Potent inhibition by tamoxifen of spontaneous and agonist-induced contractions of the human myometrium and intramyometrial arteries

Kostrzewska, Anna; Laudański, T; Batra, Satish

doi:10.1016/s0002-9378(97)70503-9

Cited by 24 publications

(16 citation statements)

References 18 publications

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“…Tx relaxes myometrial arteries and increases uterine blood flow (28). Tx inhibits spontaneous and agonist-induced myometrial contractions (29) and hyperpolarizes and relaxes cerebral arteries (30). These effects are consistent with the action of Tx on BK channels.…”

Section: Figsupporting

confidence: 61%

“…These effects are consistent with the action of Tx on BK channels. High extracellular K ϩ , which limits the degree to which openings of BK channels can hyperpolarize smooth muscle, abrogates the relaxing effect of Tx on myometrium (29). BK channels comprise one element of a negative feedback loop controlling the tone of cerebral arteries.…”

Section: Figmentioning

confidence: 99%

“…Specifically, release of Ca 2ϩ from the sarcoplasmic reticulum and subsequent activation of BK channels relaxes cerebral arteries (31). It is likely that the hyperpolarization of cerebral arteries (30) and relaxation of myometrium and myometrial arteries (28,29) by Tx is due, in part, to the activation of BK channels. BK channel activation would drive membrane potential toward E K , reducing the P o of L-type Ca 2ϩ channels independent of (and in addition to) possible direct inhibitory effects on voltage-gated Ca 2ϩ entry.…”

Section: Figmentioning

confidence: 99%

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Tamoxifen Activates Smooth Muscle BK Channels through the Regulatory β1 Subunit

Dick¹,

Rossow²,

Smirnov³

et al. 2001

Journal of Biological Chemistry

126

112

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Estrogens and xenoestrogens have non-genomic effects mediated by plasma membrane receptors unrelated to the nuclear estrogen receptor (1). One of these is to increase the NP o of BK 1 channels (2), Ca 2ϩ -sensitive members of the voltage-gated K ϩ channel superfamily with important functions in many cells (3). BK channels are composed of ␣ and ␤ subunits. The ␣ subunit forms the K ϩ -selective pore, while ␤ subunits influence the pharmacology, kinetics, and voltage/Ca 2ϩ -sensitivity of BK channels. The ␤1 subunit of smooth muscle BK channels is physiologically important because knockout mice lacking this subunit are hypertensive and demonstrate altered vascular reactivity (4, 5). Recent studies suggest that BK channels are potential targets for 17␤E and xenoestrogens. BK channel NP o is increased by 17␤E, an effect that requires the regulatory ␤1 subunit (2). 17␤E and xenoestrogens reduce coronary vascular tone by inhibiting L-type Ca 2ϩ channels and activating BK channels (6). The pharmacological nature of the putative 17␤E-binding site on the smooth muscle BK ␤1 subunit is unknown. The xenoestrogen Tx, a commonly used chemotherapeutic agent, is an antagonist of the nuclear estrogen receptor (7). It is not known, however, if this clinically important drug increases BK channel NP o . We investigated whether Tx increases BK channel NP o in smooth muscle cells and whether the ␤1 subunit is important for this effect. These findings give insight into BK channel structure and function, non-genomic regulation by xenoestrogens, and Tx-induced side effects. MATERIALS AND METHODSCell Isolation and Preparation-Smooth muscle cells were isolated by enzymatic dispersion described previously (8). Dogs were anesthetized with ketamine, and the colon was removed via a midline incision. Mice were anesthetized with chloroform and killed by cervical dislocation. Human tissue samples were obtained from consenting patients undergoing gastric bypass for the treatment of morbid obesity. Circular muscle of the canine colon and human jejunum was dissected free of mucosa, submucosa, and longitudinal muscle in Ca 2ϩ -free Hanks solution. Strips of muscle were treated with collagenase (345 units/ml; Worthington Biochemical Corp.; Freehold, NJ) in Ca 2ϩ -free Hanks at 37°C to produce suspensions of single cells by gentle stirring. Mouse colon (circular and longitudinal muscle layers) was dissected free of mucosa prior to enzymatic dispersion. Mouse aorta and canine mesenteric vein were enzymatically digested without further dissection.HEK293 cells (ATCC cell line number CRL-1573; Manassas, VA) were grown in glutamax-supplemented RPMI medium (Life Technologies, Inc., Manassas, VA) with 10% heat-inactivated horse serum (Summit Biotechnology; Fort Collins, CO) in a humidified atmosphere with 5% CO 2 at 37°C. cDNA encoding the ␣ and ␤1 subunits from canine colonic smooth was cloned into the pZEOSV mammalian expression vector (Invitrogen; Carlsbad, CA) as described previously (9). Cells were transiently transfected via electroporation with a tot...

