In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits

Liu, Xiao Ke; Katchman, Alexander N.; Whitfield, B. H.; Wan, Grace; Janowski, Einsley-Marie; Woosley, Raymond L.; Ebert, Steven N.

doi:10.1016/s0008-6363(02)00673-9

Cited by 140 publications

(97 citation statements)

References 36 publications

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“…Chronic application of androgen in vivo exhibited enhancement of the inward rectifier K ϩ current (I K1 ) and I Kr in rabbit. 19 In the present study, we found no apparent effects of testosterone on I Kr at concentrations up to 100 nmol/L. Although we have no clear explanation for the difference, it may reflect different modes of testosterone application (chronic versus acute) or species differences.…”

Section: Effects Of Testosterone On Cardiac Ion Currentscontrasting

confidence: 71%

“…18 On the other hand, testosterone does not change mRNA expression of rat ERG (ether-a-go-go-related gene) but increases the current density of the rapidly activating component of the delayed rectifier K ϩ current (I Kr ) with changes in channel gating kinetics. 19 Thus, testosterone modulates cardiac repolarization via both a transcriptional and a nontranscriptional mechanism. Testosterone rapidly induces dilatation of blood vessels and positive inotropism of cardiac muscle, which are abolished by pretreatment with a nitric oxide synthase (NOS) inhibitor, N G -nitro-L-arginine methyl ester.…”

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confidence: 99%

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Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone

et al. 2005

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Background-Women have longer QT c intervals than men and are at greater risk for arrhythmias associated with long QT c intervals, such as drug-induced torsade de pointes. Recent clinical and experimental data suggest an important role of testosterone in sex-related differences in ventricular repolarization. However, studies on effects of testosterone on ionic currents in cardiac myocytes are limited. Methods and Results-We examined effects of testosterone on action potential duration (APD) and membrane currents in isolated guinea pig ventricular myocytes using patch-clamp techniques. Testosterone rapidly shortened APD, with an EC 50 of 2.1 to 8.7 nmol/L, which is within the limits of physiological testosterone levels in men. APD shortening by testosterone was mainly due to enhancement of slowly activating delayed rectifier K ϩ currents (I Ks ) and suppression of L-type Ca 2ϩ currents (I Ca,L ), because testosterone failed to shorten APD in the presence of an I Ks inhibitor, chromanol 293B, and an I Ca,L inhibitor, nisoldipine. A nitric oxide (NO) scavenger and an inhibitor of NO synthase 3 (NOS3) reversed the effects of testosterone on APD, which suggests that NO released from NOS3 is responsible for the electrophysiological effects of testosterone. Electrophysiological effects of testosterone were reversed by a blocker of testosterone receptors, a c-Src inhibitor, a phosphatidylinositol 3-kinase inhibitor, and an Akt inhibitor. Immunoblot analysis revealed that testosterone induced phosphorylation of Akt and NOS3.

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Section: Effects Of Testosterone On Cardiac Ion Currentscontrasting

confidence: 71%

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confidence: 99%

Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone

et al. 2005

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“…Several studies have demonstrated that testosterone increases the outward potassium current or decreases the inward L-type calcium current. [24][25][26][27] These reports suggest that high testosterone levels may contribute to the BS phenotype.…”

Section: Discussionmentioning

confidence: 99%

Men With Brugada-Like Electrocardiogram Have Higher Risk of Prostate Cancer

Haruta

Matsuo

Ichimaru

et al. 2009

Circ J

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rugada syndrome (BS) is characterized by a covedtype or type 1 ST-segment elevation in the right precordial leads (V1-3) of the 12-lead electrocardiogram (ECG), as well as symptoms such as documented ventricular fibrillation (VF), polymorphic ventricular tachycardia (VT), family history of sudden death, coved-type ECGs in family members, inducibility of polymorphic VT or VF with programmed electrical stimulation, syncope, or nocturnal agonal respiration. 1,2 Several mutations in SCN5A, the α subunit of the sodium channel, have been linked to BS, 3-5 which displays an autosomal dominant mode of transmission with low penetrance. Although BS is inherited with equal frequency by men and women, most of the reported cases have been in adult men. 6,7 In 2 reported cases of Brugada-like ECG, the typical pattern of coved-type ST elevation disappeared following surgical castration for prostate cancer. 8 Men with BS have significantly higher plasma testosterone levels than age-matched male controls, 9 which suggests that testosterone may contribute to the BS phenotype. Editorial p 35There is evidence to suggest that testosterone also plays a pathophysiological role in the etiology of prostate cancer. Testosterone is essential for normal growth and maintenance of the prostate, but it also stimulates the proliferation of human prostate cancer cells in vitro and produces prostate cancer in rodents. 10,11 Thus, we examined the relationship between the Brugada-like ECG with either the covedtype or saddle-back-type ST elevation and prostate cancer. Methods General ProceduresA total of 7,564 atomic bomb survivors (3,374 men; 4,190 women) have been followed biennially in Nagasaki, Japan since July 1, 1958 as part of a follow-up program conducted by the Radiation Effects Research Foundation (RERF). Detailed descriptions of the program have been published elsewhere. 12,13 Each examination includes a physical check-up, 12-lead ECG, and blood pressure measurement by sphygmomanometer while the subjects are seated after resting for at least 5 min. First and fifth Korotkoff phases, respectively, are used for the systolic and diastolic blood pressure (SBP and DBP) readings. Standing height (m) and body weight (kg) are measured without socks or outer clothing and the body mass index (BMI: kg/m 2 ) is calculated. Blood is sampled from a cubital vein for determination of serum cholesterol (mg/dl) and hemoglobin (g/dl). At each examination up to 12 clinical diagnoses are made and stored in a database using the International Classification of Disease (ICD) 7 th , 8 th , 9 th and 10 th editions.

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“…Moreover, a synergistic effect of estradiol and I Kr -blocking drugs on I Kr currents was recently reported [35]. In contrast, testosterone increases I Kr and I K1 in rabbits' cardiomyocytes [38], and increases I Ks and decreases I Ca,L in guinea pigs' cardiomyocytes [39], thus shortening APD and QT duration. Progesterone also shortens APD by decreasing I Ca,L and increasing I Ks [31,39] (Table 1, Fig.…”

Section: + -Cycling Proteinsmentioning

confidence: 93%

Sex differences and sex hormone effects in long-QT syndrome: what can we learn from rabbit models?

Odening

Zehender

Bode

et al. 2013

Clin Res Cardiol Suppl

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Patients with inherited long-QT syndrome (LQTS) exhibit pronounced sex differences in cardiac repolarization and in the incidence of arrhythmias: Adult women have longer QT intervals and a higher risk to develop potentially lethal torsade-de-pointes (TdP) ventricular tachycardia and sudden cardiac death (SCD) than men. Rabbit models exhibit similar sex differences with longer QT intervals and a higher propensity to additional drug-induced QT prolongation and drug-induced TdP in females. Since rabbits also have similar cardiac repolarizing currents as human subjects, they provide a useful system to explore sex differences in cardiac repolarization and arrhythmogenesis in LQTS and to reveal the underlying molecular mechanisms. This review article summarizes clinical observations on sex differences and sex hormone effects on cardiac repolarization and arrhythmogenesis in patients with LQTS and recapitulates findings on underlying mechanisms (sex hormone effects on ion channels and Ca

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In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits

Cited by 140 publications

References 36 publications

Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone

Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone

Men With Brugada-Like Electrocardiogram Have Higher Risk of Prostate Cancer

Sex differences and sex hormone effects in long-QT syndrome: what can we learn from rabbit models?

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