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1.
J Physiol ; 595(6): 2065-2084, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28083928

RESUMEN

KEY POINTS: Older pregnant women have a greater risk of operative delivery, still birth and post-term induction. This suggests that maternal age can influence the timing of birth and processes of parturition. We have found that increasing maternal age in C57BL/6J mice is associated with prolongation of gestation and length of labour. Older pregnant mice also had delayed progesterone withdrawal and impaired myometrial function. Uterine ageing and labour dysfunction should be investigated further in older primigravid women. ABSTRACT: Advanced maternal age (≥35 years) is associated with increased rates of operative delivery, stillbirth and post-term labour induction. The physiological causes remain uncertain, although impaired myometrial function has been implicated. To investigate the hypothesis that maternal age directly influences successful parturition, we assessed the timing of birth and fetal outcome in pregnant C57BL/6J mice at 3 months (young) and 5 months (intermediate) vs. 8 months (older) of age using infrared video recording. Serum progesterone profiles, myometrium and cervix function, and mitochondrial electron transport chain complex enzymatic activities were also examined. Older pregnant mice had a longer mean gestation and labour duration (P < 0.001), as well as reduced litter size (P < 0.01) vs. 3-month-old mice. Older mice did not exhibit the same decline in serum progesterone concentrations as younger mice. Cervical tissues from older mice were more distensible than younger mice (P < 0.05). Oxytocin receptor and connexin-43 mRNA expression were reduced in the myometrium from 8-month-old vs. 3-month-old mice (P < 0.05 and P < 0.01 respectively) in tandem with more frequent but shorter duration spontaneous myometrial contractions (P < 0.05) and an attenuated contractile response to oxytocin. Myometrial mitochondrial copy number was reduced in older mice, although there were no age-induced changes to the enzymatic activities of the mitochondrial electron transport chain complexes. In conclusion, 8-month-old mice provide a useful model of reproductive ageing. The present study has identified potential causes of labour dysfunction amenable to investigation in older primigravid women.


Asunto(s)
Envejecimiento/fisiología , Útero/fisiología , Animales , Colágeno/metabolismo , ADN Mitocondrial/genética , Femenino , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Oxitócicos/farmacología , Oxitocina/farmacología , Parto/fisiología , Embarazo , Progesterona/sangre , Resistencia a la Tracción , Contracción Uterina/efectos de los fármacos , Útero/anatomía & histología , Útero/efectos de los fármacos , Útero/metabolismo
2.
Cardiovasc Diabetol ; 13: 54, 2014 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-24572210

RESUMEN

BACKGROUND: Saturated fatty acid-rich high fat (HF) diets trigger abdominal adiposity, insulin resistance, type 2 diabetes and cardiac dysfunction. This study was aimed at evaluating the effects of nascent obesity on the cardiac function of animals fed a high-fat diet and at analyzing the mechanisms by which these alterations occurred at the level of coronary reserve. MATERIALS AND METHODS: Rats were fed a control (C) or a HF diet containing high proportions of saturated fatty acids for 3 months. Thereafter, their cardiac function was evaluated in vivo using a pressure probe inserted into the cavity of the left ventricle. Their heart was isolated, perfused iso-volumetrically according to the Langendorff mode and the coronary reserve was evaluated by determining the endothelial-dependent (EDV) and endothelial-independent (EIV) vasodilatations in the absence and presence of endothelial nitric oxide synthase and cyclooxygenase inhibitors (L-NAME and indomethacin). The fatty acid composition of cardiac phospholipids was then evaluated. RESULTS: Although all the HF-fed rats increased their abdominal adiposity, some of them did not gain body weight (HF- group) compared to the C group whereas other ones had a higher body weight (HF+). All HF rats displayed a higher in vivo cardiac activity associated with an increased EDV. In the HF- group, the improved EDV was due to an increase in the endothelial cell vasodilatation activity whereas in the HF+ group, the enhanced EDV resulted from an improved sensitivity of coronary smooth muscle cells to nitric oxide. Furthermore, in the HF- group the main pathway implicated in the EDV was the NOS pathway while in the HF+ group the COX pathway. CONCLUSIONS: Nascent obesity-induced improvement of cardiac function may be supported by an enhanced coronary reserve occurring via different mechanisms. These mechanisms implicate either the endothelial cells activity or the smooth muscle cells sensitivity depending on the body adiposity of the animals.


