Discovery and characterization of alamandine, a novel component of the renin-angiotensin system

Rationale: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte and water balance. Here we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of ACE2 angiotensin A, or directly from angiotensin-(1-7). Objective: To characterize a novel component of the RAS, alamandine. Methods and Results: Using Mass Spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, anti-fibrosis, anti-hypertensive and central effects. Interestingly, our data reveals that its actions are independent of the known vasodilator receptors of the RAS, Mas and AT2. Rather, we demonstrate that alamandine acts through the Mas-related G-Protein coupled receptor, MrgD. Binding of alamandine to MrgD is blocked by D-Pro7-Ang-(1-7), the MrgD ligand beta-alanine and PD-123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/beta-hydroxypropyl cyclodextrin produced a long-lasting anti-hypertensive effect in spontaneously hypertensive rats and anti-fibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or anti-proliferative effect in human tumoral cell lines. Conclusions: The identification of these two novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS, and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders

Nutrientes foliares de espécies arbóreas de três estádios sucessionais de floresta ombrófila densa no sul do Brasil Leaf nutrient content of tree species from three successional stages of tropical rain forest in south Brazil

As concentrações de macro e micronutrientes foliares de espécies arbóreas foram avaliadas em três estádios sucessionais (inicial, intermediário e avançado) de uma floresta ombrófila densa das terras baixas, no litoral do Estado do Paraná, crescendo sobre solo arenoso e oligotrófico. Dentre as espécies arbóreas mais importantes de cada estádio sucessional (quatro iniciais; oito intermediárias; 11 avançadas), coletou-se folhas maduras de cinco diferentes indivíduos de cada estádio sucessional para a análise química dos seguintes elementos: N, P, K, Ca, Mg, C, Zn, Fe, Cu e Mn. As espécies do estádio inicial possuem as menores concentrações médias foliares de N, P, K, Zn, Fe e a maior concentração de Mg e estas concentrações são estatisticamente diferentes (p <0,05), quando comparadas com os valores médios dos demais estádios. Nos estádios intermediário e avançado, as concentrações médias de N, Ca e Mg, assim como os micronutrientes estão dentro dos valores esperados para florestas tropicais. As concentrações médias de K, nos estádios inicial e intermediário, e as concentrações médias de P, em todos os estádios, encontram-se abaixo dos valores reportados para as florestas tropicais. A relação C/N é alta (>25:1), apesar da tendência de diminuir à medida que avança a sucessão. O aumento da concentração da maioria dos nutrientes foliares analisados ao longo do gradiente sucessional está associado, possivelmente, com o incremento do acúmulo da serapilheira sobre o solo, o que proporciona ciclagem de nutrientes mais intensa e maiores concentrações de nutrientes no solo.<br>We investigated the leaf nutrient content of trees species from three distinct successional stages (early, intermediate, late) of a lowland rain forest located near the coast of Paraná State, Brazil. This forest grows on sandy soil with low nutrient content. We collected mature leaves from five different individuals of each sucessional stages of the most important tree species of each successional stage (four of the early; eight of the intermediate and 11 of the late stages) for chemical analysis of following elements: N, P, K, Ca, Mg, C, Zn, Fe, Cu e Mn. The species from early sucessional stage have lower contents of N, P, K, Zn, Fe, and higher contents of Mg. These concentrations are statistically different (p <0,05) when compared to mean values of the other stages. For the intermediate and late successional stages, the average nutrient concentrations of N, Ca, Mg and micronutrients are within the range of values expected for tropical forests. Foliar K concentration, from early and intermediate successional stages, and foliar P concentration, for all successional stages, are below the reported range of values for tropical forests. The C/N ratio is high (>25:1), despite of the tendency to decrease as succession advances. The increment of concentration of the most studied foliar nutrients along the successional gradient is probably related to the accumulation of litter above the soil that provides a more adequate environment for efficient nutrient cycling and higher nutrient concentration in the soil