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Section: Figsupporting

confidence: 61%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Tamoxifen Activates Smooth Muscle BK Channels through the Regulatory β1 Subunit

Dick¹,

Rossow²,

Smirnov³

et al. 2001

Journal of Biological Chemistry

126

112

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“…Tamoxifen is able to antagonize the action of calmodulin, protein kinase C, and compete for membrane-binding sites for neurotransmitter substances (Lam 1984, Kroeger & Brandes 1985, Horgan et al 1986, Batra 1990. Myometrial strips from non-pregnant human myometrium showed a marked inhibition of spontaneous and vasopressin-induced contractions when tamoxifen was added to the bathing solution (Kostrzewska et al 1997). This spasmolytic activity on smooth muscle was also demonstrated in the rat myometrium, where tamoxifen antagonized the contractions induced by exogenous calcium (Lipton & Morris 1986).…”

Section: Controlmentioning

confidence: 99%

The effects of tamoxifen and estradiol on myometrial differentiation and organization during early uterine development in the CD1 mouse

Mehasseb

Bell²,

Habiba³

2009

Reproduction

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We used a neonatal mouse model to examine the histogenesis of uterine adenomyosis, and to test whether adenomyosis is due to an abnormality in myometrial differentiation, or in extracellular matrix proteins expression. We also studied the effects of tamoxifen and estradiol on uterine development, myometrial differentiation, and organization. Female CD1 pups were treated with oral tamoxifen (1 mg/kg) (nZ27) or estradiol (0.1 mg/kg) (nZ24) from age 1 to 5 days. Uteri from control (nZ27) and treated mice were obtained on days 2, 5, 10, 15, and 42 of age. We examined the sections histologically, using image analysis and immunohistochemistry for a-smooth muscle actin (a-SMA), desmin, vimentin, laminin, fibronectin, and estrogen receptor-a. Following tamoxifen exposure, all uteri showed adenomyosis by 6 weeks of age (seen as early as day 10). The inner myometrium showed thinning, lack of continuity, disorganization, and bundling. a-SMA expression was normal. Desmin expression normally showed a wave of maturation that was absent in tamoxifen-treated mice. In the estradiol group, adenomyosis was not observed. All uterine layers were normally developed, but hypertrophied. The inner myometrium retained its circular arrangement. There was no difference in the localization of laminin or fibronectin between groups (laminin expression was reduced in the tamoxifen treated uteri). Vimentin could not be detected in all groups. Our results suggest that the development of the inner myometrium is particularly sensitive to estrogen antagonism, and can be affected by steroid receptors modulation. Disruption of the inner myometrium may play a role in the development of uterine adenomyosis.

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“…Tamoxifen relaxes myometrial arteries (Marshall and Senior, 1987), increases uterine blood flow (Marshall and Senior, 1987), and hyperpolarizes and relaxes cerebral arteries (Nelson et al, 1997). Elevated extracellular K ϩ , which limits the degree to which openings of BK channels can hyperpolarize smooth muscle, inhibits the relaxing effect of tamoxifen on myometrial smooth muscle (Kostrzewska et al, 1997). However, it is important to realize that tamoxifen also affects other ion channels, including volume-sensitive Cl Ϫ , L-type Ca 2ϩ , and delayed rectifier K ϩ currents in canine colonic smooth muscle (Dick et al, 1999).…”

Section: Extracellular Tamoxifen Activates Potassium Channels 1111mentioning

confidence: 99%

Ethylbromide Tamoxifen, a Membrane-Impermeant Antiestrogen, Activates Smooth Muscle Calcium-Activated Large-Conductance Potassium Channels from the Extracellular Side

2002

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Smooth-muscle calcium-activated large-conductance potassium channels (BK channels) are activated by tamoxifen and 17-␤-estradiol. This increase in NP o , the number of channels, N, multiplied by open probability, depends on the presence of the regulatory ␤1-subunit. Furthermore, a previous study indicated that 17-␤-estradiol might bind an extracellular site on the ␤1-subunit. Because tamoxifen and 17-␤-estradiol may share a common binding site, we hypothesized that tamoxifen activates BK channels through a site on the extracellular surface of the membrane. A membrane-impermeant analog of tamoxifen, ethylbromide tamoxifen, was synthesized and used to test this hypothesis in whole-cell, outside-out, cell-attached, and inside-out patches from canine colonic smooth muscle cells. Ethylbromide tamoxifen is positively charged and is therefore membrane-impermeant. In whole-cell experiments, ethylbromide tamoxifen increased K ϩ current at potentials positive to ϩ40 mV, which has previously been attributed to BK channels. Unlike tamoxifen, ethylbromide tamoxifen did not inhibit delayed rectifier current. In outside-out patches, ethylbromide tamoxifen increased BK channel NP o with an EC 50 value of 1 M. Ethylbromide tamoxifen did not increase BK channel NP o in cell-attached or inside-out patches; however, subsequent addition of equimolar tamoxifen did. Both drugs diminished BK channel unitary conductance to a degree that paralleled the effect on NP o , suggesting an additional interaction with the pore-forming ␣-subunit. An interaction of tamoxifen with the pore was supported by a right shift in the concentration-response curve for tetraethylammonium; similar results were evident with iberiotoxin and charybdotoxin block. Our data suggest that ethylbromide tamoxifen does not easily traverse the plasma membrane and that tamoxifen binding responsible for activation of BK channels is at an extracellular site. The tamoxifen binding site may be within the extracellular loop of the BK channel ␤1-subunit or, alternatively, on an as-yet-unidentified mediator that has an extracellular binding site.

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Potent inhibition by tamoxifen of spontaneous and agonist-induced contractions of the human myometrium and intramyometrial arteries

Cited by 24 publications

References 18 publications

Tamoxifen Activates Smooth Muscle BK Channels through the Regulatory β1 Subunit

Tamoxifen Activates Smooth Muscle BK Channels through the Regulatory β1 Subunit

The effects of tamoxifen and estradiol on myometrial differentiation and organization during early uterine development in the CD1 mouse

Ethylbromide Tamoxifen, a Membrane-Impermeant Antiestrogen, Activates Smooth Muscle Calcium-Activated Large-Conductance Potassium Channels from the Extracellular Side

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