Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats

Borgo, Mariana Veronez; Claudio, Erick Roberto Gonçalves; Silva, F.B.; Romero, Walckiria Garcia; Gouvêa, Sônia Alves; Moysés, Margareth Ribeiro; Santos, Roger Lyrio dos; Almeida, Simone Alves de; Podratz, Priscila L.; Graceli, Jones Bernardes; Abreu, Gláucia Rodrigues de

doi:10.1590/1414-431x20154655

Cited by 21 publications

(20 citation statements)

References 39 publications

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“…Another suggestion is that the beneficial effects from the treatment are probably dependent on circulating estrogen levels in the blood, since we observed that animals with normal estrogen levels (Sham) showed the benefits generated by the treatment. In view of this hypothesis, we suggest that the castration may have caused a reduction in the beneficial effects of estrogen, perhaps by reduction of its receptors in coronary arteries of the hypertensive rats, as previously showed (Borgo et al, 2016). …”

Section: Discussionsupporting

confidence: 73%

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

et al. 2017

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Decline in estrogen levels promotes endothelial dysfunction and, consequently, the most prevalent cardiovascular diseases in menopausal women. The use of natural therapies such as pomegranate can change these results. Pomegranate [Punica granatum L. (Punicaceae)] is widely used as a phytotherapeutic agent worldwide, including in Brazil. We hypothesized that treatment with pomegranate hydroalcoholic extract (PHE) would improve coronary vascular reactivity and cardiovascular parameters. At the beginning of treatment, spontaneously hypertensive female rats were divided into Sham and ovariectomized (OVX) groups, which received pomegranate extract (PHE) (250 mg/kg) or filtered water (V) for 30 days by gavage. Systolic blood pressure was measured by tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed by Langendorff retrograde perfusion technique. A dose-response curve for bradykinin was performed, followed by L-NAME inhibition. The protein expression of p-eNOS Ser1177, p-eNOS Thr495, total eNOS, p-AKT Ser473, total AKT, SOD-2, and catalase was quantified by Western blotting. The detection of coronary superoxide was performed using the protocol of dihydroethidium (DHE) staining Plasma nitrite measurement was analyzed by Griess method. Systolic blood pressure increased in both Sham-V and OVX-V groups, whereas it was reduced after treatment in Sham-PHE and OVX-PHE groups. The baseline coronary perfusion pressure was reduced in the Sham-PHE group. The relaxation was significantly higher in the treated group, and L-NAME attenuated the relaxation in all groups. The treatment has not changed p-eNOS (Ser1177), total eNOS, p-AKT (Ser473) and total AKT in any groups. However, in Sham and OVX group the treatment reduced the p-eNOS (Thr495) and SOD-2. The ovariectomy promoted an increasing in the superoxide anion levels and the treatment was able to prevent this elevation and reducing oxidative stress. Moreover, the treatment prevented the decreasing in plasmatic nitrite. We observed a reduction in total cholesterol and LDL in the Sham-PHE group. The treatment with PHE enhances the endothelium-dependent coronary relaxation and improves cardiovascular parameters, which suggests a therapeutic role of PHE.

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Section: Discussionsupporting

confidence: 73%

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

et al. 2017

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“…Moreover, adult female rats exhibited higher eNOS activity and/or expression than males. These data suggest a higher protected status in adult females and are consistent with other studies showing that treatment with estradiol and progesterone increases eNOS-derived NO production both in isolated endothelial cells and in vascular tissue [61,62]. The protective effect of estrogens and progesterone is absent in 6-day-old rats since their gonads are not fully mature and the levels of these hormones are much lower compared with adults.…”

Section: Discussionsupporting

confidence: 91%

Developmental programming of vascular dysfunction by prenatal and postnatal zinc deficiency in male and female rats

Abregú

Gobetto

Juriol

et al. 2018

The Journal of Nutritional Biochemistry

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Micronutrient malnutrition during intrauterine and postnatal growth may program cardiovascular diseases in adulthood. We examined whether moderate zinc restriction in male and female rats throughout fetal life, lactation and/or postweaning growth induces alterations that can predispose to the onset of vascular dysfunction in adulthood. Female Wistar rats were fed low- or control zinc diets from pregnancy to offspring weaning. After weaning, offspring were fed either a low- or a control zinc diet until 81 days. We evaluated systolic blood pressure (SBP), thoracic aorta morphology, nitric oxide (NO) system and vascular reactivity in 6- and/or 81-day-old offspring. At day 6, zinc-deficient male and female offspring showed a decrease in aortic NO synthase (NOS) activity accompanied by an increase in oxidative stress. Zinc-deficient 81-day-old male rats exhibited an increase in collagen deposition in tunica media, as well as lower activity of endothelial NOS (eNOS) that could not be reversed with an adequate zinc diet during postweaning life. Zinc deficiency programmed a reduction in eNOS protein expression and higher SBP only in males. Adult zinc-deficient rats of both sexes showed reduced vasodilator response dependent on eNOS activity and impaired aortic vasoconstrictor response to angiotensin-II associated with alterations in intracellular calcium mobilization. Female rats were less sensitive to the effects of zinc deficiency and exhibited higher eNOS activity and/or expression than males, without alterations in SBP or aortic histology. This work strengthens the importance of a balanced intake of micronutrients during perinatal growth to ensure adequate vascular function in adult life.