Asunto(s)
Adiposidad/fisiología , Vasos Coronarios/fisiología , Dieta Alta en Grasa/efectos adversos , Obesidad/fisiopatología , Vasodilatación/fisiología , Animales , Vasos Coronarios/citología , Masculino , Obesidad/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar
3.
Cardiovasc Diabetol ; 12: 49, 2013 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-23530768

RESUMEN

BACKGROUND: There has been accumulating evidence associating diabetes mellitus and cardiovascular dysfunctions. However, most of the studies are focused on the late stages of diabetes and on the function of large arteries. This study aimed at characterizing the effects of the early phase of diabetes mellitus on the cardiac and vascular function with focus on the intact coronary microvasculature and the oxidative stress involved. MATERIALS AND METHODS: Zucker diabetic fatty rats and their lean littermates fed with standard diet A04 (Safe) were studied at the 11th week of age. Biochemical parameters such as glucose, insulin and triglycerides levels as well as their oxidative stress status were measured. Their hearts were perfused ex vivo according to Langendorff and their cardiac activity and coronary microvascular reactivity were evaluated. RESULTS: Zucker fatty rats already exhibited a diabetic state at this age as demonstrated by the elevated levels of plasma glucose, insulin, glycated hemoglobin and triglycerides. The ex vivo perfusion of their hearts revealed a decreased cardiac mechanical function and coronary flow. This was accompanied by an increase in the overall oxidative stress of the organs. However, estimation of the active form of endothelial nitric oxide synthase and coronary reactivity indicated a preserved function of the coronary microvessels at this phase of the disease. Diabetes affected also the cardiac membrane phospholipid fatty acid composition by increasing the arachidonic acid and n-3 polyunsaturated fatty acids levels. CONCLUSIONS: The presence of diabetes, even at its beginning, significantly increased the overall oxidative stress of the organs resulting to decreased cardiac mechanical activity ex vivo. However, adaptations were adopted at this early phase of the disease regarding the preserved coronary microvascular reactivity and the associated cardiac phospholipid composition in order to provide a certain protection to the heart.


Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Endotelio Vascular/fisiología , Corazón/fisiología , Microvasos/fisiología , Estrés Oxidativo/fisiología , Vasodilatación/fisiología , Animales , Circulación Coronaria/fisiología , Diabetes Mellitus Experimental/metabolismo , Masculino , Técnicas de Cultivo de Órganos , Ratas , Ratas Zucker , Factores de Tiempo
4.
J Cardiovasc Pharmacol ; 58(3): 284-94, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21697734

RESUMEN

Cariporide, an Na/H exchanger inhibitor, is a drug with cardioprotective properties. However, chronic treatment with cariporide may modify the protein phenotype of the cardiomyocytes. Disruption of the equilibrium between a cariporide-modified phenotype and the supply of cariporide could be deleterious. The aim of this study was to test the effects of this equilibrium rupture (EqR) on cardiac function at baseline and acute ischemia reperfusion. Rats were chronically treated with cariporide (2.5 mg·kg·d) or with placebo for 21 days, after which isolated Langendorff-mode heart perfusion experiments utilized cariporide-free buffer. During this type of perfusion, the drug is rapidly cleared from the cellular environment. After 30 minutes of stabilization, the hearts were subjected to global zero-flow ischemia (25 minutes) followed by reperfusion (45 minutes). Measures of mechanical function, oxygen consumption, lactate plus pyruvate, CO2 and proton release into the coronary effluent were determined. The gene and protein expression of proton extruders was also evaluated. Chronic cariporide administration followed by EqR reduced the expression of the Na/H exchanger, increased the expression of the HCO3 or Na exchanger, decreased monocarboxylate/H carrier expression, reduced the lactate plus pyruvate release but did not change the glucose oxidation rate and mechanical function compared with baseline conditions. The resulting low glycolytic rate was associated with a stronger contracture during ischemia. During reperfusion, the early release of acidic forms was higher and redirected toward the use of the Na/H and HCO3 /Na exchangers to the detriment of the safe monocarboxylate/H carrier. Both phenomena were assumed to increase the Na uptake and activate the Na/Ca exchanger, resulting in Na and Ca overload and further cellular damage. This explains the impaired recovery of the contractile function observed in the EqR group during reperfusion. In conclusion, although cariporide is usually cardioprotective, a disruption of its chronic treatment followed by an ischemia/reperfusion event can become deleterious.


