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  • The RAS may have different functions depending on


    The RAS may have different functions depending on whether we consider the circulatory component or the different local tissue systems (including brain) well described previously [29]. The cardiovascular control and hydroelectrolytic balance (among other functions), are largely the result of the influence of central and peripheral RAS, interconnected through the autonomic nervous system and acting in a coordinated manner. In this mechanism, the hypothalamus plays a major role modulating the function of the autonomic nervous system [34], [49] and the vasopressin release by the stimulatory effect of Ang III [20]. Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) are the main strains used for cardiovascular studies. Whereas these two strains markedly differ in their anxiety-related behaviors [3], they also diverge essentially in the functional status of their autonomic nervous system and RAS [31], [32], [41], [51]. Compared to WKY, SHR demonstrated an increased excitability of hypothalamic neurons responsible for the augmented sympathetic tone [6]. A functional relationship between the central and peripheral local RAS systems, such as JNJ-26481585 and kidney, was proposed depending on the tissue involved and the sympathetic tone [34]. In addition, an influence of the autonomic innervation of the vessels was suggested for the modulation of a probable GluAP release to plasma [2]. However, no studies so far have compared the hypothalamic and systemic aminopeptidases of the RAS cascade in WKY and SHR depending on the sympathetic status of the animal. According to that background, we hypothesize that the regulatory mechanisms of aminopeptidase activities may differ between WKY and SHR in hypothalamus and plasma according to the sympathetic tone of the animal. This study may clarify our understanding of the functional interaction between central and systemic aminopeptidase activities and indirectly suggest the possible interaction of the substrates of these enzymes, including those of the RAS or others. Therefore, our objective was to analyze GluAP, AspAP, AlaAP and CysAP activities in the plasma and hypothalamus of non-treated (controls) and propranolol-treated WKY and SHR. Since membrane bound enzymatic activities were suggested to act in a more tissue-specific manner than the soluble ones [35], our study focused on the analysis of membrane-bound activities in hypothalamic samples. Systolic blood pressure, water intake and diuresis were measured as physiologic parameters modulated by angiotensin peptides and vasopressin. Since these parameters and some of the substrates of the assayed enzymes may also be related to food intake [18], [25], [24], [15], this feature was also measured. Because both RAS and autonomic nervous system are involved in cardiovascular and hydroelectrolytic control, these parameters were also measured under propranolol treatment in order to analyze possible differences between WKY and SHR and to search for a possible interaction with aminopeptidases of hypothalamus and/or plasma. Specifically our objectives were 1) to analyze the difference of aminopeptidase activities between SHR and WKY in hypothalamus and plasma of control or propranolol-treated rats, 2) to analyze the influence of propranolol on aminopeptidase activities in hypothalamus and plasma of WKY or SHR 3) to analyze the effect on physiologic parameters in the 1) and 2) comparisons and 4) to search for possible interactions between all the parameters studied in hypothalamus and plasma of WKY and SHR.
    Materials and methods
    Discussion The present results generally show an opposed response of aminopeptidase activities between hypothalamus and plasma but also the contrasting effect of propranolol on aminopeptidase activities between WKY and SHR in hypothalamus as well as in plasma (Fig. 2). In summary, propranolol increased aminopeptidase activities in the hypothalamus of WKY rats but decreased them in SHR (Fig. 2: column C compared with D). In contrast, propranolol decreased aminopeptidase activities in plasma of WKY rats and increased them in SHR (Fig. 2: column G compared with H). On the contrary, comparing WKY and SHR, when the activity was higher in hypothalamus, it was lower in plasma and vice versa (Fig. 2: columns A, B compared with columns E, F). Since the aminopeptidase activities analyzed in the present work possess angiotensinase and vasopressinase activity, these results may reveal a mutual inverse interaction between central hypothalamic RAS and peripheral plasmatic RAS metabolism (Fig. 5). In addition, as previously indicated, these aminopeptidase activities may reflect their action on other substrates than angiotensins and vasopressin such as cholecystokinin, enkephalins or oxytocin, which must also be taken into account.