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“…Premenopausal women undergo fluctuations in E2 and P4 during the menstrual cycle [ 38 , 40 ]. Exogenous administration of E2 and P4 has demonstrated to provide cytoprotection against several different acute and chronic myocardial stressors [ 17 , 22 , 26 , 27 , 44 , 45 ]. The role of endogenous hormones providing cytoprotection against DOX-induced myocardial dysfunction is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…This indicates that heightened endogenous E2 levels did not partly suppress DOX-induced cardiotoxicity in SHRs. SHRs are known to already possess cardiac damage prior to DOX treatment [ 27 , 42 , 46 ]; therefore, a non-hypertensive rat model should be used for further investigations. Collectively, our study provides the first evidence that DOX treatment during a specific estrous stage can influence the extent of DOX-induced cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of E2 to suppress DOX-induced cardiotoxicity in the presence of hypertension is unknown. In the absence of DOX, SHR-administered E2 did suppress endothelium-dependent coronary vascular dysfunction induced by oxidative damage [ 27 ]. This supports that SHR-administered E2 may suppress DOX-induced cardiotoxicity, but further investigation was required.…”

Section: Introductionmentioning

confidence: 99%

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Doxorubicin-induced cardiotoxicity is suppressed by estrous-staged treatment and exogenous 17β-estradiol in female tumor-bearing spontaneously hypertensive rats

et al. 2018

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BackgroundDoxorubicin (DOX), an anthracycline therapeutic, is widely used to treat a variety of cancer types and known to induce cardiomyopathy in a time and dose-dependent manner. Postmenopausal and hypertensive females are two high-risk groups for developing adverse effects following DOX treatment. This may suggest that endogenous reproductive hormones can in part suppress DOX-induced cardiotoxicity. Here, we investigated if the endogenous fluctuations in 17β-estradiol (E2) and progesterone (P4) can in part suppress DOX-induced cardiomyopathy in SST-2 tumor-bearing spontaneously hypersensitive rats (SHRs) and evaluate if exogenous administration of E2 and P4 can suppress DOX-induced cardiotoxicity in tumor-bearing ovariectomized SHRs (ovaSHRs).MethodsVaginal cytology was performed on all animals to identify the stage of the estrous cycle. Estrous-staged SHRs received a single injection of saline, DOX, dexrazoxane (DRZ), or DOX combined with DRZ. OvaSHRs were implanted with time-releasing pellets that contained a carrier matrix (control), E2, P4, Tamoxifen (Tam), and combinations of E2 with P4 and Tam. Hormone pellet-implanted ovaSHRs received a single injection of saline or DOX. Cardiac troponin I (cTnI), E2, and P4 serum concentrations were measured before and after treatment in all animals. Cardiac damage and function were further assessed by echocardiography and histopathology. Weight, tumor size, and uterine width were measured for all animals.ResultsIn SHRs, estrous-staged DOX treatment altered acute estrous cycling that ultimately resulted in prolonged diestrus. Twelve days after DOX administration, all SHRs had comparable endogenous circulating E2. Thirteen days after DOX treatment, SHRs treated during proestrus had decreased cardiac output and increased cTnI as compared to animals treated during estrus and diestrus. DOX-induced tumor reduction was not affected by estrous-staged treatments. In ovaSHRs, exogenous administration of E2 suppressed DOX-induced cardiotoxicity, while P4-implanted ovaSHRs were partly resistant. However, ovaSHRs treated with E2 and P4 did not have cardioprotection against DOX-induced damage.ConclusionsThis study demonstrates that estrous-staged treatments can alter the extent of cardiac damage caused by DOX in female SHRs. The study also supports that exogenous E2 can suppress DOX-induced myocardial damage in ovaSHRs.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0183-9) contains supplementary material, which is available to authorized users.

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Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats

Cited by 21 publications

References 39 publications

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

Pomegranate Extract Enhances Endothelium-Dependent Coronary Relaxation in Isolated Perfused Hearts from Spontaneously Hypertensive Ovariectomized Rats

Developmental programming of vascular dysfunction by prenatal and postnatal zinc deficiency in male and female rats

Doxorubicin-induced cardiotoxicity is suppressed by estrous-staged treatment and exogenous 17β-estradiol in female tumor-bearing spontaneously hypertensive rats

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