RESUMEN
BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of women's mortality, linked to aging and reduced estrogen during menopause. Estrogen replacement therapy (ERT) is suggested for CVDs prevention. Yet, its timing initiation remains contentious. Thus, we aimed to evaluate the effect of early and late estrogen therapy on cardiac function and lipid metabolism in ovariectomized old female Wistar rats. METHODS: Fifty randomized female Wistar rats were included in 5 groups (n = 10, 18 months old): (1) Sham, (2) 10 weeks post ovariectomy (Ovx-10 w), (3) 10 weeks post Ovx + early estrogen replacement therapy (Ovx 10 w-early ERT), (4) 20 weeks post Ovx (Ovx-20 w) and (5) Ovx 20 w-late ERT. Three days (early ERT) or 10 weeks (late ERT) after surgery 17-ß estradiol was given (5 µg/kg/day), and 10 weeks after the start of ERT, we assessed cardiac function by echocardiography, electrocardiography, and cardiac catheterization. Estradiol, cholesterol, triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels were determined. Cardiac histology was performed with Masson's staining. RESULTS: Ovariectomy (Ovx) increases left ventricle internal systolic diameter (0.4 vs 0.3 cm, *p = 0.020) and decreases shortening fraction (40 vs 54 %, *p = 0.030) regardless of therapy. ERT prevents the increase in left ventricle mass after 10 weeks post-Ovx and the ejection fractionreduction after 20 weeks. Lower P wave amplitudes (18.8 vs 24.2 ms, *p = 0.013) were found in the Ovx-20 w group. A longer duration of the QRS complex after 20 weeks post-Ovx with and without ERT was found (32.5 and 32.1 vs 28.3 ms, *p = 0.003; *p = 0.007). Diastolic blood pressure was higher 20 weeks post-Ovx (86 vs 76 mmHg, *p = 0.047), regardless of ERT. The left ventricle (LV) -dP/dt was decreased in Ovx groups without ERT (-750 vs -1320 mmHg, *p = 0.034). An increase in LV collagen deposition was found in the Ovx 10 w group vs Sham (9.58 vs 4.54 %, *p = 0.028). Early ERT avoids the increase in body weight, cholesterol and LDL caused by Ovx. CONCLUSIONS: Ovariectomy causes time-dependent alterations in lipid metabolism, morphology, electrical activity, and heart contractile function. Early but not late ERT prevents some of these effects.
Asunto(s)
Terapia de Reemplazo de Estrógeno , Cardiopatías , Humanos , Ratas , Animales , Femenino , Lactante , Ratas Wistar , Ovariectomía , Estradiol/farmacología , Envejecimiento , Presión Sanguínea , Estrógenos , ColesterolRESUMEN
Cardiovascular disease incidence increases after menopause due to the loss of estrogen cardioprotective effects. However, there are conflicting data regarding the timing of estrogen therapy (ERT) and its effect on vascular dysfunction associated with impaired glucose metabolism. The aim of this work was to evaluate the effect of early and late ERT on blood glucose/insulin balance and vascular reactivity in aged ovariectomized Wistar rats. Eighteen-month-old female Wistar rats were randomized as follows: (1) sham, (2) 10-week postovariectomy (10 w), (3) 10 w postovariectomy+early estradiol therapy (10 w-early E2), (4) 20-week postovariectomy (20 w), and (5) 20-week postovariectomy+late estradiol therapy (20 w-late E2). Early E2 was administered 3 days after ovariectomy and late therapy after 10 weeks, in both groups. 17ß-Estradiol (E2) was administered daily for 10 weeks (5 µg/kg/day). Concentration-response curves to angiotensin II, KCl, and acetylcholine (ACh) were performed. Heart rate (HR), diastolic and systolic blood pressure (DBP and SBP), glucose, insulin, HOMA-IR, and nitric oxide (NO) levels were determined. Higher glucose levels were found in all groups compared to the sham group, except the 20 w-late E2 group. Insulin was increased in all ovariectomized groups compared to sham. The HOMA-IR index showed insulin resistance in all ovariectomized groups, except for the 10 w-early E2 group. The 10 w-early E2 group increased NO levels vs. the 10 w group. After 10 w postovariectomy, the vascular response to KCl and Ach increases, despite early E2 administration. Early and late E2 treatment decreased vascular reactivity to Ang II. At 20-week postovariectomy, DBP increased, even with E2 administration, while SBP and HR remained unchanged. The effects of E2 therapy on blood glucose/insulin balance and vascular reactivity depend on the timing of therapy. Early ERT may provide some protective effects on insulin resistance and vascular function, whereas late ERT may not have the same benefits.
