Inhibitory Effects of the Antiestrogen Agent Clomiphene on Cardiac Sarcolemmal Anionic and Cationic Currents

Borg, John J.; Yuill, Kathryn H.; Hancox, Jules C.; Spencer, Ian; Kozlowski, Roland Z.

doi:10.1124/jpet.102.038901

Cited by 16 publications

(22 citation statements)

References 36 publications

(59 reference statements)

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“…2a). These results are consistent with previous observations that CLM reduced outward current at the end of depolarizing voltage ramps in rat ventricular myocytes 10 …”

Section: Resultssupporting

confidence: 94%

“…There is increasing evidence that triphenylethylene anti‐oestrogens can exert effects independent of the oestrogen receptor 3–7 . For example, triphenylethylene anti‐oestrogens have been shown to modulate plasmalemmal ion channels, including volume‐sensitive chloride channels, 3–5,7–10 and voltage‐gated cation currents 10–14 . Moreover they have been shown to inhibit Ca 2+ uptake by the cardiac sarcoplasmic reticulum (SR), possibly through indirect effects on SR membrane K + or Cl – channels, and to modulate cardiac gap junctions 6,15–17 …”

Section: Introductionmentioning

confidence: 99%

“…However, there is also evidence for important differences in the oestrogen receptor‐independent actions of triphenylethylene anti‐oestrogens on the heart 6,15–17 . In a previous study, we investigated the effects of CLM on cardiac ion currents and demonstrated inhibition of voltage‐gated sodium current (I Na ), L‐type calcium current (I Ca,L ), inward rectifier K + (I K1 ) and net outward K + (I Kv ) currents in rat ventricular myocytes 10 . However, because the currents were elicited using a ramp protocol in that study, it was not possible to determine the nature of the outward K + currents inhibited by CLM 10 …”

Section: Introductionmentioning

confidence: 99%

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Actions of the anti-oestrogen agent clomiphene on outward K+ currents in rat ventricular myocytes

Borg¹,

Hancox

Hogg³

et al. 2004

Clin Exp Pharmacol Physiol

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1. The effects of clomiphene (CLM) on cardiac outward K+ current components from rat isolated ventricular myocytes were investigated using the whole-cell patch-clamp technique. Clomiphene (10 micromol/L) significantly inhibited both peak (Ipeak) and end-pulse (Ilate) outward currents (elicited by a 500 msec voltage step from -40 to +50 mV in the presence of K+-containing intracellular and extracellular solutions) by approximately 37% (n = 6; P < 0.01) and 49% (n = 6; P < 0.01), respectively. In contrast, CLM had no effect on outward currents when K+-free solutions were used. 2. A double-pulse protocol and Boltzmann fitting were used to separate individual K+ current components on the basis of their voltage-dependent inactivation properties. At potentials positive to -80 mV, two inactivating transient outward components (Ito) and (IKx) and a non-inactivating steady state component (Iss) could be distinguished. 3. Clomiphene inhibited both Ito and Iss. The maximal block of Ito and Iss induced by CLM (100 micromol/L) was approximately 61% (n = 5) and 43% (n = 5) with IC50 values of 1.54 +/- 0.39 and 2.2 +/- 0.4 micromol/L, respectively. In contrast, the peak magnitude of IKx was unaltered by CLM, although its time-course of inactivation was accelerated. 4. Further experiments whereby myocytes were superfused with the vasoactive peptide endothelin (ET)-1 (20 nmol/L) revealed that CLM (10 micro mol/L) completely abolished the ET-1-sensitive component of Iss. 5. Our findings demonstrate, for the first time, the effects of CLM on distinct cardiac K+ current components and show that CLM modulates the voltage-gated K+ current components Ito and IKx and inhibits the steady state outward current Iss in rat ventricular myocytes.

