Effects of topical capsaicin combined with moderate exercise on insulin resistance, body weight and oxidative stress in hypoestrogenic obese rats.

BACKGROUND: Hypoestrogenic (HE) women are one of the most vulnerable groups for the development of obesity and its complications. Capsaicin and exercise have demonstrated to reduce body weight and to improve insulin sensitivity in different animal models, but it is unknown whether their combination could be useful in HE obese females. METHODS: We investigated whether topical capsaicin, exercise or their combination had better therapeutic effects in an obesity-hypoestrogenism model. Ovariectomized Wistar rats were given a 30% sucrose solution (HE-Obese (HEOb)) or purified water (HE) during 28 weeks ad libitum; four experimental groups per each condition. After shaving the abdominal skin, cold cream vehicle was applied to the Sedentary groups (Sed) and capsaicin cream 0.075% (0.6 mg kg-1 per day) to the Capsaicin groups (Cap). Exercise (Ex) groups ran on a treadmill every day for 20 min at speeds from 9 to 18 m per min increased every 10 days; combination groups (Cap+Ex) were given topical capsaicin 90 min before exercise. The treatments were performed for 6 weeks, and caloric intake and body weight were monitored. At the end of the experimental protocol, glucose tolerance tests were performed, the animals were killed by decapitation; blood and organs were obtained to perform oxidative profile, histology, biochemical analyses and Western blot. RESULTS: In HEOb rats, the combined therapy reduced caloric intake, body weight and abdominal fat in a higher proportion than the individual treatments; it also decreased insulin resistance (IR), oxidative stress and pancreatic islet size. It was the only treatment that significantly increased p-AMPK levels in the soleus muscle. In HE rats, topical capsaicin was the only treatment that reduced glucose intolerance and improved the oxidative profile in a higher proportion than the combined therapy or Ex alone. CONCLUSIONS: Capsaicin per se or its combination with moderate exercise could be a useful therapy against complications linked to obesity-IR in HE females.

[Recombinant tissue plasminogen activator for the management of intracardiac thrombi in newborns]. / Activador del plasminógeno tisular recombinante en el manejo de trombos cardiacos en recién nacidos.

INTRODUCTION: The incidence of cardiac thrombi in newborns has increased with the use of central venous catheters. Thrombolysis with recombinant tissue plasminogen activator (rTPA) has been used as an alternative to heparin in life threatening giant thrombus and embolization. The aim of this study is to describe the response and complications related to the use of rTPA in the management of life- threatening cardiac thrombi in newborns. PATIENTS AND METHOD: The medical records of 8 newborn were reviewed in a retrospective study, of whom 7 were preterm with cardiac thrombi, and rTPA was used in all of them. RESULTS: The patients included 4 males with a mean weight of 1580 gr. The principal pathology was sepsis (7/8), all of them used venous central catheter. The superior vena cava was the most frequent location, with a mean time of installation before the diagnosis of 12 days. RN 7/8 thrombi were located in the right atrium with a size between 7 to 20 mm. Three patients received low molecular weight heparin prior to using rTPA. They received between 1 to 5 cycles with rTPA. In 4 patients complete resolution of the thrombus was achieved in a mean of 3.5 days. Four patients had intracranial haemorrhage grade I, without sequelae at follow-up. There were no deaths or embolism. CONCLUSION: This study is the first series of infants treated with rTPA in Chile, and where its use has quickly achieved complete resolution of the thrombus in 50% of cases, and partially in the others, thus reducing the secondary life-threatening risk of this disease.

Activador del plasminógeno tisular recombinante en el manejo de trombos cardiacos en recién nacidos / Recombinant tissue plasminogen activator for the management of intracardiac thrombi in newborns

