The blockade of angiotensin AT1 and aldosterone receptors protects rats from synthetic androgen-induced cardiac autonomic dysfunction.

AIM: This study aimed to evaluate the combined effects of exercise and antagonists of the angiotensin II and aldosterone receptors on cardiac autonomic regulation and ventricular repolarization in rats chronically treated with nandrolone decanoate (ND), a synthetic androgen. METHODS: Thirty male Wistar rats were divided into six groups: sedentary, trained, ND-treated, trained and ND-treated, trained and treated with both ND and spironolactone, and trained and treated with both ND and losartan. ND (10 mg kg(-1) weekly) and the antagonists (20 mg kg(-1) daily) of the angiotensin II AT1 (losartan) and aldosterone (spironolactone) receptors were administered for 8 weeks. Exercise training was performed using a treadmill five times each week for 8 weeks. Following this 8-week training and treatment period, electrocardiogram recordings were obtained to determine the time and frequency domains of heart rate variability (HRV) and corrected QT interval (QTc). RESULTS: Nandrolone decanoate treatment increased the QTc interval and reduced the parasympathetic indexes of HRV (RMSSD, pNN5 and high-frequency power) in sedentary and trained rats. The ratio between low- and high-frequency power (LF/HF) was higher in ND-treated groups. Both losartan and spironolactone treatments prevented the effects of ND on the QTc interval and the HRV parameters (RMSSD, pNN5, high-frequency power, and the LF/HF ratio). CONCLUSION: Our results show that chronic treatment with a high dose of ND induces cardiac parasympathetic dysfunction and disturbances in ventricular repolarization in both sedentary and exercised rats. Furthermore, inhibiting the renin-angiotensin-aldosterone system using losartan, or spironolactone, prevented these deleterious effects.

Cardiac autonomic dysfunction in anabolic steroid users.

This study aimed to evaluate if androgenic-anabolic steroids (AAS) abuse may induce cardiac autonomic dysfunction in recreational trained subjects. Twenty-two men were volunteered for the study. The AAS group (n = 11) utilized AAS at mean dosage of 410 ± 78.6 mg/week. All of them were submitted to submaximal exercise testing using an Astrand-Rhyming protocol. Electrocardiogram (ECG) and respired gas analysis were monitored at rest, during, and post-effort. Mean values of VO2 , VCO2 , and VE were higher in AAS group only at rest. The heart rate variability variables were calculated from ECG using MATLAB-based algorithms. At rest, AAS group showed lower values of the standard deviation of R-R intervals, the proportion of adjacent R-R intervals differing by more than 50 ms (pNN50), the root mean square of successive differences (RMSSD), and the total, the low-frequency (LF) and the high-frequency (HF) spectral power, as compared to Control group. After submaximal exercise testing, pNN50, RMSSD, and HF were lower, and the LF/HF ratio was higher in AAS group when compared to control group. Thus, the use of supraphysiological doses of AAS seems to induce dysfunction in tonic cardiac autonomic regulation in recreational trained subjects.

Cardiac effects of anabolic steroids: hypertrophy, ischemia and electrical remodelling as potential triggers of sudden death.

Anabolic-androgenic steroids (AAS) are synthetic testosterone derivatives developed to maximise anabolic activity and minimise androgenic activity. AAS abuse is widespread among both athletes and non-athletes at fitness centres and is becoming a public health issue. In addition to their atherogenic, thrombogenic and spastic effects, AAS have direct cardiotoxic effects by causing hypertrophy, electrical and structural remodelling, and contractile dysfunction and by increasing the susceptibility to ischemic injuries. All of these factors contribute to an increased risk of ventricular arrhythmias and sudden cardiac death.

The negative inotropic action of canrenone is mediated by L-type calcium current blockade and reduced intracellular calcium transients.

BACKGROUND AND PURPOSE: Adding spironolactone to standard therapy in heart failure reduces morbidity and mortality, but the underlying mechanisms are not fully understood. We analysed the effect of canrenone, the major active metabolite of spironolactone, on myocardial contractility and intracellular calcium homeostasis. EXPERIMENTAL APPROACH: Left ventricular papillary muscles and cardiomyocytes were isolated from male Wistar rats. Contractility of papillary muscles was assessed with force transducers, Ca(2+) transients by fluorescence and Ca(2+) fluxes by electrophysiological techniques. KEY RESULTS: Canrenone (300-600 micromol L(-1)) reduced developed tension, maximum rate of tension increase and maximum rate of tension decay of papillary muscles. In cardiomyocytes, canrenone (50 micromol L(-1)) reduced cell shortening and L-type Ca(2+) channel current, whereas steady-state activation and inactivation, and reactivation curves were unchanged. Canrenone also decreased the Ca(2+) content of the sarcoplasmic reticulum, intracellular Ca(2+) transient amplitude and intracellular diastolic Ca(2+) concentration. However, the time course of [Ca(2+)](i) decline during transients evoked by caffeine was not affected by canrenone. CONCLUSION AND IMPLICATIONS: Canrenone reduced L-type Ca(2+) channel current, amplitude of intracellular Ca(2+) transients and Ca(2+) content of sarcoplasmic reticulum in cardiomyocytes. These changes are likely to underlie the negative inotropic effect of canrenone.

