Search PubMed⌕ Search

Biomedical subjects

M Wehling

Publications and source records attributed to M Wehling.

At least 37 records · Page 2Linked to original sources
PubMed2002

Comparison of the mechanisms of nongenomic actions of thyroid hormone and steroid hormones.

Steroids and thyroid hormone are thought primarily to act via binding to hormone-specific nuclear receptor superfamily members. The nuclear ligand-receptor complexes then initiate transcriptional activity. Actions of steroids and iodothyronines that are nongenomic or extranuclear in mechanism have been recognized recently and new insights into such mechanisms are available. Despite their distinct structures and biologic effects, the two families of hormones have similarities in the mechanisms of their nongenomic actions. That is, both steroids and thyroid hormone appear to interact with specific cell surface G protein-coupled receptors and to activate signal transducing kinases such as those involved in the mitogen-activated protein kinase (MAPK) pathway. Much is known about the ability of certain steroids such as estrogen and mineralocorticoids to increase [Ca2+]i acutely and stimulation of the MAPK cascade by L-T4 appears to depend upon a hormone-induced increase in [Ca2+]i via phosphoinositide pathway activation. At least in the case of iodothyronines, hormone activation of the MAPK pathway modulates the cellular activities of certain cytokines and growth factors. One of the two cell surface estrogen receptors (ERs) may be an expression of the same transcript as that for nuclear ER, whereas the mineralocorticoid and progesterone-binding proteins in the plasma membrane appear to be products of genes different from those of nuclear receptors. Iodothyronine structure-activity relationships at the plasma membrane binding site for thyroid hormone suggest that the cell surface receptor for T4 that also binds 3,5,3'-triiodo-L-T3 is different from the nuclear T3 receptor (TR). There are interfaces of nongenomic and genomic mechanisms for both steroids and thyroid hormone. For example, by nongenomic mechanisms, estrogen and thyroid hormone can promote serine phosphorylation, respectively, of nuclear ER and TR. Transcriptional activity of the nuclear receptor proteins can be altered by such phosphorylation.

Animals↗
PubMed2002

Alterations in platelet function during the ovarian cycle.

Steroid hormones may profoundly influence hemostasis; for example, as discussed for hormone replacement therapy, pregnancy and, being less obvious, for the ovarian cycle. We investigated primary hemostasis parameters using a platelet function analyzer (PFA-100) during the follicular and luteal phases in 18 healthy young women without oral contraceptives. During the follicular phase, the mean closure time (CT) was 164.7 +/- 56.7 s, and it decreased to 130.2 +/- 30.6 s in collagen/epinephrine cartridges in the luteal phase (P = 0.0095). No significant difference could be found for CT values in collagen/adenosine diphosphate cartridges during the follicular phase as compared with the luteal phase (97.2 +/- 24.2 s versus 89.6 +/- 18.4 s, P = 0.174). Negative correlations between the CT values in collagen/epinephrine cartridges and von Willebrand factor from both phases of the cycle were found (follicular phase: r = -0.53; luteal phase: r = -0.54). Fibrinogen and fibrinogen degradation products were significantly increased in the luteal phase (2.49 +/- 0.62 g/l versus 2.05 +/- 0.59 g/l and 0.12 +/- 014 versus 0.04 +/- 0.04, P = 0.02 for both parameters) as compared with the follicular phase. No significant differences could be detected for plasminogen, plasmin-antiplasmin complex, prothrombin fragment 1 + 2 and D-dimer between the groups. This study indicates that platelet function is periodically altered during the ovarian cycle due to the influence of progesterone and estrogen on von Willebrand factor concentrations.

Adult↗
PubMed2002

Seminal plasma hormone concentration after oral application of progesterone.

