RÉSUMÉ
Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women.
Sujet(s)
Animaux , Femelle , Rats , Androstènes/administration et posologie , Vaisseaux coronaires/effets des médicaments et des substances chimiques , Endothélium vasculaire/effets des médicaments et des substances chimiques , Oestradiol/administration et posologie , Hormonothérapie substitutive/méthodes , Hypertension artérielle/traitement médicamenteux , Vasodilatation/effets des médicaments et des substances chimiques , Technique de Western , Bradykinine/pharmacologie , Association thérapeutique , Vaisseaux coronaires/anatomopathologie , Récepteur alpha des oestrogènes/effets des médicaments et des substances chimiques , Oestrogènes/administration et posologie , Éthidium/analogues et dérivés , Artère fémorale , Hémodynamique , Antagonistes des récepteurs des minéralocorticoïdes/administration et posologie , Nitric oxide synthase type III/effets des médicaments et des substances chimiques , Ovariectomie , Stress oxydatif/effets des médicaments et des substances chimiques , Répartition aléatoire , Rats de lignée SHR , Vasodilatateurs/pharmacologieRÉSUMÉ
Organotin compounds are typical environmental contaminants and suspected endocrine-disrupting substances, which cause irreversible sexual abnormality in female mollusks, called "imposex". However, little is known about the capability of triorganotin compounds, such as tributyltin and triphenyltin, to cause disorders in the sexual development and reproductive functions of mammals, including humans and rodents. Moreover, these compounds can act as potential competitive inhibitors of aromatase enzyme and other steroidogenic enzymes, affecting the reproductive capacity of male and female mammals. In this review, we discuss the cellular, biochemical, and molecular mechanisms by which triorganotin compounds induce adverse effects in the mammalian reproductive function.