Cardiac effects of oxytocin: is there a role for this peptide in cardiovascular homeostasis?

Oxytocin is well known for its role in reproduction. However, evidence has emerged suggesting a role in cardiovascular and hydroelectrolytic homeostasis. Although its renal effects have been characterized, the cardiac ones have not been much studied. Therefore, we aimed to investigate the cardiac effects of oxytocin both in vivo and in vitro. In unanesthetized rats (n=6) intravenous oxytocin (1 mug) decreased dP/dt(max) by 15% (P<0.05) and heart rate by 20% (P<0.001), at the first minute after injection. dP/dt(max) was still lower in OT-treated rats than in controls (n=8) after 15 min (P<0.05), while heart rate returned to control values after 5 min. In isolated hearts, oxytocin was able to promote negative inotropic and chronotropic effects. Perfusion with 10(-5), 10(-6) and 10(-7)M oxytocin resulted in approximately 60% (P<0.01), 25% (P<0.01) and 10% (P<0.05) reduction of left ventricle developed pressure, without effect in lower concentrations (10(-10) to 10(-8) M). Also, dP/dt(max) was reduced by 45 and 20% (10(-5) e 10(-6) M; P<0.01), while diastolic pressure raised and heart rate fell only with 10(-5)M oxytocin (P<0.05). Intravenous oxytocin (1 mug; n=6) increased arterial pressure by 22% at the first minute (+23+/-3 mm Hg; P<0.001), returning to control value thereafter. Thus, oxytocin is able to promote directly negative inotropic and chronotropic effects, but its in vivo effect also involves a reflex mechanism, originated from its pressor effect.

Eletrophysiological properties of L-type Ca2+ currents in isolated adult mouse ventricular myocytes

The Whole-cell configuration of the patch-clamp technique was used to analyze the electrophysiological characteristics of the L-type calcium current (Ica) in single ventricular myocytes from hearts of adult mice. In Tyrode solution, ICa activated at -30 mV peaked at 0mV, and reverted near +60 mV. At 0mV, the peak current density was -8.1 + 2.5 pA/pF (N = 14). In a Na+ - and K+ -free solution containing 12 muM tetrodotoxin, and 10 mM Ca2+ or Ba2+ as charge carrier, the current-voltage relationship and the voltage dependence of inactivation were shifted about 10 mV to more depolarized voltages. The maximum Ba2+ current was two-times greater than the maximum Ca2+ current. The voltage dependencies of steady-state activation and inactivation were determined within the range of -70 to +50 mV and fitted with Boltzmann relations. The Ca2+ current showed half-maximal activation at -9.94 + 3.86 mV (slope factor (k) = 5.9 + 0.68 mV) and half-maximal inactivation at -27.65 + 5.74 mV (k = 6.37 + 2.79 mV), while the Ba2+ current showed half-maximal activation at -0.35 + 2.43 mV (k = 6.0 + 0.84 mV) and half-maximal inactivation at -20.33 + 2.40 mV (k = 5.36 + 1.10 mV). The time course of recovery of Ba2+ current from inactivation could be described using a single exponential function with a time constant of 83.37 msec. The overlap of activation and inactivation curves suggests the existence of an L-type Ca2+ window current with a maximal amplitude near -20mV.

Frequency-dependent excitability enhancement in isolated ventricular myocardial cells

The understanding of the mechanisms underling the frquency-dependent slow response ecitability enhancement has been hndered by the problem inhyerent in multicellular preparations. These include ion acdcumulation/depletion in intercellular space and difficulties in the spatial control of transmembrane voltage. In the present communication we show that isolated ventricular cells exposed to a depolarizing (high potassium-barium containing) solution present electrophysiological properties similar to those of mulcellular preparations: stable resting potential of -45.2 ñ 0.7 mV (mean ñ SEM, N = 57) in 75% of the cells and spontaneous activity in the remaining 25% (maximum diatolic potential of -41.9 ñ 1.2 mV, N=19)ñ high input resistance and slow response, under current clamp conditions. Under whole cell voltage clamp conditions with -45 mV holding potential, transient outward and delayed potassium currents as well as typical L type calcium channel are present. These cells also present thye frequency-dependent excitability enhancement of the slow response, with the threshold stimulus at 1 Hz corresponding to about 50% of that obtained at 0.1 Hz. Thus, isolated ventricular cells constitute a suitable model for the study of frequency-dependent exitability enhancement of the slow response