Asunto(s)
Antiarrítmicos/farmacología , Arritmias Cardíacas/prevención & control , Cardiotónicos/farmacología , Guanidinas/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Sulfonas/farmacología , Animales , Antiarrítmicos/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Análisis Químico de la Sangre , Cardiotónicos/metabolismo , Esquema de Medicación , Guanidinas/metabolismo , Pruebas de Función Cardíaca , Homeostasis/efectos de los fármacos , Masculino , Transportadores de Ácidos Monocarboxílicos/biosíntesis , Transportadores de Ácidos Monocarboxílicos/genética , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/fisiopatología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Simportadores de Sodio-Bicarbonato/biosíntesis , Simportadores de Sodio-Bicarbonato/genética , Intercambiadores de Sodio-Hidrógeno/genética , Sulfonas/metabolismo , Simportadores/biosíntesis , Simportadores/genética , Factores de Tiempo
5.
Physiol Rep ; 5(13)2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28684640

RESUMEN

If it is sustained for several days, sepsis can trigger severe abnormalities of cardiac function which leads to death in 50% of cases. This probably occurs through activation of toll-like receptor-9 by bacterial lipopolysaccharides and overproduction of proinflammatory cytokines such as TNF-α and IL-1ß In contrast, early sepsis is characterized by the development of tachycardia. This study aimed at determining the early changes in the cardiac function during sepsis and at finding the mechanism responsible for the observed changes. Sixty male Wistar rats were randomly assigned to two groups, the first one being made septic by cecal ligation and puncture (sepsis group) and the second one being subjected to the same surgery without cecal ligation and puncture (sham-operated group). The cardiac function was assessed in vivo and ex vivo in standard conditions. Several parameters involved in the oxidative stress and inflammation were determined in the plasma and heart. As evidenced by the plasma level of TNF-α and gene expression of IL-1ß and TNF-α in the heart, inflammation was developed in the sepsis group. The cardiac function was also slightly stimulated by sepsis in the in vivo and ex vivo situations. This was associated with unchanged levels of oxidative stress, but several parameters indicated a lower cardiac production of reactive oxygen species in the septic group. In conclusion, despite the development of inflammation, early sepsis did not increase reactive oxygen species production and did not reduce myocardial function. The depressant effect of TNF-α and IL-1ß on the cardiac function is known to occur at very high concentrations. The influence of low- to moderate-grade inflammation on the myocardial mechanical behavior must thus be revisited.


Asunto(s)
Contracción Miocárdica , Especies Reactivas de Oxígeno/metabolismo , Sepsis/metabolismo , Animales , Interleucina-1beta/sangre , Masculino , Miocardio/metabolismo , Estrés Oxidativo , Ratas , Ratas Wistar , Sepsis/fisiopatología , Factor de Necrosis Tumoral alfa/sangre
6.
J Physiol Biochem ; 72(3): 525-37, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26255304

RESUMEN

Abdominal obesity increases the incidence of cardiac events but reduces mortality when one of these events occurs. The phenomenon called obesity paradox might be related to myocardial energetics. This study was aimed at determining whether long-term abdominal adiposity alters cardiac energy function. Two groups of male Wistar rats were fed a standard or a Western-type (WD) diet for 8 months. The ex vivo coronary reactivity and mechanical function as well as the mitochondrial oxidative phosphorylation (mOxPhos) and hydrogen peroxide release (mH2O2r) were determined. Abdominal adiposity was augmented by the WD. This was also the case for the coronary reactivity to acetylcholine, but the rate pressure product remained roughly stable despite a reduction of the left ventricle-developed pressure partly compensated by a slight increase in heart rate. The prolonged WD administration resulted in an improvement of mOxPhos, but the mH2O2r was exaggerated which was confirmed in the whole cell by a reduced aconitase to fumarase ratio. This did not modify the plasma oxidative stress due to an increased plasma antioxidant status. In conclusion, long-term WD administration improved the cardiac fitness and might predispose the organism to the obesity paradox. Conversely, the increased mitochondrial mH2O2r can precipitate the heart toward cardiomyopathy if the WD is maintained for a longer duration.


