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Mineralocorticoid receptor (MR) antagonists decrease the incidence of sudden cardiac death in patients with heart failure, as has been reported in two clinical trials (Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). Aldosterone has been shown to increase the propensity to arrhythmias by changing the expression or function of various ion channels. In this study, we investigate the effect of aldosterone on the expression of hyperpolarization-activated current ([I.sub.f]) channels in cultured neonatal rat ventricular myocytes, using the whole cell patch-clamp technique, real-time PCR, and Western blotting. Incubation with 10 nM aldosterone for 17-24 h significantly accelerates the rate of spontaneous beating by increasing diastolic depolarization. [I.sub.f] current elicited by hyperpolarization from -50 to -130 mV significantly increases aldosterone by 10 nM (by 1.9-fold). Exposure to aldosterone for 1.5 h increases hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 mRNA by 26.3% and HCN4 mRNA by 47.2%, whereas HCN1 mRNA expression remains unaffected. Aldosterone (24-h incubation) increases the expression of HCN2 protein (by 60.0%) and HCN4 protein (by 84.8%), but not HCN1 protein. MR antagonists (1 [micro]M eplerenone or 0.1 [micro]M spironolactone) abolish the increase of [I.sub.f] channel expression (currents, mRNA, and protein levels) by 10 nM aldosterone. In contrast, 1 [micro]M aldosterone downregulated [I.sub.f] channel gene expression. Glucocorticoid receptor antagonist (100 nM RU-38486) did not affect the increase of [I.sub.f] current by 10 nM aldosterone. These findings suggest that aldosterone in physiological concentrations upregulates [I.sub.f] channel gene expression by MR activation in cardiac myocytes and may increase excitability, which may have a potential proarrhythmic bearing under pathophysiological conditions. eplerenone; spironolactone; automaticity; arrhythmia; HCN gene

Abstract: T-type Ca2+ channels (TCCs) are involved in cardiac cell growth and proliferation in cultured cardiomyocytes. Underlying molecular mechanisms are not well understood. In this study, we investigated the role of TCCs in signal transduction in cardiac hypertrophy compared with L-type Ca2+ channels (LCCs). Cardiomyocytes dissociated from neonatal mouse ventricles were cultured until stabilization. Cell hypertrophy was induced by reapplication of 1% fatal bovine serum (FBS) following a period (24 h) of FBS depletion. Cell surface area increased from 862±73 μm2 to 2153±131 μm2 by FBS stimulation in control (250±1.8%). T-type Ca2+ current (I CaT) was inhibited dose-dependently by kurtoxin (KT) and efonidipine (ED) with IC50 0.07 μM and 3.2 μM, respectively in whole-cell voltage clamp. On the other hand, 1 μM KT which inhibits I CaT over 90% did not effect on L-type Ca2+ current (I CaL). 10 μM ED had the ability of I CaL blockade as well as that of I CaT blockade. 3 μM nisoldipine (ND) suppressed I CaL by over 80%. The increase in cell surface area following reapplication of FBS as observed in control (250±1.8%) was significantly reduced in the presence of 1 µM KT (216±1.2%) and virtually abolished in the presence of 10 µM ED (97±0.8%) and 3 μM ND (80±1.1%). Hypertrophy was associated with an increase in BNP mRNA of 316±3.6% in control and this increase was reduced as well in the presence of 1 µM KT (254±1.8%) and almost abolished in the presence of 10 µM ED (116±1.1%) and 3 μM ND (93±0.8%). Immunolabeling showed that translocation of nuclear factor of activated T cells (NFAT3) into the nucleus in response to FBS stimulation was markedly inhibited by either KT or ED as well as ND. Calcineurin phosphatase activity was upregulated 2.2-fold by FBS, but KT, ED and ND decreased this upregulation (1.7-fold, 0.8-fold, and 0.7-fold with KT, ED and ND respectively). These results suggest that blockade of Ca2+ entry into cardiomyocytes via TCCs may block pathophysiological signaling pathways leading to hypertrophy as well as via LCCs. The mechanism may be the inhibition of calcineurin-mediated NFAT3 activation resulting in prevention of its translocation into the nucleus. [Copyright &y& Elsevier]

Mineralocorticoid receptor (MR) antagonists decrease the incidence of sudden cardiac death in patients with heart failure, as has been reported in two clinical trials (Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). Aldosterone has been shown to increase the propensity to arrhythmias by changing the expression or function of various ion channels. In this study, we investigate the effect of aldosterone on the expression of hyperpolarization-activated current (If) channels in cultured neonatal rat ventricular myocytes, using the whole cell patch-clamp technique, real-time PCR, and Western blotting. Incubation with 10 nM aldosterone for 17-24 h significantly accelerates the rate of spontaneous beating by increasing diastolic depolarization. If current elicited by hyperpolarization from -50 to -130 mV significantly increases aldosterone by 10 nM (by 1.9-fold). Exposure to aldosterone for 1.5 h increases hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 mRNA by 26.3% and HCN4 mRNA by 47.2%, whereas HCN1 mRNA expression remains unaffected. Aldosterone (24-h incubation) increases the expression of HCN2 protein (by 60.0%) and HCN4 protein (by 84.8%), but not HCN1 protein. MR antagonists (1 μM eplerenone or 0.1 μ.M spironolactone) abolish the increase of If channel expression (currents, mRNA, and protein levels) by 10 nM aldosterone. In contrast, 1 μM aldosterone downregulated It channel gene expression. Glucocorticoid receptor antagonist (100 nM RU-38486) did not affect the increase of If current by 10 nM aldosterone. These findings suggest that aldosterone in physiological concentrations upregulates If channel gene expression by MR activation in cardiac myocytes and may increase excitability, which may have a potential proarrhythmic bearing under pathophysiological conditions. [ABSTRACT FROM AUTHOR]

Background: We reported an anesthetic technique for thyroplasty employing voice test. Thyroplasty is performed to improve voice quality in patients with unilateral vocal cord paralysis. Correct displacement of the vocal cord is assessed by asking the patient to phonate. At this point all patients should have recovered from general anesthesia and cooperate to phonation, facilitating correct displacement of the vocal cords., Methods: Anesthesia was induced with i.v. pentazocine 15-30 mg and continuous propofol infusion 10 mg x kg(-1) x hr(-1). The patients received propofol infusion 4-6 mg x kg(-1) x hr(-1) with spontaneous ventilation. At the point of correct displacement of the vocal cords, we stopped propofol infusion and all the patients woke up immediately and cooperated. After determining the voice propofol was given at a rate of 4-6 mg x kg(-1) x hr(-1)., Results: The average times of surgery and anesthesia were 98 +/- 23 min and 139 +/- 22 min, respectively. At the point of correct displacement of the vocal cords, the average time from the end of propofol infusion until awakening with good quality of recovery was 313 +/- 93 sec. No patients complained of pain during or after, Conclusions: This anesthetic technique provided both optimal operating conditions and patient comfort without serious complications.