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1.
Naunyn Schmiedebergs Arch Pharmacol ; 397(9): 7103-7115, 2024 09.
Artículo en Inglés | MEDLINE | ID: mdl-38643455

RESUMEN

Estrone (E1) constitutes the primary component in oral conjugated equine estrogens (CEEs) and serves as the principal estrogen precursor in the female circulation in the post-menopause. E1 induces endothelium-dependent vasodilation and activate PI3K/NO/cGMP signaling. To assess whether E1 mitigates vascular dysfunction associated with postmenopause and explore the underlying mechanisms, we examined the vascular effects of E1 in ovariectomized (OVX) rats, a postmenopausal experimental model. Blood pressure was measured using tail-cuff plethysmography, and aortic rings were isolated to assess responses to phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Responses to ACh in rings pre-incubated with superoxide dismutase (SOD), catalase (CAT), or apocynin were also evaluated. Protein expression of SOD, CAT, NOX1, NOX2, and NOX4 was determined by Western blotting. E1 treatment resulted in decreased body weight and retroperitoneal fat, increased uterine weight, and prevented elevated blood pressure in the OVX group. Furthermore, E1 improved endothelium-dependent ACh vasodilation, activated compensatory antioxidant mechanisms - i.e. increased SOD and CAT antioxidant enzymes activity, and decreased NOX4 expression. This, in turn, helped prevent oxidative stress and endothelial dysfunction in OVX rats. Additionally, E1 treatment reversed the increased total LDL cholesterol observed in the OVX group. The findings underscore protective effects of E1 on the cardiovascular system, counteracting OVX-related oxidative stress and endothelial dysfunction in Wistar rats. E1 exhibits promising therapeutic benefits for managing cardiovascular health, particularly in postmenopausal conditions.


Asunto(s)
Endotelio Vascular , Estrona , NADPH Oxidasa 4 , Ovariectomía , Ratas Wistar , Especies Reactivas de Oxígeno , Vasodilatación , Animales , Femenino , NADPH Oxidasa 4/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Vasodilatación/efectos de los fármacos , Estrona/farmacología , Presión Sanguínea/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas
2.
PLoS One ; 9(10): e109620, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25279805

RESUMEN

Hypernatremia stimulates the secretion of oxytocin (OT), but the physiological role of OT remains unclear. The present study sought to determine the involvement of OT and renal nerves in the renal responses to an intravenous infusion of hypertonic saline. Male Wistar rats (280-350 g) were anesthetized with sodium thiopental (40 mg. kg(-1), i.v.). A bladder cannula was implanted for collection of urine. Animals were also instrumented for measurement of mean arterial pressure (MAP) and renal blood flow (RBF). Renal vascular conductance (RVC) was calculated as the ratio of RBF by MAP. In anesthetized rats (n = 6), OT infusion (0.03 µg • kg(-1), i.v.) induced renal vasodilation. Consistent with this result, ex vivo experiments demonstrated that OT caused renal artery relaxation. Blockade of OT receptors (OXTR) reduced these responses to OT, indicating a direct effect of this peptide on OXTR on this artery. Hypertonic saline (3 M NaCl, 1.8 ml • kg(-1) b.wt., i.v.) was infused over 60 s. In sham rats (n = 6), hypertonic saline induced renal vasodilation. The OXTR antagonist (AT; atosiban, 40 µg • kg(-1) • h(-1), i.v.; n = 7) and renal denervation (RX) reduced the renal vasodilation induced by hypernatremia. The combination of atosiban and renal denervation (RX+AT; n = 7) completely abolished the renal vasodilation induced by sodium overload. Intact rats excreted 51% of the injected sodium within 90 min. Natriuresis was slightly blunted by atosiban and renal denervation (42% and 39% of load, respectively), whereas atosiban with renal denervation reduced sodium excretion to 16% of the load. These results suggest that OT and renal nerves are involved in renal vasodilation and natriuresis induced by acute plasma hypernatremia.


Asunto(s)
Vías Eferentes , Hipernatremia/fisiopatología , Oxitocina/farmacología , Arteria Renal/patología , Solución Salina Hipertónica/farmacología , Vasodilatación/efectos de los fármacos , Animales , Frecuencia Cardíaca , Masculino , Oxitócicos/farmacología , ARN Mensajero/genética , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Oxitocina/genética , Receptores de Oxitocina/metabolismo , Arteria Renal/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
3.
PLoS One ; 9(8): e106029, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25170617

RESUMEN

It has been clearly established that mitogen-activated protein kinases (MAPKS) are important mediators of angiotensin II (Ang II) signaling via AT1 receptors in the vasculature. However, evidence for a role of these kinases in changes of Ang II-induced vasoconstriction in obesity is still lacking. Here we sought to determine whether vascular MAPKs are differentially activated by Ang II in obese animals. The role of AT2 receptors was also evaluated. Male monosodium glutamate-induced obese (obese) and non-obese Wistar rats (control) were used. The circulating concentrations of Ang I and Ang II, determined by HPLC, were increased in obese rats. Ang II-induced isometric contraction was decreased in endothelium-intact resistance mesenteric arteries from obese compared with control rats and exhibited a retarded AT1 receptor antagonist response. Blocking of AT2 receptors and inhibition of either endothelial nitric oxide synthase (eNOS) or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) restored Ang II-induced contraction in obese rats. Western blot analysis revealed increased protein expression of AT2 receptors in arteries from obese rats. Basal and Ang II-induced ERK1/2 phosphorylation was also increased in obese rats. Blockade of either AT1 or AT2 receptors corrected the increased ERK1/2 phosphorylation in arteries from obese rats to levels observed in control preparations. Phosphorylation of eNOS was increased in obese rats. Incubation with the ERK1/2 inhibitor before Ang II stimulation did not affect eNOS phosphorylation in control rats; however, it corrected the increased phosphorylation of eNOS in obese rats. These results clearly demonstrate that enhanced AT2 receptor and ERK1/2-induced, NO-mediated vasodilation reduces Ang II-induced contraction in an endothelium-dependent manner in obese rats.


