WKY and SHR strains have

WKY and SHR strains have important differences mainly in their sympathetic status but also in the activity of the RAS. The development of hypertension in SHR is clearly related to an increase in sympathetic activity [51], [11]. In addition, increased renal sympathetic nerve activity led to an increased renin secretion that activates the systemic RAS [13]. SHR also exhibit an overactive RAS in comparison with WKY [31], partly due to an increased excitatory transmission via catecholamines [17]. In the anterior hypothalamus, renin-like activity was higher in SHR compared to WKY during the development of hypertension [41]. The Ang II content and turnover within the hypothalamus is also increased in SHR compared to WKY [32]. All these previous studies focused only on the action of Ang II. However, the function of the whole RAS is the consequence of the coordinated action of the various active Ang peptides of the system which sometimes counteract each other. Clearly, angiotensin peptides pattern may be different depending on the type of treatment [35]. On the other hand, propranolol markedly reduced food intake, water intake and diuresis to a greater degree in WKY rats than in SHR (Fig. 3). It was reported that the inhibition of ACE with captopril increased markedly water intake and diuresis in WKY. However, captopril did not modify water intake in SHR and only slightly increased diuresis [35]. Again, the influence of the treatment on the physiological parameters was higher in WKY than in SHR but in this case in the opposite direction: while propranolol decreased diuresis, captopril increased it, both treatments causing stronger effects in WKY than SHR. Differences in the influence of these drug treatments on the RAS cascade by influencing the prevalence or reduction of certain Ang peptides may account for these divergences. This assumption is based on still unpublished results that demonstrate a different pattern of the same aminopeptidase activities as the ones analyzed in the present study after captopril treatment in WKY and SHR (I Prieto, AB Segarra, AB Villarejo, M de Gasparo, MM Martínez and M Ramírez-Sánchez). The analyzed aminopeptidase activities have been clearly related with cardiovascular control and hydro-electrolytic balance, essentially due to their action on angiotensin peptides and ADH [40]. However, other peptides such as Y27632 synthesis or enkephalins may also be regulated by these aminopeptidases [15], [24]. Enkephalin injections into the paraventricular nucleus produced a dose-dependent increase of food intake in rats [23]. Subcutaneous enkephalin injections also increased food intake and water intake [42]. Cholecystokinin injected intracerebroventricularly produced a decrease in ADH and oxytocin in neurohypophysis followed by a reduction in water intake and body weight [12]. In the case of food intake, SHR-PR had higher level than WKY-PR (Fig. 3). In this comparison, SHR-PR had markedly lower AlaAP activity than WKY-PR in hypothalamus (Fig. 2 column B). Therefore, a lower activity of enkephalinase (AlaAP) may indicate a higher availability of enkephalin in hypothalamus which may account for the higher food intake observed in SHR under propranolol-treatment. In addition to the fact that individually cholecystokinin produces satiety and enkephalin hunger, both peptides may interact to elicit their physiologic responses. Indeed, it has been reported that peripheral injections of cholecystokinin decreased enkephalin in hypothalamus [22]. This may be related to the difference observed in the present results. For example, while there was an increase of AspAP (lower cholecystokinin availability) in SHR-PR in comparison with WKY-PR in plasma (Fig. 2 column F), a decrease of AlaAP (higher enkephalin availability) in SHR-PR in comparison with WKY-PR (Fig. 2 column B) was observed in hypothalamus. Hypothalamic AlaAP and CysAP activities correlated positively with diuresis in WKY animals treated with propranolol (Fig. 4). These animals had lower levels of diuresis than controls but unchanged systolic blood pressure (Fig. 3). Therefore, this correlation may be compatible with higher hypothalamic secretion of ADH. Further, hypothalamic CysAP activity of SHR correlated positively with systolic blood pressure (Fig. 4): the higher the hypothalamic CysAP activity, the higher the systolic blood pressure levels. Moreover, in SHR-PR there was a negative correlation between hypothalamic CysAP and plasmatic AlaAP (Fig. 4) that supports the opposite relationship between hypothalamus and plasma observed in the present article. It is necessary however to take into account that correlation does not equal causation but our findings suggest a mechanistic pathway.