 min.) on tyrosine protein-phosphorylation was determined in VSMC. Our findings show that aldosterone (100 nmol/l) in combination with shear stress as additional stimulus induces a rapid (within 10 min.) small but consistent increase in tyrosine-phosphorylation compared with aldosterone or shear stress alone. Immunoprecipitation of the MAPK-isoforms ERK 1 and ERK 2 showed an increased phosphorylation after 3 and 5 min.

Aldosterone↗
PubMed1999

Inhibition of platelet aggregation after intake of acetylsalicylic acid detected by a platelet function analyzer (PFA-100).

OBJECTIVE: The aim of the investigation was to determine the inhibition of platelet aggregation detected by the platelet function analyzer PFA-100 in patients with coronary artery disease who routinely take 100 mg acetylsalicylic acid once daily. METHOD: The PFA-100 (Dade International Inc., Miami, USA) is a new device for in vitro measurement of platelet function in citrated whole blood. The time needed to form a platelet plug occluding the aperture cut into a collagen/epinephrine- or collagen/ADP-coated membrane is determined under high shear conditions. Typically, acetylsalicylic acid-induced inhibition of platelet aggregation is detected by prolonged closure time in collagen/epinephrine or and normal values for collagen/ADP. Blood samples of 48 patients were investigated, the control group consisted of 10 healthy volunteers without intake of acetylsalicylic acid. The upper limits of normal values of the control group were 137 sec closure time for collagen/epinephrine and 150 sec for collagen/ADP (mean + 2 SD). RESULTS: Statistical analysis (Wilcoxon test) did not show a significant difference (p = 0.46) between the patient group (129 +/- 11 sec) and the control group (92 +/- 7 sec) for collagen/epinephrine (mean +/- SEM). Only 31% of patients had closure time values above those upper limits defined above. CONCLUSION: The effect of 100 mg acetylsalicylic acid daily appears to be too small and too variable to detect a sufficient inhibition of platelet aggregation by the PFA-100 in all patients with coronary artery disease.

Adult↗
PubMed1998

Effect of ribose on cardiac adenine nucleotides in a donor model for heart transplantation.

Preservation time of explanted hearts is short. Cardiac function after transplantation declines dramatically in hearts that have been preserved for more than 4 to 6 hours. This has been linked to a critical decrease in high energy phosphates (HEP) after explantation. Ribose has previously been shown to stimulate HEP synthesis and to improve cardiac function. In this study, ribose was infused into 20 rats for 24 hours continuously before explantation (donor treatment) and also added to the solutions used for preservation. Saline was used in the control group. Myocardial tissue biopsies were taken after 24h of infusion and after 4h of preservation. High energy phosphates were determined by HPLC. Adenosine triphosphate content (ATP), energy charge and total adenine nucleotides (TAN) were significantly lower after 4h of preservation in both the ribose-treated and the control group compared to hearts before preservation. The difference in mean ATP concentrations between the 4 hours preserved ribose group and the control group was not significant. Single case analysis however revealed a minimum ATP level of 12.3 micromol/g dry weight in 10 ribose treated hearts whereas 2 out of 11 control hearts showed ATP levels below 10 micromol/g dry weight. - This study supports the hypothesis that ribose treatment is capable of maintaining ATP at a higher level in preserved rat hearts. Donor treatment and metabolic support with ribose during organ preservation may be suitable to prolong preservation time of donor hearts.

Adenine Nucleotides↗
PubMed1998

[Conversion from oral ACE inhibitor to intravenous quinaprilat administration in mild to moderate essential hypertension].

AIM: This study was designed to evaluate the efficacy of intravenous quinaprilat in maintaining blood pressure control and to assess the safety of directly switching from oral angiotensin-converting enzyme (ACE) inhibitors to intravenous quinaprilate. PATIENTS AND METHOD: Following an initial 1-day open-label phase, patients with essential mild to moderate hypertension controlled by ACE inhibitor monotherapy were randomly assigned to treatment with intravenous quinaprilate (n = 36) or oral quinapril (n = 19) for a 3-day double-blind period. Quinaprilate (2.5, 5, or 10 mg BID) and quinapril (10, 20, or 40 mg OD) dosages were based on the patient's previous ACE inhibitor doses. The intravenously used dosages were half the dosages of orally administered enalapril, lisinopril and quinapril. Patients returned to their previous ACE inhibitor therapy during a second 1-day open-label phase. RESULTS: Quinaprilate and quinapril maintained diastolic blood pressure control at levels comparable to those during the initial open-label ACE inhibitor treatment. The mean difference between quinaprilate and quinapril treatment groups in diastolic blood pressure showed no clinically relevant differences between treatment groups with regard to mean changes from baseline. Mean reductions in systolic blood pressure were similar to those of diastolic blood pressure. CONCLUSION: Quinaprilate, at half the dose of quinapril, administered BID maintains blood pressure control, is well tolerated, and allows for safe conversion from previously applied oral ACE inhibitors. This finding is important for the antihypertensive treatment of patients in intensive care units or peri/post-operatively who cannot swallow orally administered drugs.