Introducción: La incidencia de trombos cardíacos en recién nacidos (RN) ha aumentado con el uso de catéteres venosos centrales. La trombólisis con activador del plasminógeno tisular recombinante (rTPA) se ha utilizado como alternativa a la heparina en trombos gigantes con riesgo vital y de embolización. Nuestro objetivo fue describir la respuesta y las complicaciones relacionadas con el uso del rTPA en el manejo de trombos cardíacos con riesgo vital en RN. Pacientes y método: Estudio retrospectivo de 8 RN, 7 prematuros, con trombos cardíacos en los cuales se utilizó rTPA. Se analizó la edad gestacional y al diagnóstico, peso, sexo, enfermedades asociadas, hemograma, niveles de fibrinógeno, dímero D, tiempo parcial de tromboplastina activada y de protrombina, antes y al término de la infusión de rTPA. El diagnóstico del trombo se realizó por ecocardiografía doppler. La indicación de rTPA fue trombo mayor de 10 mm o que ocupara más del 50% de la cavidad donde se localizaba; aumento del tamaño a pesar del tratamiento con heparina, aspecto fragmentado y lobulado con riesgo embólico pulmonar o sistémico o que comprometiera la función valvular o cardíaca. Resultados: Cuatro hombres; peso promedio de 1.580 g. La principal enfermedad fue la sepsis (7/8), se usó catéter venoso central en todos, la vena cava superior fue la localización más frecuente, con tiempo promedio de instalación previo al diagnóstico de 12 días. En 7/8 RN los trombos se ubicaron en la aurícula derecha, con un tamaño entre 7 a 20 mm. Tres pacientes recibieron heparina de bajo peso molecular previo al uso de rTPA, se realizaron entre uno a 5 ciclos con rTPA. En 4 pacientes se logró resolución completa del trombo a los 3,5 días en promedio. No hubo embolia ni fallecidos. Cuatro pacientes presentaron hemorragia intracraneana grado I, sin secuelas en el seguimiento. Conclusión: Este estudio constituye la primera serie de neonatos tratados con rTPA en Chile, lográndose la resolución completa del trombo en un 50% de los RN y parcial en el resto, permitiendo con ello disminuir el riesgo vital secundario a este proceso patológico.

Introduction: The incidence of cardiac thrombi in newborns has increased with the use of central venous catheters. Thrombolysis with recombinant tissue plasminogen activator (rTPA) has been used as an alternative to heparin in life threatening giant thrombus and embolization. The aim of this study is to describe the response and complications related to the use of rTPA in the management of life- threatening cardiac thrombi in newborns. Patients and method: The medical records of 8 newborn were reviewed in a retrospective study, of whom 7 were preterm with cardiac thrombi, and rTPA was used in all of them. Results: The patients included 4 males with a mean weight of 1580 gr. The principal pathology was sepsis (7/8), all of them used venous central catheter. The superior vena cava was the most frequent location, with a mean time of installation before the diagnosis of 12 days. RN 7/8 thrombi were located in the right atrium with a size between 7 to 20 mm. Three patients received low molecular weight heparin prior to using rTPA. They received between 1 to 5 cycles with rTPA. In 4 patients complete resolution of the thrombus was achieved in a mean of 3.5 days. Four patients had intracranial haemorrhage grade I, without sequelae at follow-up. There were no deaths or embolism. Conclusion: This study is the first series of infants treated with rTPA in Chile, and where its use has quickly achieved complete resolution of the thrombus in 50% of cases, and partially in the others, thus reducing the secondary life-threatening risk of this disease.

Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo.

BACKGROUND AND PURPOSE: The mitochondrial permeability transition pore (mPTP), an energy-dissipating channel activated by calcium, contributes to reperfusion damage by depolarizing the mitochondrial inner membrane potential. As mitochondrial Ca(2+) overload is a main inductor of mPTP opening, we examined the effect of Ru(360), a selective inhibitor of the mitochondrial calcium uptake system against myocardial damage induced by reperfusion in a rat model. EXPERIMENTAL APPROACH: Myocardial reperfusion injury was induced by a 5-min occlusion of the left anterior descending coronary artery, followed by a 5-min reperfusion in anaesthetized open-chest rats. We measured reperfusion-induced arrhythmias and functions indicative of unimpaired mitochondrial integrity to evaluate the effect of Ru(360) treatment. KEY RESULTS: Reperfusion elicited a high incidence of arrhythmias, haemodynamic dysfunction and loss of mitochondrial integrity. A bolus intravenous injection of Ru(360) (15-50 nmol kg(-1)), given 30-min before ischaemia, significantly improved the above mentioned variables in the ischaemic/reperfused myocardium. Calcium uptake in isolated mitochondria from Ru(360)-treated ventricles was partially diminished, suggesting an interaction of this compound with the calcium uniporter. CONCLUSIONS AND IMPLICATIONS: We showed that Ru(360) treatment abolishes the incidence of arrhythmias and haemodynamic dysfunction elicited by reperfusion in a whole rat model. Ru(360) administration partially inhibits calcium uptake, preventing mitochondria from depolarization by the opening of the mPTP. We conclude that myocardial damage could be a consequence of failure of the mitochondrial network to maintain the membrane potential at reperfusion. Hence, it is plausible that Ru(360) could be used in reperfusion therapy to prevent the occurrence of arrhythmia.

Myocardial damage due to ischemia and reperfusion in hypertriglyceridemic and hypertensive rats: participation of free radicals and calcium overload.