Asunto(s)
Arterias Mesentéricas/fisiología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Obesidad/fisiopatología , Receptor de Angiotensina Tipo 2/metabolismo , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 2 de Angiotensina II/farmacología , Animales , Western Blotting , Endotelio Vascular/fisiología , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Arterias Mesentéricas/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Obesidad/metabolismo , Fosforilación/efectos de los fármacos , Piridinas/farmacología , Ratas Wistar , Regulación hacia Arriba , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología
4.
PLoS One ; 8(5): e63449, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23667622

RESUMEN

Impaired vascular function, manifested by an altered ability of the endothelium to release endothelium-derived relaxing factors and endothelium-derived contracting factors, is consistently reported in obesity. Considering that the endothelium plays a major role in the relaxant response to the cannabinoid agonist anandamide, the present study tested the hypothesis that vascular relaxation to anandamide is decreased in obese rats. Mechanisms contributing to decreased anandamide-induced vasodilation were determined. Resistance mesenteric arteries from young obese Zucker rats (OZRs) and their lean counterparts (LZRs) were used. Vascular reactivity was evaluated in a myograph for isometric tension recording. Protein expression and localization were analyzed by Western blotting and immunofluorescence, respectively. Vasorelaxation to anandamide, acetylcholine, and sodium nitroprusside, as well as to CB1, CB2, and TRPV1 agonists was decreased in endothelium-intact mesenteric arteries from OZRs. Incubation with an AMP-dependent protein kinase (AMPK) activator or a fatty acid amide hydrolase inhibitor restored anandamide-induced vascular relaxation in OZRs. CB1 and CB2 receptors protein expression was decreased in arteries from OZRs. Incubation of mesenteric arteries with anandamide evoked endothelial nitric oxide synthase (eNOS), AMPK and acetyl CoA carboxylase phosphorylation in LZRs, whereas it decreased phosphorylation of these proteins in OZRs. In conclusion, obesity decreases anandamide-induced relaxation in resistance arteries. Decreased cannabinoid receptors expression, increased anandamide degradation, decreased AMPK/eNOS activity as well as impairment of the response mediated by TRPV1 activation seem to contribute to reduce responses to cannabinoid agonists in obesity.


Asunto(s)
Ácidos Araquidónicos/farmacología , Endocannabinoides/farmacología , Endotelio Vascular/fisiopatología , Arterias Mesentéricas/fisiopatología , Obesidad/fisiopatología , Alcamidas Poliinsaturadas/farmacología , Vasodilatación/efectos de los fármacos , Acetil-CoA Carboxilasa/metabolismo , Adenilato Quinasa/metabolismo , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Técnicas In Vitro , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/enzimología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Obesidad/metabolismo , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Ratas , Ratas Zucker , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Canales Catiónicos TRPV/metabolismo
5.
Steroids ; 78(3): 341-6, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23261957

RESUMEN

OBJECTIVE: The increased risk of cardiovascular diseases in postmenopausal women has been linked to the decrease in plasma estrogen levels. Preparation of conjugate equine estrogens (CEE) is one of the most routinely used hormone therapy in postmenopausal women. However, studies on the vascular effects of CEE are still sparse and the mechanism of action is not completely elucidated. In this context, we have determined the effects of CEE in the vascular oxidative stress observed in ovariectomyzed (OVX) spontaneously hypertensive rats (SHR). Mechanisms by which CEE interferes with redox-sensitive pathways and endothelial function were also determined. RESULTS: Aortas from OVX rats exhibited increased generation of reactive oxygen species (ROS), NADPH oxidase activity and reduced catalase protein expression, compared to aortas from sham SHR. Endothelium-intact aortic rings from OVX were hyperreactive to NE when compared to Sham aortas. This hyperreactivity was corrected by superoxide dismutase (SOD), catalase, and endothelium removal. Treatment of OVX-SHR with CEE reduced vascular ROS generation, NADPH oxidase activity, enhanced SOD and catalase expression and also corrected the NE-hyperreactivity in aortic rings from OVX-SHR. CONCLUSION: Our study indicates a potential benefit of CEE therapy through a mechanism that involves reduction in oxidative stress, improving endothelial function in OVX hypertensive rats.


Asunto(s)
Aorta/efectos de los fármacos , Estrógenos Conjugados (USP)/farmacología , Hipertensión/tratamiento farmacológico , Ovariectomía , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Animales , Aorta/metabolismo , Catalasa/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Caballos , Humanos , Hipertensión/metabolismo , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Técnicas de Cultivo de Tejidos
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