Previous studies have revealed beneficial in vitro effects of progesterone on sperm function. The aim of this pilot study was to prove if orally given micronized progesterone leads to elevations in progesterone and/or 17alpha-hydroxyprogesterone levels in seminal plasma, since higher seminal plasma levels of these hormones could possibly have a beneficial effect on sperm function as seen in in vitro investigations. Multiple application of micronized progesterone given over 4 days (daily dose 400 mg) to 6 healthy subjects resulted in elevated seminal plasma levels of progesterone (10.90 +/- 9.02 nmol/l vs. 1.43 +/- 0.56 nmol/l, p = 0.04) and 17alpha-hydroxyprogesterone (3.09 +/- 1.72 nmol/l vs. 1.62 +/- 1.26 nmol/l, p = 0.04) whereas no significant difference could be found in testosterone levels (34.82 +/- 13.00 vs. 30.91 +/- 8.56 nmol/l, p = 0.43). In contrast, androstendione levels in seminal plasma were reduced (2.68 1.28 nmol/l vs. 3.65 +/- 1.36 nmol/l, p = 0.01). Although micronized progesterone is rapidly metabolized, oral application resulted in pronounced elevations of progesterone and 17alpha-hydroxyprogesterone in seminal plasma. Further studies will show if oral application of micronized progesterone can induce beneficial effects on sperm function such as those seen in in vitro investigations.

17-alpha-Hydroxyprogesterone↗
PubMed2001

[Drug therapy in the old age. Drug effects in the elderly].

The frequency of multimorbidity in elderly patients may mislead the physician into practicing polypragmasy (polypharmacy), resulting in unpredictable drug interactions. Such interactions are a quite common cause of hospitalization in geriatric patients. Pharmacokinetics are often altered in the aged, and individualized medication should take into consideration not only the patient's age, liver and kidney function, but also the individual variability of hepatic metabolism and drug absorption from the gastrointestinal tract dictated by genetic polymorphism. Drug treatment in the elderly should always be carefully assessed as to its risks and benefits, and, where indicated, certain medications should be replaced by or omitted.

Age Factors↗
PubMed2001

A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice.

Dystrophin-deficient muscles experience large reductions in expression of nitric oxide synthase (NOS), which suggests that NO deficiency may influence the dystrophic pathology. Because NO can function as an antiinflammatory and cytoprotective molecule, we propose that the loss of NOS from dystrophic muscle exacerbates muscle inflammation and fiber damage by inflammatory cells. Analysis of transgenic mdx mice that were null mutants for dystrophin, but expressed normal levels of NO in muscle, showed that the normalization of NO production caused large reductions in macrophage concentrations in the mdx muscle. Expression of the NOS transgene in mdx muscle also prevented the majority of muscle membrane injury that is detectable in vivo, and resulted in large decreases in serum creatine kinase concentrations. Furthermore, our data show that mdx muscle macrophages are cytolytic at concentrations that occur in dystrophic, NOS-deficient muscle, but are not cytolytic at concentrations that occur in dystrophic mice that express the NOS transgene in muscle. Finally, our data show that antibody depletions of macrophages from mdx mice cause significant reductions in muscle membrane injury. Together, these findings indicate that macrophages promote injury of dystrophin-deficient muscle, and the loss of normal levels of NO production by dystrophic muscle exacerbates inflammation and membrane injury in muscular dystrophy.

Animals↗
PubMed2001

Hypoxia modulates rapid effects of aldosterone on oxidative metabolism in human calf muscle.

Non-genomic effects of aldosterone on oxidative metabolism of skeletal muscle have been shown, recently. To further characterize these rapid effects on the increase of phosphocreatine (PCr) in the recovery period after isometric exercise, a randomized cross-over placebo-controlled study was conducted on 9 healthy volunteers. Hypoxia was chosen to test the dependence of the effect on oxygen supply and thus its relation to oxidative vs non-oxidative metabolism. Parameters related to the energy metabolism of calf muscles were measured by 31P magnetic resonance spectroscopy during four repetitive contractions in four different tests (hypoxia [FiO2=0.13] vs normoxia [FiO2=0.21], +/- 0.5 mg aldosterone). The area-under-curves of post-exercise PCr levels after the 4th contraction were significantly increased by aldosterone vs placebo during normoxia (875.5 +/- 5.1 vs 857.2 +/- 8.3%-min; p=0.02). In addition, aldosterone induced an undershoot of inorganic phosphate (Pi) in the recovery after isometric exercise (77.5 +/- 5.4 vs 88.9 +/- 5.1 mmol/l x min; p=0.05). Hypoxia blocked effects of aldosterone on PCr overshoot and Pi undershoot. Concentrations of ATP, ADP, phosphomonoesters, and intracellular pH were not affected by those interventions. In conclusion, these data demonstrate rapid actions of aldosterone on post-excercise PCr and Pi levels in human calf muscle, which are blocked by hypoxia. We hypothesize that aldosterone rapidly interferes with oxidative metabolism probably by direct modulation of ATP-turnover, which is induced by an oxygen-dependent imbalance of the ATP-synthesis and utilization rate.