OBJECTIVE: In a model of hypertriglyceridemia and hypertension in rats (HTG), induced by adding refined sugar to the animals' drinking water, we investigated the response to an acute stress, such as ischemia and reperfusion. In addition, we examined the contribution of calcium overload and free radical release to the injury caused by the post-ischemic reperfusion in a pathological state compared with the normal state. METHODS: Ischemia was induced in the whole anaesthetized animal, by occlusion of the left coronary artery for 4 min, followed by reperfusion for 6 min. To prevent either calcium overload or lipid oxidative processes during reperfusion, either Ketorolac (KET), a calcium ionophore-like drug, or alpha-Phenyl-N-ter-butyl nitrone (PBN), a spin-trapping agent, was administered beforehand. RESULTS: Ketorolac failed to protect the HTG animals from heart damage, as seen by the incidence of reperfusion dysrhythmias, release of lactate dehydrogenase and creatine kinase to the plasma, and non-recovery of the sinus rhythm. On the other hand, PBN was able to prevent these harmful events in the HTG heart by diminishing lipoperoxidation. CONCLUSIONS: The results suggest that, in HTG animals, the oxidative processes make a major contribution to the reperfusion injury and that the sole protection from calcium overload provided by KET is not sufficient to avoid damage compared with control rats.

[Protective effect of dantrolene in post-ischemic reperfusion myocardial damage]. / Efecto protector del dantrolene en las lesiones miocárdicas producidas por la reperfusión post-isquémica.

This study shows that the hydantoin drug, dantrolene, protects against myocardial damage induced by reperfusion. This effect was analyzed after 5 minutes of left coronary artery occlusion in Wistar rats hearts. The results made evident that dantrolene protects the myocardium against myocardial dysfunction (stunning heart) and reperfusion arrhythmias. Furthermore, it decreases the release of the enzymes creatine cinase and lactate dehydrogenase to the plasma, and protects from the structural damage of myocardium. We propose that the protective effect of the drug, might be due to its blocking effect on cardiac calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum; thus, decreasing the high level of cytoplasmic calcium concentration (calcium overload), that is a characteristic of reperfusion injury.

Effect of perezone on arrhythmias and markers of cell injury during reperfusion in the anesthetized rat.

In the in vivo rat heart model with transient (5 min) regional ischemia, as induced by left coronary artery ligation, we have demonstrated that perezone reduces dramatically the incidence of reperfusion-induced-arrhythmias. Administered 5 minutes before coronary occlusion, at a dose of 3.1 mg/kg, this drug effectively protects against the high incidence of arrhythmias and the fall of blood pressure. In addition, it inhibits the release of lactic dehydrogenase and creatine-kinase enzymes to the plasma. We propose that the protective effect of perezone might be related to its well documented action of promoting the release of intramitochondrial Ca2+, thus, maintaining ATP production during reperfusion.

Vascular reactivity and effect of serum in a rat model of hypertriglyceridemia and hypertension.

It has not been definitely established whether elevated circulating triglyceride-rich lipoproteins constitute an independent risk factor for hypertension, atherosclerosis, myocardial infarction, and coronary heart disease. To investigate some aspects of the physiopathology of this lipid metabolism abnormality, a model of experimental hypertriglyceridemia and hypertension in rats was studied. The animals received commercially refined sugar (30%) in their drinking water during a period of 12 to 17 weeks. Monthly measurements of blood pressure and serum triglycerides were taken during and at the end of the treatment period; the levels of glucose and insulin were also determined. The blood, the aorta, and mesenteric artery were removed. Age- and weight-matched controls were used. The reactivity of the isolated vessels to norepinephrine and acetylcholine and the effect of control and hypertriglyceridemic serum on the same preparations were investigated. In hypertriglyceridemic rats, the response to acetylcholine in the tissues was reduced compared to the control arteries; the hypertriglyceridemic serum elicited contractions that were greater than those induced by control serum. The impaired response of hypertriglyceridemic tissue to the vasodilator and the effect of the hypertriglyceridemic serum on artery contraction suggest that the overall dyslipidemia could contribute to a chronic increase in vascular tone and, consequently, to hypertension.

[The biochemical and cellular bases of myocardial ischemia-reperfusion damage]. / Bases bioquímicas y celulares del daño por isquemia y reperfusión en el miocardio.

In recent years evidence has accumulated indicating a possible myocardial injury secondary to reperfusion. However, it is not exactly known whether injury, at the time of reperfusion, merely represents an acceleration of the damage resulting from ischemia, or whether there is a specific additional injury caused by reperfusion itself. Some pathological events have been associated to reperfusion such as reperfusion arrhythmias, stunning myocardium and vascular damage with no reflow. In this review we discuss the hypotheses that explain the cellular events involved in reperfusion damage: calcium overload, free radical damage and others; also we describe both the experimental models commonly used and drugs assayed in recent years to lower the intensity of this phenomenon.