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“…2a). These results are consistent with previous observations that CLM reduced outward current at the end of depolarizing voltage ramps in rat ventricular myocytes 10 …”

Section: Resultssupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Actions of the anti-oestrogen agent clomiphene on outward K+ currents in rat ventricular myocytes

Borg¹,

Hancox

Hogg³

et al. 2004

Clin Exp Pharmacol Physiol

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“…Tamoxifen also inhibited VGSC activity in the SHG-44 glioma cell line [13] and in rat cortical neurons [63]. Similar effects of SERMs were seen on rodent hypothalamic neurons [64] and ventricular myocytes [65]. …”

Section: Hormonesmentioning

confidence: 93%

Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation

Fraser

Ozerlat-Gunduz

Brackenbury

et al. 2014

Phil. Trans. R. Soc. B

124

106

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Although ion channels are increasingly being discovered in cancer cells in vitro and in vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression. Here, we focus on voltage-gated Na+ channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play a significant role in the regulation. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative association between genomic steroid hormone sensitivity and functional VGSC expression. Activity-dependent regulation by positive feedback has been demonstrated in strongly metastatic cells whereby the VGSC is self-sustaining, with its activity promoting further functional channel expression. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via negative feedback. Throughout, we highlight the possible clinical implications of functional VGSC expression and regulation in cancer.

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“…Moreover, several animal model studies have reported that tamoxifen induces cataracts 198–200. The mechanism of cataract induction involves the blockage of swelling-activated chloride channels in the lens,201, 202 and it is at least partly independent of the actions of tamoxifen on ERs 203,204. The increased risk of posterior subcapsular cataracts may be as high a factor of 4,169 which is important because posterior subcapsular cataracts tend to impair function more than other types of cataracts 205.…”

Section: Adjuvant Endocrine Therapymentioning

confidence: 99%

Breast Cancer Medications and Vision: Effects of Treatments for Early-stage Disease

Eisner¹,

Luoh²

2011

Current Eye Research

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This review concerns the effects on vision and the eye of medications prescribed at three phases of treatment for women with early-stage breast cancer (BC): (1) adjuvant cytotoxic chemotherapy, (2) adjuvant endocrine therapy, and (3) symptomatic relief. The most common side effects of cytotoxic chemotherapy are epiphora and ocular surface irritation, which can be caused by any of several different regimens. Most notably, the taxane docetaxel can lead to epiphora by inducing canalicular stenosis. The selective-estrogen-receptor-modulator (SERM) tamoxifen, long the gold-standard adjuvant-endocrine-therapy for women with hormone-receptor-positive BC, increases the risk of posterior subcapsular cataract. Tamoxifen also affects the optic nerve head more often than previously thought, apparently by causing subclinical swelling within the first 2 years of use for women older than ∼50 years. Tamoxifen retinopathy is rare, but it can cause foveal cystoid spaces that are revealed with spectral-domain optical coherence tomography (OCT) and that may increase the risk for macular holes. Tamoxifen often alters the perceived color of flashed lights detected via short-wavelength-sensitive (SWS) cone response isolated psychophysically; these altered perceptions may reflect a neural-response sluggishness that becomes evident at ∼2 years of use. The aromatase inhibitor (AI) anastrozole affects perception similarly, but in an age-dependent manner suggesting that the change of estrogen activity towards lower levels is more important than the low estrogen activity itself. Based on analysis of OCT retinal thickness data, it is likely that anastrozole increases the tractional force between the vitreous and retina. Consequently, AI users, myopic AI users particularly, might be at increased risk for traction-related vision loss. Because bisphosphonates are sometimes prescribed to redress AI-induced bone loss, clinicians should be aware of their potential to cause scleritis and uveitis occasionally. We conclude by suggesting some avenues for future research into the visual and ocular effects of AIs, particularly as relates to assessment of cognitive function.

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Inhibitory Effects of the Antiestrogen Agent Clomiphene on Cardiac Sarcolemmal Anionic and Cationic Currents

Cited by 16 publications

References 36 publications

Actions of the anti-oestrogen agent clomiphene on outward K+ currents in rat ventricular myocytes

Actions of the anti-oestrogen agent clomiphene on outward K+ currents in rat ventricular myocytes

Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation

Breast Cancer Medications and Vision: Effects of Treatments for Early-stage Disease

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