Raloxifene lowers ischaemia susceptibility by increasing nitric oxide generation in the heart of ovariectomized rats in vivo.
We studied the effects of a 2-week period of oral raloxifene therapy on the cardiac level of nitric oxide (NO) and on the susceptibility to angina in ovariectomized rats. Ovariectomy decreased the activity of Ca2+-dependent nitric oxide synthase (NOS) in the left ventricle, an effect restored by raloxifene (0.2-5 mg kg(-1) day(-1)) or 17beta-oestradiol (0.3 mg kg(-1) day(-1)). Ovariectomy led to a significant ST segment depression after the injection of (1) ornithine-vasopressin (0.5 IU kg(-1), i.v.) or (2) epinephrine (10 microg kg(-1), i.v.), followed 30 s later by phentolamine (15 mg kg(-1), i.v.); both effects were reversed by raloxifene or 17beta-oestradiol treatment. Inhibition of nitric oxide synthase (with NG-nitro-L-arginine methyl ester [L-NAME]; 5 mg kg(-1), s.c.) augmented the ST segment depression in the ovariectomized rat and abolished the anti-ischaemic effect of 17beta-oestradiol or raloxifene. Thus, an oestrogen deficiency down-regulates the cardiac constitutive nitric oxide synthase, which increases the susceptibility of the heart to ishaemia because both actions can be blocked by exogenous administration of the natural oestrogen 17beta-oestradiol or the selective oestrogen-receptor modulator (SERM) raloxifene. In the present in vivo system, raloxifene exerts oestrogen-agonist properties.
Nemcsik
János
J
Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43, Hungary.
Morschl
Eva
E
Egresits
József
J
Kordás
Krisztina
K
László
Ferenc
F
László
Ferenc A
FA
Pávó
Imre
I
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D017202:Myocardial Ischemia / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009951:Ornipressin / Q000494:pharmacology; D010052:Ovariectomy; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D020845:Selective Estrogen Receptor Modulators; D009951:Ornipressin; D009569:Nitric Oxide; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D019001:Nitric Oxide Synthase; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D004837:Epinephrine