Asunto(s)
Terapia de Reemplazo de Estrógeno , Resistencia a la Insulina , Ratas , Humanos , Animales , Femenino , Ratas Wistar , Resistencia a la Insulina/fisiología , Glucemia , Estrógenos/farmacología , Estradiol/farmacología , Insulina/metabolismo , Glucosa/metabolismo , Acetilcolina/farmacologíaRESUMEN
Clinical guidelines suggest the combination of 2 drugs as a strategy to treat hypertension. However, some antihypertensive combinations have been shown to be ineffective. Therefore, it is necessary to determine whether differences exist between the results of monotherapy and combination therapy by temporal monitoring of the responses to angiotensin II and norepinephrine, which are vasoconstrictors involved in the development of hypertension. Thus, the purpose of this work was to determine the vascular reactivity to angiotensin II and norepinephrine in spontaneously hypertensive rat (SHR) aortic rings after treatment with valsartan, lisinopril, nebivolol, nebivolol-lisinopril, and nebivolol-valsartan for different periods of time. In this study, male SHR and Wistar Kyoto normotensive (WKY) rats were divided into 7 groups treated for 1, 2, and 4 weeks: (1) WKY + vehicle, (2) SHR + vehicle; (3) SHR + nebivolol; (4) SHR + lisinopril; (5) SHR + valsartan; (6) SHR + nebivolol-lisinopril; and (7) SHR + nebivolol-valsartan. Blood pressure was measured by the tail-cuff method, and vascular reactivity was determined from the concentration-response curve to angiotensin II and norepinephrine in aortic rings. The results showed that the combined and individual treatments reduced mean blood pressure at all times evaluated. All treatments decreased vascular reactivity to angiotensin II; however, in the case of lisinopril and nebivolol-lisinopril, the effect observed was significant up to 2 weeks. All treatments decreased the reactivity to norepinephrine up to week 4. These results show a time-dependent difference in vascular reactivity between the pharmacological treatments, with nebivolol-valsartan and nebivolol-lisinopril being both effective combinations. Additionally, the results suggest crosstalk between the renin-angiotensin and sympathetic nervous systems to reduce blood pressure and to improve treatment efficacy.
Asunto(s)
Angiotensina II/farmacología , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Norepinefrina/farmacología , Vasoconstrictores/farmacología , Animales , Combinación de Medicamentos , Lisinopril/farmacología , Masculino , Nebivolol/farmacología , Ratas Endogámicas SHR , Ratas Wistar , Tiempo , Valsartán/farmacología , Resistencia Vascular/efectos de los fármacosRESUMEN
BACKGROUND: There is some evidence that components of the renin-angiotensin system and kallikrein-kinin system are not similarly regulated in both sexes. The aim of this work was to analyze the expression of angiotensin-converting enzyme, angiotensin-converting enzyme 2, angiotensin 1 receptor, angiotensin 2 receptor, beta-1 receptor, and beta-2 receptor during the evolution of myocardial infarction. METHODS: Thirty-six male and 36 female Wistar rats were used. Myocardial infarction was induced. Six groups of both sexes were formed, (n=6): (a) sham; (b) 48 h myocardial infarction; (c) one week myocardial infarction; (d) two weeks myocardial infarction; (e) three weeks myocardial infarction and (f) four weeks myocardial infarction. The expression was evaluated by real-time polymerase chain reaction on the penumbra of left ventricle. RESULTS: The mRNA expression of most biomarkers was lower in females than in males. During acute infarction, an increase of all protein expression was found in female and at two weeks while in the male only biomarker changes occurred at three weeks. In addition, in male biomarkers mRNA expression decreased during chronic infarction while in females it did not. CONCLUSIONS: The renin-angiotensin system and kallikrein-kinin system biomarkers expression occurs at earlier times in the female than in the male rat. In addition, during chronic myocardial infarction these biomarkers remained unchanged in females while in males they decreased.
