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Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L-type calcium current.
Br J Pharmacol. 2004 May; 142(1):89-96.BJ

Abstract

1. The selective oestrogen (ER) receptor modulator, raloxifene, is widely used in the treatment of postmenopausal osteoporosis, but may also possess cardioprotective properties. We investigated whether it directly suppresses myocyte contractility through Ca(2+) channel antagonism in a similar way to 17beta-oestradiol. 2. Cell shortening and Ca(2+) transients were measured in single guinea-pig ventricular myocytes field-stimulated (1 Hz, 37 degrees C) in a superfusion chamber. Electrophysiological recordings were performed using single electrode voltage-clamp. 3. Raloxifene decreased cell shortening (EC(50) 2.4 microm) and the Ca(2+) transient amplitude (EC(50) 6.4 microm) in a concentration-dependent manner. At a concentration of 1 microm, raloxifene produced a 33+/-2% (mean+/-s.e.m) and 24+/-2% reduction, respectively (P<0.001, n=14 for both parameters). 4. These inhibitory actions were not observed in myocytes that had been incubated with the specific antagonist, ICI 182,780 (10 microm) (n=11). 5. Raloxifene (1 microm) shortened action potential durations at 50 and 90% repolarisation (P<0.05 and <0.001, respectively; n=27) and decreased peak L-type Ca(2+) current by 45%, from -5.1+/-0.5 pA/pF to -2.8+/-0.3 pA/pF (P<0.001, n=18). 6. Raloxifene did not significantly alter sarcoplasmic reticulum Ca(2+) content, as assessed by integrating the Na(+)/Ca(2+) exchanger currents following rapid caffeine application. 7. The present study provides evidence for direct inhibitory actions of raloxifene on ventricular myocyte contractility, mediated through Ca(2+) channel antagonism.

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Authors+Show Affiliations

Liew R
Cardiac Medicine, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, SW3 6LY.
Stagg MA
No affiliation info available
MacLeod KT
No affiliation info available
Collins P
No affiliation info available

MeSH

AnimalsCalcium Channel BlockersCalcium Channels, L-TypeCell SizeDose-Response Relationship, DrugGuinea PigsHeart VentriclesMaleMembrane PotentialsMyocardial ContractionMyocytes, CardiacRaloxifene HydrochlorideVentricular Function

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15023859

Citation

Liew, Reginald, et al. "Raloxifene Acutely Suppresses Ventricular Myocyte Contractility Through Inhibition of the L-type Calcium Current." British Journal of Pharmacology, vol. 142, no. 1, 2004, pp. 89-96.
Liew R, Stagg MA, MacLeod KT, et al. Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L-type calcium current. Br J Pharmacol. 2004;142(1):89-96.
Liew, R., Stagg, M. A., MacLeod, K. T., & Collins, P. (2004). Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L-type calcium current. British Journal of Pharmacology, 142(1), 89-96.
Liew R, et al. Raloxifene Acutely Suppresses Ventricular Myocyte Contractility Through Inhibition of the L-type Calcium Current. Br J Pharmacol. 2004;142(1):89-96. PubMed PMID: 15023859.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L-type calcium current. AU - Liew,Reginald, AU - Stagg,Mark A, AU - MacLeod,Kenneth T, AU - Collins,Peter, Y1 - 2004/03/15/ PY - 2004/3/17/pubmed PY - 2004/12/16/medline PY - 2004/3/17/entrez SP - 89 EP - 96 JF - British journal of pharmacology JO - Br J Pharmacol VL - 142 IS - 1 N2 - 1. The selective oestrogen (ER) receptor modulator, raloxifene, is widely used in the treatment of postmenopausal osteoporosis, but may also possess cardioprotective properties. We investigated whether it directly suppresses myocyte contractility through Ca(2+) channel antagonism in a similar way to 17beta-oestradiol. 2. Cell shortening and Ca(2+) transients were measured in single guinea-pig ventricular myocytes field-stimulated (1 Hz, 37 degrees C) in a superfusion chamber. Electrophysiological recordings were performed using single electrode voltage-clamp. 3. Raloxifene decreased cell shortening (EC(50) 2.4 microm) and the Ca(2+) transient amplitude (EC(50) 6.4 microm) in a concentration-dependent manner. At a concentration of 1 microm, raloxifene produced a 33+/-2% (mean+/-s.e.m) and 24+/-2% reduction, respectively (P<0.001, n=14 for both parameters). 4. These inhibitory actions were not observed in myocytes that had been incubated with the specific antagonist, ICI 182,780 (10 microm) (n=11). 5. Raloxifene (1 microm) shortened action potential durations at 50 and 90% repolarisation (P<0.05 and <0.001, respectively; n=27) and decreased peak L-type Ca(2+) current by 45%, from -5.1+/-0.5 pA/pF to -2.8+/-0.3 pA/pF (P<0.001, n=18). 6. Raloxifene did not significantly alter sarcoplasmic reticulum Ca(2+) content, as assessed by integrating the Na(+)/Ca(2+) exchanger currents following rapid caffeine application. 7. The present study provides evidence for direct inhibitory actions of raloxifene on ventricular myocyte contractility, mediated through Ca(2+) channel antagonism. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/15023859/Raloxifene_acutely_suppresses_ventricular_myocyte_contractility_through_inhibition_of_the_L_type_calcium_current_ DB - PRIME DP - Unbound Medicine ER -