Adult↗
PubMed2001

Chemical modification and structural analysis of the progesterone membrane binding protein from porcine liver membranes.

In addition to the classical genomic steroid actions on modulation of transcription and protein synthesis, rapid, nongenomic effects have been described for various steroids. These effects on cellular signaling and function are supposed to be transmitted by membrane binding sites unrelated to the classical intracellular receptors. Recently, a high affinity progesterone membrane binding protein (mPR) has been characterized in porcine liver membranes. In the present study, amino acid residues that are essential for progesterone binding to porcine liver microsomal mPR have been identified by the use of protein modifying reagents. Among all reagents tested, agents with specificity for carboxyl groups, methionine and tryptophan such as N,N'-dicyclohexylcarbodiimide, chloramine T and N-bromosuccinimide induced a reduction in [3H]progesterone binding. To evaluate the presence of essential disulfide bridges, porcine liver microsomes were incubated with the disulfide reducing agent dithiothreitol (DTT) and [3H]progesterone binding was measured. This treatment also resulted in a reduction of binding activity with an IC50 of 20 mM for DTT. Western-blotting analysis in the presence or absence of the reducing agent suggested that mPR--in its binding state--consists of at least two identical subunits with an apparent molecular mass of 28 kDa which are linked by a disulfide bridge. In conclusion, in the present study evidence for an involvement of carboxyl-, tryptophan- and methionine residues in [3H]progesterone binding to porcine liver microsomes is given. In addition, it is shown that mPR can form disulfide-linked homodimers.

Animals↗
PubMed2001

The phosphodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis.

BACKGROUND: The beneficial effects of phosphodiesterase 4 (PDE4) inhibitors in allergic asthma have been shown in previous preclinical and clinical studies. Because allergic rhinitis and asthma share several epidemiologic and pathophysiologic factors, PDE4 inhibitors might also be effective in allergic rhinitis. OBJECTIVE: The main objective of this study was to investigate the efficacy of oral roflumilast (500 microg/day) in allergic rhinitis. METHODS: In a randomized, placebo-controlled, double-blinded, crossover study, 25 subjects (16 male, 9 female; median age, 28 years) with histories of allergic rhinitis but asymptomatic at screening received roflumilast (500 microg once daily) and placebo for 9 days each with a washout period of at least 14 days in between treatment periods. In each of the treatment periods, controlled intranasal allergen provocation with pollen extracts was performed daily beginning the third day of treatment, each time approximately 2 hours after study drug administration. Five and 30 minutes after each allergen provocation, rhinal airflow was measured by means of anterior rhinomanometry and the subjective symptoms obstruction, itching, and rhinorrhea were assessed by means of a standardized visual analog scale. RESULTS: Rhinal airflow improved almost consistently during the 9 days of roflumilast treatment, and it was significantly higher at study day 9 on roflumilast in comparison with placebo, a result also found for itching and rhinorrhea. With respect to the subjective obstruction score, a significant difference in comparison with placebo could be demonstrated within 4 days. CONCLUSION: This study shows that a PDE4 inhibitor, roflumilast, effectively controls symptoms of allergic rhinitis. Thus PDE4 inhibitors might be a future treatment option not only in allergic asthma but also in allergic rhinitis or the combination of the 2 diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Impact of plasmapheresis on platelet hemostatic capacity in healthy voluntary blood donors detected by the platelet function analyzer PFA-100.

Previous flow cytometry studies showed that platelet activation may occur during cytapheresis, cardiopulmonary bypass and hemodialysis. The aim of this pilot study was to determine if the impact of plasmapheresis leads to alterations in platelet hemostatic capacity. Plasmapheresis was carried out in 30 volunteers using an Autopherese C (Baxter) and an MCS3p (Haemonetics). Blood samples were collected and analyzed immediately before and after plasmapheresis. As a result of the plasmapheresis on the Autopherese C, the mean closure time (CT) for collagen/epinephrine (Col/Epi) increased from 118.2 +/- 25.1 to 149.9 +/- 35.0 s and from 88.7 +/- 16.9 to 98.5 +/- 26.3 s for collagen/ADP (Col/ADP), respectively. Seven subjects showed impaired CTs after plasmapheresis for Col/Epi. For Col/ADP, five subjects showed impaired CTs after apheresis. Statistical analysis (McNemar test) showed a significant difference before and after apheresis for Col/Epi (P = 0.024) but not for Col/ADP (P = 0.088). Similar results were shown for plasmapheresis carried out with the MCS3p. These findings show that plasmapheresis can cause an impairment of platelet function in healthy volunteers as measured by the PFA-100, an effect of so far unknown clinical significance.

