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.

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.

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.

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.

Rapid cardiovascular action of aldosterone in man.

Rapid nongenomic in vitro effects of aldosterone have been demonstrated recently in cultured vascular smooth muscle and endothelial cells. But there is, as yet, little evidence for corresponding in vivo effects. The present study thus investigates the rapid nongenomic effects of aldosterone on human cardiovascular function. In a double-blind placebo-controlled randomized parallel trial on 17 patients with suspected coronary heart disease, the effect of 1 mg aldosterone iv on cardiovascular function was assessed during cardiac catheterization. Hemodynamic parameters (such as heart rate, left ventricular and atrial pressures, arterial pressures, vascular resistances, and cardiac output) were measured before and 3 and 10 min after administration of aldosterone or placebo. Significant changes were found for systemic vascular resistance, cardiac output, and cardiac index, compared with the placebo group (Wilcoxon test, P < 0.02-0.05). The effect of aldosterone dissipated within 10 min. The results are in line with the in vitro data cited above and consistent with earlier findings on acute cardiovascular effects of aldosterone, which have now been confirmed and extended by contemporary techniques. The hypotheses of rapid nongenomic in vivo effects of aldosterone are further substantiated by this study.

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.

Chromatin organization and breast cancer prognosis. Two-dimensional and three-dimensional image analysis.

BACKGROUND: The assessment of breast cancer prognosis still relies on clinical staging and histologic grading. Among the different prognostic parameters, attention has been focused on features of chromatin structure. Although data from two-dimensional (2-D) analysis of chromatin structure show significant correlation with the survival, their biologic interpretation remains difficult. In this respect, insights into the spatial organization of chromatin appear important. METHODS: The authors performed computerized three-dimensional (3-D) reconstructions of Feulgen-stained tumor cell nuclei, correlating the results with those of 2-D image analysis. Forty-nine ductal-invasive carcinomas with 10-18 years follow-up were investigated. RESULTS: The 2-D analysis demonstrated that along with nuclear size and shape, chromatin features such as marginal concentration of condensed chromatin are of prognostic importance. As 3-D analysis revealed, chromatin changes concern ordered organization and were associated with the increase of spatial entropy. CONCLUSIONS: The 3-D description of chromatin structure by means of spatial models provides evidence that tumor aggressiveness correlates with events of clustering and randomization. These indicate disturbances of ordered chromatin organization.