Raloxifene Acutely Relaxes Rabbit Coronary Arteries In Vitro by an Estrogen Receptor–Dependent and Nitric Oxide–Dependent Mechanism

Figtree, Gemma A.; Lu, Yumao; Webb, Carolyn; Collins, Peter

doi:10.1161/01.cir.100.10.1095

Cited by 127 publications

(103 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In previous studies, either raloxifene or idoxifene was shown to cause vasorelaxation, mainly in a nitric oxide-dependent manner. 27,28 These differences between our data and other studies may be because of the differences of SERMs, target tissues, or animals.…”

Section: Discussioncontrasting

confidence: 88%

Raloxifene Prevents Cardiac Hypertrophy and Dysfunction in Pressure-Overloaded Mice

Ogita

Node²,

Liao³

et al. 2004

Hypertension

View full text Add to dashboard Cite

Abstract-17␤-Estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [ 3 H]leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein (MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [3 H]leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N G -nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent. Key Words: echocardiography Ⅲ heart failure Ⅲ hormones Ⅲ hypertrophy Ⅲ signal transduction T he incidence of left ventricular hypertrophy caused by essential hypertension is one of the major causes of impaired cardiac function followed by heart failure. 1,2 Although the increase in left ventricular mass may represent adaptation of the heart in response to pressure overload, left ventricular hypertrophy is associated with an increased risk of cardiovascular complications and mortality/morbidity. 2-5 Reduction or prevention of left ventricular hypertrophy by treatment with appropriate antihypertensive drugs reduces the risk of cardiovascular diseases or death. 6,7 In postmenopausal women, left ventricular hypertrophy is common and is likely to be a strong cardiovascular risk factor compared with men, suggesting that estrogen has potential protective effects in the cardiovascular system. 2 In fact, hormone replacement therapy in hypertensive postmenopausal women contributes to reducing left ventricular mass, improving cardiac function, and decreasing future cardiovascular events. 8 -10 However, the applicati...

show abstract

Section: Discussioncontrasting

confidence: 88%

Raloxifene Prevents Cardiac Hypertrophy and Dysfunction in Pressure-Overloaded Mice

Ogita

Node²,

Liao³

et al. 2004

Hypertension

View full text Add to dashboard Cite

show abstract

“…30,31 Third, raloxifene acutely dilates rabbit coronary arteries via NO-and calcium influx-dependent pathways and increases uterine and coronary blood flow in ovariectomized ewes. 14,32 However, it has not yet been elucidated whether long-term treatment with raloxifene leads to reduced blood pressure and improved vascular function in hypertensive males. The presented data provide evidence that raloxifene treatment exerts vasoprotection in male SHR.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] Raloxifene, a prominent member of the SERM family, has been shown to acutely improve endothelial function and to induce endothelium-dependent and -independent vasodilatation by NO release and calcium channel blockade in rabbit coronary arteries. 14 However, little is known about the long-term effects of raloxifene on vascular function.…”

mentioning

confidence: 99%

Raloxifene Improves Endothelial Dysfunction in Hypertension by Reduced Oxidative Stress and Enhanced Nitric Oxide Production

Waßmann

Laufs²,

Stamenkovic³

et al. 2002

Circulation

115

View full text Add to dashboard Cite

show abstract

“…Cell shortening and the indo-1 ratio were measured in the continuing presence of 10 mM ICI 182,780 before and after the addition of 1 mM raloxifene. The concentration of ICI 182,780 chosen (10 mM) has previously been shown to be effective in inhibiting the acute relaxing effects of raloxifene on coronary arteries (Figtree et al, 1999).…”

Section: Effects Of Ici 182780mentioning

confidence: 99%

“…Animal studies investigating the effects of raloxifene on atherosclerosis have produced contradictory results (Bjarnason et al, 1997;Clarkson et al, 1998), while studies investigating the direct vascular actions of raloxifene have demonstrated beneficial effects. For example, raloxifene has been shown to exert acute, nongenomic, ER-mediated actions on rabbit coronary arteries and human umbilical vein endothelial cells through rapid activation of nitric oxide synthase (Figtree et al, 1999;Simoncini et al, 2002). In addition, raloxifene improves endothelial dysfunction and reduces blood pressure in spontaneously hypertensive male rats (Wassmann et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L‐type calcium current

Liew

Stagg

MacLeod

et al. 2004

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

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 þ channel antagonism in a similar way to 17b-oestradiol. 2 Cell shortening and Ca 2 þ transients were measured in single guinea-pig ventricular myocytes fieldstimulated (1 Hz, 371C) in a superfusion chamber. Electrophysiological recordings were performed using single electrode voltage-clamp. 3 Raloxifene decreased cell shortening (EC 50 2.4 mM) and the Ca 2 þ transient amplitude (EC 50 6.4 mM) in a concentration-dependent manner. At a concentration of 1 mM, raloxifene produced a 3372% (mean7s.e.m) and 2472% reduction, respectively (Po0.001, n ¼ 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 mM) (n ¼ 11). 5 Raloxifene (1 mM) shortened action potential durations at 50 and 90% repolarisation (Po0.05 and o0.001, respectively; n ¼ 27) and decreased peak L-type Ca 2 þ current by 45%, from À5.170.5 pA/pF to À2.870.3 pA/pF (Po0.001, n ¼ 18). 6 Raloxifene did not significantly alter sarcoplasmic reticulum Ca 2 þ content, as assessed by integrating the Na þ /Ca 2 þ 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 þ channel antagonism.

show abstract

Raloxifene Acutely Relaxes Rabbit Coronary Arteries In Vitro by an Estrogen Receptor–Dependent and Nitric Oxide–Dependent Mechanism

Abstract: These data demonstrate that raloxifene has vascular relaxing properties. The surprising finding is that the receptor-dependent effects via the endothelium are observed in coronary arteries from both male and female animals.

Cited by 127 publications

References 51 publications

Raloxifene Prevents Cardiac Hypertrophy and Dysfunction in Pressure-Overloaded Mice

Raloxifene Prevents Cardiac Hypertrophy and Dysfunction in Pressure-Overloaded Mice

Raloxifene Improves Endothelial Dysfunction in Hypertension by Reduced Oxidative Stress and Enhanced Nitric Oxide Production

Raloxifene acutely suppresses ventricular myocyte contractility through inhibition of the L‐type calcium current

Contact Info

Product

Resources

About