Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone

Bai, Chang-Xi; Kurokawa, Junko; Tamagawa, Masaji; Nakaya, Haruaki; Furukawa, Tetsushi

doi:10.1161/circulationaha.104.523217

Cited by 226 publications

(180 citation statements)

References 47 publications

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“…Women are known to have on average a longer QTc interval than men (CPMP/986/96 1997). The shorter QTc interval in men is attributed to the role of testosterone on the duration of the action potential, mainly due to enhancement of slowly activating delayed rectifier K C currents and suppression of L-type Ca 2C currents (Bai et al 2005). In cardiomyocytes, sex hormone receptors influence the activity of cardiac Na C /K C ATPase.…”

Section: Discussionmentioning

confidence: 99%

High free thyroxine levels are associated with QTc prolongation in males

Noord¹,

Deure²,

Sturkenboom³

et al. 2008

Journal of Endocrinology

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The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T 4 ) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T 4 /TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was no significant association between TSH and QTc interval (0 . 8 ms (95% confidence interval (CI) K3 . 5, 5 . 2) in the first quintile compared with the fifth quintile). Subjects in the fifth quintile of free T 4 did not have an increased QTc interval (3 . 2 ms (95% CI K1 . 1, 7 . 6)); stratification on gender showed an increment of 10 . 9 ms (95% CI 3 . 4, 18 . 3) in the fifth quintile in men and 1 . 1 ms (95% CI K4 . 2, 6 . 3) in the fifth quintile of free T 4 in women. When compared with subjects in the first quintile, male subjects in the fifth quintile of free T 4 had a significantly increased risk of a borderline QTc interval and QTc prolongation (odds ratio 2 . 40 (95% CI 1 . 20, 4 . 80)). High levels of free T 4 are associated with substantial QTc prolongation in men of up to 10 ms. The fact that free T 4 is also associated with a significantly increased risk of borderline and prolonged QTc values with its risk of sudden cardiac death, endorses the clinical importance of our findings.

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Section: Discussionmentioning

confidence: 99%

High free thyroxine levels are associated with QTc prolongation in males

Noord¹,

Deure²,

Sturkenboom³

et al. 2008

Journal of Endocrinology

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“…We therefore examined acute effects of testosterone on APD and membrane currents using patch-clamped guinea pig ventricular myocytes. 61) Testosterone rapidly shortened action potential duration (APD) with an EC 50 of ca. 5 nM that is within physiological testosterone levels in men.…”

Section: Non-genomic Regulation Of Cardiac Ion Channels By Sex Steroimentioning

confidence: 99%

“…Produced NO inhibits I Ca,L in a cGMP-dependent manner and enhances I Ks in a cGMP-independent manner, and thus APD is shortened. 61) mones was discussed. The regulation may have a major impact on sex-related difference in QT intervals and susceptibility to drug-induced arrhythmias.…”

Section: Closing Remarksmentioning

confidence: 99%

Compartmentalized Regulations of Ion Channels in the Heart

Kurokawa

2007

Biological & Pharmaceutical Bulletin

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The rate and force of contraction of the heart are precisely controlled by compartmentalized regulation of cardiac ion channels which determine electrical activities. It is known that modulation of cardiac ion channels, which is caused by drug administration, sympathetic nervous system stimulation and gender difference, can increase risks of lethal arrhythmias in carriers of inherited disease mutations. These modulations are thought to also be involved in common cardiac arrhythmias. Because many signaling molecules are localized within single cells, an understanding of the molecular basis of compartmentalized regulation of cardiac channels is a key for understanding and treating the lethal arrhythmias. In this review, I will discuss molecular mechanisms of compartmentalized regulation of cardiac ion channels via drugs, cAMP and sex hormones.

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“…The female hormone progesterone (P4) activates the principal calcium channel of sperm (CatSper) (2)(3)(4)(5) and blocks the potassium channel KSper (6) via these nongenomic pathways (7). The modulation of ion channel functions by steroid hormones has been reported in the heart (8,9), neurons (10)(11)(12), smooth muscle (13), and pancreatic beta cells (14). In marine invertebrates, the sulfated steroid cholestane acts as a chemoattractant for sea squirt sperm, which also happens via the nongenomic pathway (15).…”

mentioning

confidence: 99%

Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids

Mannowetz

Miller

Lishko

2017

Proc. Natl. Acad. Sci. U.S.A.

106

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The calcium channel of sperm (CatSper) is essential for sperm hyperactivated motility and fertility. The steroid hormone progesterone activates CatSper of human sperm via binding to the serine hydrolase ABHD2. However, steroid specificity of ABHD2 has not been evaluated. Here, we explored whether steroid hormones to which human spermatozoa are exposed in the male and female genital tract influence CatSper activation via modulation of ABHD2. The results show that testosterone, estrogen, and hydrocortisone did not alter basal CatSper currents, whereas the neurosteroid pregnenolone sulfate exerted similar effects as progesterone, likely binding to the same site. However, physiological concentrations of testosterone and hydrocortisone inhibited CatSper activation by progesterone. Additionally, testosterone antagonized the effect of pregnenolone sulfate. We have also explored whether steroid-like molecules, such as the plant triterpenoids pristimerin and lupeol, affect sperm fertility. Interestingly, both compounds competed with progesterone and pregnenolone sulfate and significantly reduced CatSper activation by either steroid. Furthermore, pristimerin and lupeol considerably diminished hyperactivation of capacitated spermatozoa. These results indicate that (i) pregnenolone sulfate together with progesterone are the main steroids that activate CatSper and (ii) pristimerin and lupeol can act as contraceptive compounds by averting sperm hyperactivation, thus preventing fertilization.CatSper | steroids | lupeol | triterpenoids | pristimerin S teroid hormones control fundamental organism functions such as development, metabolism, inflammation, ion homeostasis, and reproduction. According to the conventional model, steroid hormones signal through a corresponding genomic receptor, which upon binding to a steroid hormone initiates the translocation of the hormone-receptor complex to the nucleus. There it acts as a transcription factor by altering gene expression, and such a process can take hours (1). However, there is another, much faster pathway that is initiated by steroid hormone binding to its membrane receptor on the extracellular side of the cell. The latter signaling involves second messengers and signal-transduction cascades, which often result in the activation of ion channels (1). The female hormone progesterone (P4) activates the principal calcium channel of sperm (CatSper) (2-5) and blocks the potassium channel KSper (6) via these nongenomic pathways (7). The modulation of ion channel functions by steroid hormones has been reported in the heart (8, 9), neurons (10-12), smooth muscle (13), and pancreatic beta cells (14). In marine invertebrates, the sulfated steroid cholestane acts as a chemoattractant for sea squirt sperm, which also happens via the nongenomic pathway (15). The latter represents an unconventional chemoattractant for ascidian sperm, as such factors are usually proteins or peptides and not steroids. In humans, pregnenolone sulfate (PregS), a sulfated steroid hormone similar in structure to P4, i...

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Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone

Cited by 226 publications

References 47 publications

High free thyroxine levels are associated with QTc prolongation in males

High free thyroxine levels are associated with QTc prolongation in males

Compartmentalized Regulations of Ion Channels in the Heart

Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids

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