Asunto(s)
Sistema Calicreína-Quinina/genética , Infarto del Miocardio/fisiopatología , Sistema Renina-Angiotensina/genética , Enzima Convertidora de Angiotensina 2/biosíntesis , Enzima Convertidora de Angiotensina 2/genética , Animales , Biomarcadores , Peso Corporal , Enfermedad Crónica , Femenino , Regulación de la Expresión Génica , Ventrículos Cardíacos/metabolismo , Masculino , Peptidil-Dipeptidasa A/biosíntesis , Peptidil-Dipeptidasa A/genética , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/biosíntesis , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 2/biosíntesis , Receptor de Angiotensina Tipo 2/genética , Caracteres SexualesRESUMEN
Antihypertensive pharmacological treatments focus on the use of angiotensin-converting enzyme (ACE) inhibitors, AT1 receptor antagonists, and beta-blockers as single and combined treatments. The effect of single treatments on the mRNA expression of some components of the renin-angiotensin system has been studied, but not the effect of combined treatments. This study determined the expression of the AT1, AT2, B1, and B2 receptors and of the enzymes ACE and ACE2 in hypertensive rats treated with captopril-propranolol or losartan-propranolol. Methods: The mRNA expression of the receptors and enzymes was determined by reverse transcription-quantitative polymerase chain reaction in the aorta of spontaneously hypertensive rats under different treatments. Results: Rats under combined treatments showed a decrease in the expression of AT1 and ACE, and an increase in the expression of the B1 receptor (captopril + propranolol group: 0.43 ± 0.046, 2.243 ± 0.269, 3.356 ± 0.418; Group: losartan + propranolol: 0.727 ± 0.071, 0.852 ± 0.102, 1.277 ± 0.131 compared to the spontaneously hypertensive group: 1 ± 0.212, 1 ± 0.192, 1 ± 0.214). This decrease in the expression of ACE and AT1 suggests a reduction in the expression of Ang II that could be related to a lower response to this vasoconstrictor. An increase in the expression of B1 would improve vasodilation, which would be a beneficial effect of combined therapies for hypertension.
Asunto(s)
Antihipertensivos/farmacología , Aorta Torácica/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Sistema Calicreína-Quinina/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Antagonistas Adrenérgicos beta/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatología , Presión Sanguínea/efectos de los fármacos , Captopril/farmacología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Hipertensión/genética , Hipertensión/metabolismo , Hipertensión/fisiopatología , Sistema Calicreína-Quinina/genética , Losartán/farmacología , Masculino , Propranolol/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismo , Receptor de Bradiquinina B1/genética , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/genética , Receptor de Bradiquinina B2/metabolismo , Sistema Renina-Angiotensina/genéticaRESUMEN
In hypertension, the combination therapy is frequently used to obtain a better therapeutic effect and reduce adverse effects. One effective combination is with inhibitors and ß-blockers of renin-angiotensin system. Although the mechanisms of action of each drug are already known, the antihypertensive mechanism is more complex and therefore the combined treatment mechanism is unclear. Specifically, the effect of the treatments of angiotensin-converting enzyme inhibitor or AT1 receptor antagonist with ß-blocker on the angiotensin II and bradykinin reactivity has not been studied. For this reason, we evaluated the interaction between propranolol and captopril or losartan on vascular reactivity to bradykinin and angiotensin II in spontaneously hypertensive rat. We constructed concentration-response curves to angiotensin II and bradykinin after treatment of SHR with propranolol-captopril or propranolol-losartan by using rat aortic rings. While losartan or captopril with propranolol potentiated bradykinin-induced vasodilation effect, the propranolol-losartan interaction decreased the angiotensin II-induced vasoconstriction. In addition, the combinations did not reduce the heart rate significantly. These results suggest that the combined therapy decreased blood pressure to normotensive values and showed less effect for angiotensin II and greater effect for bradykinin than monotherapy which could contribute in the antihypertensive effect.
RESUMEN
We evaluated the antihypertensive properties of 4-tert-buthyl-2,6-bis(thiomorpholine-4-ilmethyl)phenol (TBTIF). Spontaneously hypertensive rats were treated with TBTIF or captopril (both at 1 mg·kg⻹·d⻹ intramuscularly for 4 days), and their blood pressure (BP) was assessed. In some experiments, concentration response curves to angiotensin I or angiotensin II were generated in rat aortic rings and in the absence or presence of Ang-(1-7), N(G)-monomethyl L-arginine, or both; additionally, the angiotensin-converting enzyme (ACE) and ACE2 mRNA levels were quantified in the aortic rings using reverse transcription-polymerase chain reaction. TBTIF diminished BP and reduced angiotensin I- or angiotensin II-induced vasoconstriction. The presence of Ang-(1-7) induced a greater reduction in vasoconstriction, and this effect was reversed by L-N(G)-monomethyl arginine. Moreover, TBTIF decreased the mRNA of ACE and increased the mRNA of ACE2. In conclusion, TBTIF diminished rat BP through nitric oxide-dependent and nitric oxide-independent mechanisms. In contrast to captopril, TBTIF exhibits better antihypertensive properties through mechanisms that involve ACE2.