Cardioprotective Effects of Leucine Supplementation against Doxorubicin-Induced Cardiotoxicit.

Doxorubicin is one of the most important antitumor drugs used in oncology; however, its cardiotoxic effect limits the therapeutic use and raises concerns regarding patient prognosis. Leucine is a branched-chain amino acid used in dietary supplementation and has been studied to attenuate the toxic effects of doxorubicin in animals, which increases oxidative stress. Oxidative stress in different organs can be estimated using several methods, including catalase expression analysis. This study aimed to analyze the effect of leucine on catalase levels in rat hearts after doxorubicin administration. Adult male Wistar rats were separated into two groups: Standard diet (SD) and 5% Leucine-Enriched Diet (LED). The animals had free access to diet from D0 to D28. At D14, the groups were subdivided in animals injected with Doxorubicin and animals injected with vehicle, until D28, and the groups were SD, SD + Dox, LED and LED + Dox. At D28, the animals were submitted do Transthoracic Echocardiography and euthanized. Despite Dox groups had impaired body weight gain, raw heart weight was not different between the groups. No substantial alterations were observed in macroscopic evaluation of the heart. Although, Doxorubicin treatment increased total interstitial collagen in the heart, which in addition to Type I collagen, is lower in LED groups. Western blot analysis showed that catalase expression in the heart of LED groups was lower than that in SD groups. In conclusion, leucine supplementation reduced both the precocious Dox-induced cardiac remodeling and catalase levels in the heart.

Evidence for a role of nitric oxide in hindlimb vasodilation induced by hypothalamic stimulation in anesthetized rats

Em animais anestesiados a EE do hipotálamo produz um padrão de ajustes cardiovasculares caracterizado por hipertensão arterial, taquicardia, vasodilatação muscular e vasoconstrição mesentérica, entretanto, os mecanismos periféricos envolvidos nestes ajustes cardiovasculares ainda não foram completamente esclarecidos. O presente estudo teve como objetivo caracterizar os mecanismos periféricos responsáveis pela redistribuição de fluxo sanguíneo produzidas pela EE do hipotálamo. Os resultados obtidos demonstraram que 1) em ratos anestesiados a EE do hipotálamo produziu hipertensão arterial, taquicardia, vasoconstrição no leito mesentérico e acentuada vasodilatação dos membros posteriores; 2) a combinação do bloqueio farmacológico de receptores a1 e a2 adrenérgicos com fentolamina mais adrenalectomia bilateral reduziu a vasoconstrição mesentérica e a vasodilatação dos membros posteriores. Nestes animais o bloqueio da síntese de NO com L-NAME provocou nova redução significante da vasodilatação dos membros posteriores; 3) a administração de L-NAME, previamente o bloqueio farmacológico com fentolamina mais adrenalectomia bilateral, reduziu as respostas de vasoconstrição mesentérica e de vasodilatação dos membros posteriores. Estes resultados sugerem a existência de pelo menos três possíveis mecanismos responsáveis pela vasodilatação dos membros posteriores induzida pela EE do hipotálamo: 1) ativação de receptores b-adrenérgicos por catecolaminas liberadas pela medula adrenal; 2) redução do tono vasoconstritor simpático e 3) um terceiro mecanismo que utiliza NO como mediador.

Evidence for a role of nitric oxide in hindlimb vasodilation induced by hypothalamic stimulation in anesthetized rats.

Electrical stimulation of the hypothalamus produces cardiovascular adjustments consisting of hypertension, tachycardia, visceral vasoconstriction and hindlimb vasodilation. Previous studies have demonstrated that hindlimb vasodilation is due a reduction of sympathetic vasoconstrictor tone and to activation of beta2-adrenergic receptors by catecholamine release. However, the existence of a yet unidentified vasodilator mechanism has also been proposed. Recent studies have suggested that nitric oxide (NO) may be involved. The aim of the present study was to investigate the role of NO in the hindquarter vasodilation in response to hypothalamic stimulation. In pentobarbital-anesthetized rats hypothalamic stimulation (100 Hz, 150 microA, 6 s) produced hypertension, tachycardia, hindquarter vasodilation and mesenteric vasoconstriction. Alpha-adrenoceptor blockade with phentolamine (1.5 mg/kg, iv) plus bilateral adrenalectomy did not modify hypertension, tachycardia or mesenteric vasoconstriction induced by hypothalamic stimulation. Hindquarter vasodilation was strongly reduced but not abolished. The remaining vasodilation was completely abolished after iv injection of the NOS inhibitor L-NAME (20 mg/kg, iv). To properly evaluate the role of the mechanism of NO in hindquarter vasodilation, in a second group of animals L-NAME was administered before alpha-adrenoceptor blockade plus adrenalectomy. L-NAME treatment strongly reduced hindquarter vasodilation in magnitude and duration. These results suggest that NO is involved in the hindquarter vasodilation produced by hypothalamic stimulation.