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The renin-angiotensin system (RAS), vasopressin, and nitric oxide (NO) interact to regulate blood pressure at central and peripheral level. To improve our understanding of their interaction and their relationship with the hypothalamus and the cardiovascular system, we analyzed angiotensin- and vasopressin-metabolizing activities in hypothalamus (HT), left ventricle (LV), and plasma, collected from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) treated or not with L-NAME [N(G)-nitro-L-arginine methyl ester], which inhibits the formation of NO and over-activates the sympathetic nervous system. Previous observations in WKY suggested higher formation of Ang III and Ang IV in the HT and higher availability of Ang II in plasma after L-NAME treatment. Our current results show higher formation of Ang IV and higher metabolism of vasopressin after treatment with L-NAME in the LV of WKY rats. In SHR treated with L-NAME, there is higher availability of Ang III in the HT leading to higher release of vasopressin together with lower formation of Ang 2-10. In their LV, however, there is an increase of vasopressinase. Interestingly, while the enzymatic activities in the HT and LV of WKY rats and control SHR are poorly correlated, they are well but inversely correlated in the L-NAME treated SHR. On the other hand, no significant correlations between enzymatic activities in HT or LV and plasma were noticed. Our results suggest that eNOS inhibition in SHR induces or enhances an inverse reciprocal interaction between HT and LV involving the RAS and vasopressin, which may be mediated by the autonomic nervous system., (© Georg Thieme Verlag KG Stuttgart · New York.)

Sexual dysfunction is a frequent adverse effect during antihypertensive therapy. However, the mechanisms responsible for these effects are not well understood. The renin-angiotensin system has been identified in testis where it may play a role in testicular function and be involved in the detrimental effects of antihypertensive drugs. Therefore, our objective was to compare the influence of captopril and propranolol on plasma testosterone levels and on hydrolyzing angiotensin's enzymes (angiotensinases) in the testis of spontaneously hypertensive rats (SHRs) and in control animals. Twenty-four adult male SHRs were used in this study; eight were treated with captopril in drinking water, 8 with propranolol, and 8 were controls. At the end of the 4 weeks treatment period, systolic blood pressure (SBP) was recorded, blood samples were collected, and the right testis was dissected after perfusion of the rat with saline. The soluble (Sol) and membrane-bound (MB) fractions were obtained after solubilization and ultracentrifugation. Fluorometric measurement of Sol and MB angiotensinase activities were performed using arylamide derivatives as substrates. Testosterone was measured by enzyme immunoassay. SBP decreased after captopril but did not change with propranolol treatment. Whereas captopril did not affect angiotensinase activities, highly significant reductions in Sol and MB angiotensinase activities, particularly glutamyl- and aspartyl-aminopeptidases, were observed after treatment with propranolol. Plasma testosterone decreased in captopril treated rats but propranolol had a greater effect. The present results support a general functional depression of the RAS cascade in the testis of propranolol-treated SHR, which may influence the sexual function of these animals., (© Georg Thieme Verlag KG Stuttgart · New York.)

Reducing angiotensin II (Ang II) production via angiotensin-converting enzyme (ACE) inhibitors is a key approach for the treatment of hypertension. However, these inhibitors may also affect other enzymes, such as angiotensinases and vasopressinase, responsible for the metabolism of other peptides also involved in blood pressure control, such as Ang 2-10, Ang III, Ang IV, and vasopressin. We analyzed the activity of these enzymes in the hypothalamus, plasma, and kidney of normotensive adult male rats after inhibition of ACE with captopril. Aspartyl- (AspAP), glutamyl- (GluAP), alanyl- (AlaAP) and cystinyl-aminopeptidase (CysAP) activities were measured fluorimetrically using arylamides as substrates. Systolic blood pressure (SBP), water intake, and urine flow were also measured. Captopril reduced SBP and increased urine flow. In the hypothalamus, GluAP and AspAP increased, without significant changes in either AlaAP or CysAP. In contrast with effects in plasma, GluAP was unaffected, AspAP decreased, while AlaAP and CysAP increased. In the kidney, enzymatic activities did not change in the cortex, but decreased in the medulla. These data suggest that after ACE inhibition, the metabolism of Ang I in hypothalamus may lead mainly to Ang 2-10 formation. In plasma, the results suggest an increased formation of Ang IV together with increased vasopressinase activity. In the kidney, there is a reduction of vasopressinase activity in the medulla, suggesting a functional reduction of vasopressin in this location. The present data suggest the existence of alternative pathways in addition to ACE inhibition that might be involved in reducing BP after captopril treatment., (© Georg Thieme Verlag KG Stuttgart · New York.)