Adult↗
PubMed2001

Influence of aldosterone vs. endothelin receptor antagonism on renovascular function in liquorice-induced hypertension.

BACKGROUND: The enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor inactive 11-dehydro derivatives. Inhibition of 11beta-HSD2 by liquorice-derived glycyrrhizic acid (GA) therefore results in sodium retention and hypertension. The present study investigated the effect of the aldosterone receptor antagonist spironolactone in comparison with the endothelin ET(A) receptor antagonist darusentan on renovascular endothelial function in liquorice-induced hypertension. METHODS: GA, a recognized inhibitor of 11beta-HSD2 was supplemented to the drinking water (3 g/l) of Wistar Kyoto rats over a period of 21 days. From day 8 to 21, spironolactone (5.8+/-0.6 mg/kg/day), darusentan (45.2+/-6.5 mg/kg/day), or placebo was added to chow (n=7 per group). After the animals were killed, vascular function of isolated renal artery segments was assessed by isometric tension recording. RESULTS: Relaxation of pre-constricted renal artery segments in response to acetylcholine (10(-10) to 10(-5) mol/l) was impaired by GA as compared with controls (12+/-4% vs 98+/-5% of norepinephrine 3x10(-7) mol/l), whereas endothelium independent relaxations were unaffected. Endothelin receptor antagonism improved renovascular endothelium-dependent relaxation (32+/-4%, P<0.05 vs placebo) whereas endothelium-dependent relaxation was completely normalized by aldosterone receptor antagonism (85+/-4%, P<0.01 vs placebo). CONCLUSIONS: In GA-induced hypertension, both aldosterone receptor antagonism and endothelin receptor antagonism normalize blood pressure and improve renovascular function and, thus, may represent a new therapeutic approach in cardiovascular disease associated with impaired 11beta-HSD2 activity.

Animals↗
PubMed2001

Interaction of rapid nongenomic cardiovascular aldosterone effects with the adrenergic system.

Interactions between the renin-angiotensin-aldosterone system and the adrenergic system are complex and have mainly been attributed to angiotensin II, with knowledge about aldosterone action much less advanced. Only recently has evidence been forthcoming that aldosterone blunts the baroreceptor reflex and lowers heart rate variability in humans. Both effects point to an adrenergic-like action of aldosterone. It has been proposed that this blunting of baroreceptor sensitivity is mediated nongenomically and that nongenomic aldosterone action itself is modulated by the adrenergic system. The aim of the present study was to prove the hypothesis of an interaction between the autonomic nervous system and rapid, nongenomic aldosterone effects. We conducted a randomized, double blind, 8-fold cross-over trial on 18 healthy male volunteers. After pretreatment with the beta-blocking agent esmolol, the beta-agonist dobutamine, the alpha(1)-agonist phenylephrine, or placebo, placebo (0.9% NaCl) or aldosterone (0.5 mg) was injected. After aldosterone injection the peak plasma levels were supraphysiological, reaching nanomolar concentrations. Primary target variables were differences in changes in mean arterial blood pressure, systemic vascular resistance, and cardiac output depending on the pretreatment. Cardiovascular parameters were measured by impedance cardiography during the maintained infusion of the adrenergic modulators for 45 min. Comparing pretreatments, diverse acute, and thus nongenomic, effects of aldosterone on mean arterial blood pressure were observed. After esmolol pretreatment, aldosterone caused an increase in mean arterial blood pressure by 4.1%, whereas after dobutamine pretreatment mean arterial blood pressure decreased by 1.6%, and the difference was statistically significant (P < 0.01). These effects were significant (P < 0.005) for the first 12 min, underlining their nongenomic nature. Our data support the hypothesis that aldosterone, via nongenomic mechanisms, has diverse effects on the cardiovascular system that depend on the preexisting adrenergic state. Furthermore, aldosterone blunts the blood pressure-lowering effect of the beta-blocking agent esmolol by a nongenomic mechanism.