Asunto(s)
Adiposidad , Envejecimiento , Cardiomiopatías/etiología , Metabolismo Energético , Corazón/fisiopatología , Miocardio/metabolismo , Obesidad Abdominal/metabolismo , Aconitato Hidratasa/metabolismo , Alostasis , Animales , Cardiomiopatías/fisiopatología , Dieta Occidental/efectos adversos , Progresión de la Enfermedad , Fumarato Hidratasa/metabolismo , Frecuencia Cardíaca , Peróxido de Hidrógeno/metabolismo , Masculino , Miocardio/enzimología , Obesidad Abdominal/sangre , Obesidad Abdominal/etiología , Obesidad Abdominal/fisiopatología , Fosforilación Oxidativa , Estrés Oxidativo , Distribución Aleatoria , Ratas Wistar , Índice de Severidad de la Enfermedad , Taquicardia/etiología
7.
Age (Dordr) ; 36(4): 9670, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24994535

RESUMEN

This study was aimed at characterizing the functional progression of the endothelial (ECs) and smooth muscle cells (SMCs) of the coronary microvasculature between youth and old age, as well as at determining the mechanisms of the observed changes on the basis of the glucose tolerance, mitochondrial energy metabolism, and oxidative stress. Male rats were divided into four age groups (3, 6, 11, and 17 months for the young (Y), young adult (YA), middle-aged (MA), and old (O) animals). The cardiac mechanical function, endothelial-dependent dilatation (EDD) and endothelial-independent dilatation (EID) of the coronary microvasculature were determined in a Langendorff preparation. The mitochondrial respiration and H2O2 production were evaluated and completed by ex vivo measurements of oxidative stress. EDD progressively decreased from youth to old age. The relaxation properties of the SMCs, although high in the Y rats, decreased drastically between youth and young adulthood and stabilized thereafter, paralleling the reduction of mitochondrial oxidative phosphorylation. The ECs dilatation activity, low at youth, was stimulated in YA animals and returned to their initial level at middle age. That parameter followed faithfully the progression of the amount of active cardiac endothelial nitric oxide synthase and whole body glucose intolerance. In conclusion, the progressive decrease in EDD occurring with aging is due to different functional behaviors of the ECs and SMCs, which appear to be associated with the systemic glucose intolerance and cardiac energy metabolism.


Asunto(s)
Envejecimiento , Circulación Coronaria/fisiología , Vasos Coronarios/fisiopatología , Metabolismo Energético/fisiología , Glucosa/metabolismo , Estrés Oxidativo , Vasodilatación/fisiología , Animales , Modelos Animales de Enfermedad , Prueba de Tolerancia a la Glucosa , Masculino , Microcirculación , Ratas , Ratas Wistar
8.
Age (Dordr) ; 33(3): 321-36, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20878490

RESUMEN

Aging compromises restoration of the cardiac mechanical function during reperfusion. We hypothesized that this was due to an ampler release of mitochondrial reactive oxygen species (ROS). This study aimed at characterising ex vivo the mitochondrial ROS release during reperfusion in isolated perfused hearts of middle-aged rats. Causes and consequences on myocardial function of the observed changes were then evaluated. The hearts of rats aged 10- or 52-week old were subjected to global ischemia followed by reperfusion. Mechanical function was monitored throughout the entire procedure. Activities of the respiratory chain complexes and the ratio of aconitase to fumarase activities were determined before ischemia and at the end of reperfusion. H(2)O(2) release was also evaluated in isolated mitochondria. During ischemia, middle-aged hearts displayed a delayed contracture, suggesting a maintained ATP production but also an increased metabolic proton production. Restoration of the mechanical function during reperfusion was however reduced in the middle-aged hearts, due to lower recovery of the coronary flow associated with higher mitochondrial oxidative stress indicated by the aconitase to fumarase ratio in the cardiac tissues. Surprisingly, activity of the respiratory chain complex II was better maintained in the hearts of middle-aged animals, probably because of an enhanced preservation of its membrane lipid environment. This can explain the higher mitochondrial oxidative stress observed in these conditions, since cardiac mitochondria produce much more H(2)O(2) when they oxidize FADH(2)-linked substrates than when they use NADH-linked substrates. In conclusion, the lower restoration of the cardiac mechanical activity during reperfusion in the middle-aged hearts was due to an impaired recovery of the coronary flow and an insufficient oxygen supply. The deterioration of the coronary perfusion was explained by an increased mitochondrial ROS release related to the preservation of complex II activity during reperfusion.


Asunto(s)
Envejecimiento/metabolismo , Vasos Coronarios/fisiopatología , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Contracción Miocárdica/fisiología , Daño por Reperfusión Miocárdica/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Aconitato Hidratasa/análisis , Animales , Modelos Animales de Enfermedad , Fumarato Hidratasa/análisis , Peróxido de Hidrógeno/metabolismo , Técnicas In Vitro , Masculino , Mitocondrias Cardíacas/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/química , Estrés Oxidativo/fisiología , Oxígeno/metabolismo , Perfusión , Ratas , Ratas Wistar
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