The kind of fat in the diet modifies the profile of fatty acids in brain and also affects aminopeptidase activities in tissues. Although modifications in brain fatty acids, neurotransmitters, or enzymes due to dietary fat composition have been reported, no direct relationship has yet been described between specific brain fatty acid changes and neuropeptide metabolism following the fat composition of the diet. We investigated the lipid profile and some neuropeptidase activities in the frontal cortex of adult male rats after a period in which diets were supplemented with fatty acids differing in their degrees of saturation such as fish oil (rich in polyunsaturated fatty acids, PUFAs), olive oil (rich in monounsaturated fatty acids, MUFAs), and coconut oil (rich in saturated fatty acids, SAFAs). It is observed that the diet composition affects fatty acid distribution in the brain. Although there is no change of global aminopeptidase/neuropeptidase, their activities in the brain correlate positively or negatively with the dietary fat composition. It is hypothesized that fatty acid in the diet modifies membrane fluidity, peptidases tertiary structure, and therefore, the availability and function of neuropeptides. The present results support the notion that cognitive functions may be modulated depending on the type of fat used in the diet., (© Georg Thieme Verlag KG Stuttgart · New York.)

In order to study the interaction between the renin-angiotensin system (RAS) and nitric oxide (NO), we analyzed the activity of aspartyl- (AspAP), glutamyl- (GluAP), alanyl- (AlaAP), and cystinylaminopeptidase (CysAP) enzymes involved in the RAS cascade, in the hypothalamus, and plasma of normotensive adult male rats after the inhibition of NO production with the NO synthase inhibitor L-NAME (L-N (G)-nitroarginine methyl ester). L-NAME treatment produced a significant increase of systolic blood pressure (SBP). In plasma, while GluAP activity decreased significantly, suggesting a lower Ang III formation, the other aminopeptidases did not change after L-NAME treatment. In hypothalamus, the activities of AspAP and CysAP were not affected after L-NAME treatment. In contrast, GluAP and AlaAP increased significantly. These results suggested mainly a higher formation of Ang III, but also higher levels of Ang IV in the hypothalamus of L-NAME treated rats. Both peptides have hypertensive properties at central level. On the contrary, Ang III may counteract the hypertensive action of Ang II at the periphery. Therefore, the increased SBP in L-NAME treated rats may be due in part to the increased activity of GluAP and AlaAP in hypothalamus and to a decreased activity of GluAP in plasma.

Parkinson's disease (PD) is an age-related neurodegenerative disease characterized by a progressive motor disorder, but frequently is accompanied by autonomic symptoms such as hypotension. Together with the decrease of dopamine, significant decreases in aminopeptidase activities have been reported in PD brains. However, up to date there are no studies about changes of aminopeptidase activities in plasma of PD patients. We studied plasma activities of alanyl-, aspartyl-(AspAP), cystinyl-(CysAP) and glutamyl-aminopeptidase (GluAP) in two groups of subjects: control (n=41) and PD (n=48). Plasma activities of AspAP, CysAP, and GluAP showed significant decreases of 24.9% (p<0.05), 39.4% (p<0.01) and 33.3% (p<0.01), respectively, in PD group. These aminopeptidases are involved in the metabolism of circulating peptides such as the ones of the renin-angiotensin system. The importance of aminopeptidases in striatal dopamine content and in neuroendocrine system in PD is discussed.

Thyroid disorders affect renal function, which involves changes in local renin angiotensin system (RAS). Angiotensin peptide levels in the tissue are regulated by the activity of several aminopeptidases (AP) known as angiotensinases. The nature and consequences of the thyroid-induced RAS changes are not completely understood. We investigated the relationship between thyroid status (hyper- and hypothyroidism) and several kidney AP actions involved in RAS control. We have determined fluorometrically soluble (SOL) and membrane-bound (M-B) alanylaminopeptidase (AlaAP), glutamylaminopeptidase (GluAP) and aspartylaminopeptidase (AspAP) activity using naphthylamide derivatives as substrates. Sprague-Dawley rats were divided into three groups--control, hyperthyroid, and hypothyroid. Hyperthyroidism was induced by daily subcutaneous injection of L-thyroxin (300 microg/kg/day). Hypothyroidism was induced by continuous administration of methimazole (0.03%) in drinking water. Hypothyroid animals demonstrated a significant increase in SOL and M-B GluAP activity in renal cortex and a decrease in M-B AlaAP compared to euthyroid rats. This result may suggest higher Ang III availability. In hyperthyroid animals, M-B AlaAP and M-B AspAP activity increased significantly, which may suggest increased Ang III to Ang IV metabolism and greater formation of Ang 2-10, respectively. In contrast, no differences were observed between euthyroid and hypothyroid animals for SOL and M-B AP activity in renal medulla. However, hyperthyroid animals demonstrated a significant decrease in SOL and M-B GluAP activity compared to euthyroid rats, which may suggest a greater availability of Ang II in renal medulla. Alterations in angiotensin metabolism may, in part, account for some changes in renal function during thyroid disorders.