Adrenergic alpha-Agonists↗
PubMed2001

Impact of pharmacotherapy on lymphocyte volumes and activity of the Na+/H+ exchanger in patients with congestive heart failure.

Previous studies in patients with congestive heart failure (CHF) have revealed abnormalities of cellular volume that might have an impact on the dysregulation of peripheral vascular resistance. Human mononuclear leukocytes (HML) represent a model for the study of cellular volume regulation. We investigated the impact of enalapril and carvedilol on HML volume and on the activity of the Na+/H+ exchanger in 26 patients with CHF and 20 volunteers. Over a period of 4 weeks, 18 patients received enalapril in addition to the previous therapy while 8 patients additionally received carvedilol. HML diameters and the activity of the Na+/H+ exchanger were measured by a Coulter Counter. Both patient groups showed abnormally increased initial volumes of HML compared to the volunteer group at baseline. Four weeks of therapy with enalapril in addition to therapy with diuretics and digoxin did not result in a statistically significant reduction of lymphocyte volume, whereas add-on therapy with carvedilol to therapy with ACE inhibitors, diuretics and digoxin reduced the volume significantly. Alterations could not be found in the activity of the Na+/H+ exchanger in either patient group compared to volunteers. Supplementary drug therapy with carvedilol in patients with CHF leads to a reduction of the increased lymphocytic volume, possibly reflecting the beneficial effect of beta-blockade.

Aged↗
PubMed2001

The human membrane progesterone receptor gene: genomic structure and promoter analysis.

Rapid, nongenomic effects of steroids are likely to be mediated by membrane receptors not by intracellular steroid receptors. We recently identified a progesterone membrane binding protein (mPR) from human liver. The corresponding hmpr gene is comprised of 3 exons and 2 introns. The promoter sequence of hmpr lacks a typical TATA box but contains instead a high homology to a transcription Initiatior consensus sequence, which overlaps the experimentally determined transcriptional start site. The major proximal promoter is GC-rich and sequence analysis revealed a CpG island spanning the transcriptional start site. Several putative cis-regulatory DNA-motifs, which represent possible binding sites for transcription factors like AP2, NF-AT, Ahr/Arnt and C/EBP were identified in the genomic upstream region by sequence homology. Functional analysis of differently deleted fragments of the hmpr upstream region in a GFP-reportergene assay in transiently transfected cultured cells indicates the general testability of the hmpr promoter in vivo.

Animals↗
PubMed2001

Does intention-to-treat analysis answer all questions in long-term mortality trials? Considerations on the basis of the ANZ trial.

AIMS: Intention-to-treat (ITT) analyses are the gold standard in endpoint analyses of randomized clinical trials. Valuable information, however, may be lost in this approach as the actual time on trial medication is not accounted for in patients who withdraw early. Since compliance per se can be a prognostic factor and the actual treatment time is a variable likely to influence clinical outcome, this information should be added to an ITT analysis concept. Thus, the aim is to elucidate the influence of actual treatment time on the results of ITT analysis using available data from a well-conducted, large-scale clinical trial. METHODS AND RESULTS: The ANZ trial, a carvedilol study in heart failure, is characterized by a considerable number of early withdrawals in the carvedilol group. Using the ANZ trial database, the percentage of withdrawals was calculated as well as the number of days on treatment. Fourteen out of 21 deaths (67%) in the carvedilol group occurred after discontinuation of carvedilol. At the time of death, 14 out of 29 (48%) patients in the placebo group had withdrawn from treatment. Mean time of patients on medication who withdrew and died later were 301 days for placebo, but only 204 days for carvedilol. We performed a conventional ITT analysis, and an ITT-based Cox-proportional hazards model (modified ITT) in which the actual time on trial medication was entered into the model as an explanatory variable. The risk ratio in conventional ITT analysis was 0.71 (95% confidence interval (CI) 0.41 to 1.24, p = 0.228) and 0.50 (95% CI 0.28-0.90, p < 0.001 ) in modified ITT analysis. CONCLUSIONS: Incorporation of the actual treatment time substantially influences the result of this exemplary ITT analysis. The resulting risk ratio is clearly in accordance with clinical implications and in close agreement with those of other beta-blocker trials in heart failure. Entering the actual treatment time into a Cox-proportional hazards model as an explanatory variable is reasonable if not necessary from a clinical point of view and thus may strengthen the validity of ITT analysis.

Aged↗
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↗