Administration, Oral↗
PubMed1998

Are high-affinity progesterone binding site(s) from porcine liver microsomes members of the sigma receptor family?

Membrane progesterone binding sites have been purified recently from pig liver. Since progesterone is considered as an endogenous sigma (sigma) receptor ligand, these sites were characterized pharmacologically by ligands selective for sigma receptor and dopamine receptor binding sites, and by other drugs from distinct pharmacological classes. Binding studies using the radioligand [3H]progesterone were done in crude membrane preparations and solubilized fractions to determine half-maximal inhibitory concentration (IC50) values, from which inhibitory constants (Ki values) were calculated. Radioligand binding was inhibited by the sigma receptor ligands haloperidol, carbetapentane citrate, 1,3-Di(2-tolyl)guanidine (DTG), R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2 aminopropane HCl (R(-)-PPAAP HCl), or sigma receptor antagonists like (+)-3-(3-hydroxyphenyl)-N-propylpiperidine HCl (R(+)-PPP HCl) and cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]-9H-carbazole dihydrochloride (rimcazole 2HCl). The hierarchy of inhibitory action was not fully compatible with either sigma receptor class I (moderate affinity of pentazocine, diphenylhydantoin (phenytoin) insensitivity) or II sites (high affinity of carbetapentane). The data thus suggest that progesterone binding sites in porcine liver membranes are related to the sigma receptor binding site superfamily, but may represent a particular species with progesterone specificity.

Animals↗
PubMed1998

Assuming the worst may not be bad at all. Carvedilol in heart failure treatment.

OBJECTIVE: Carvedilol, a beta-adrenoceptor blocking agent with additional alpha(1)-adrenoceptor blocking properties, has been shown to improve left ventricular function in chronic heart failure (CHF). However, its effect on mortality has recently been the subject of controversial discussion. The aim of this meta-analysis is to review the data on mortality from two large study programs (the US Carvedilol Heart Failure Study and the study by the Australia/New Zealand Heart Failure Research Collaborative Group) on additional carvedilol treatment in CHF standard therapy and to analyse the design and limitations of the individual studies. METHODS AND RESULTS: For determination of overall, mortality, all patients who died and all patients who were withdrawn for other reasons during the open run-in phase of the studies were assigned to the carvedilol group to create a "worst-case analysis." Meta-analysis of mortality data using the random effects model shows a significantly reduced relative risk of 0.55 x 95%-confidence interval 0.325-0.924; p < 0.05 of death in patients treated with carvedilol compared with patient on standard treatment only. CONCLUSION: Treatment of CHF using carvedilol significantly reduces mortality in patients with CHF, even if the "worst case" is assumed by assigning all deaths in the open run-in phase to carvedilol.

Adrenergic beta-Antagonists↗
PubMed1998

Cardiovascular steroid actions: swift swallows or sluggish snails?

Steroid actions on the vascular wall have been thought to depend on direct, genomic mechanisms being characterized by a considerable delay and on secondary events, including changes of coagulation, plasma lipids, and renal electrolyte and volume regulation. Recently, rapid effects of steroids on the vascular wall have been reported being clearly incompatible with the classical theory of genomic steroid action. As these effects occur in classical target tissues for genomic steroid action, and modulation of intracellular signaling has been shown to influence genomic steroid action, a two-step model of steroid action was developed integrating both genomic and nongenomic aspects and their possible interaction. This review summarizes recent studies on both types of direct, vascular steroid actions, the swift and the sluggish ones, and discusses the role of these actions in regulation of circulatory homeostasis and their potential therapeutic implications.

Adrenal Cortex Hormones↗