Frontiers in diabetic research.
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Diabetes Mellitus↗
Biomedical subjects
Marc de Gasparo
Publications and source records attributed to Marc de Gasparo.
Atrial angiotensinase activity in hypothyroid, euthyroid, and hyperthyroid rats.
Thyroid dysfunction produces marked cardiovascular responses. Hypothyroidism and hyperthyroidism cause important changes in the circulating renin-angiotensin system (RAS). Modifications in cardiac RAS have also been involved in cardiovascular alterations. Studies have revealed that thyroid hormones activate some components of cardiac RAS. Angiotensin (Ang) peptides are regulated by the activity of several aminopeptidases (AP) called angiotensinases. Previous results in our laboratory have demonstrated that thyroid dysfunction altered angiotensinase activities in hypothalamus, pituitary, and kidney. In the present study, we investigated the relationship between thyroid status and local angiotensinase activities in the atrium of hypothyroid, euthyroid, and hyperthyroid adult male rats. We have determined fluorometrically soluble and membrane-bound alanyl, glutamyl, and aspartyl aminopeptidase activities using naphthylamide derivatives as substrates. These activities have been, respectively, involved in the metabolism of Ang III to Ang IV, Ang II to Ang III, and Ang I to des-Asp Ang I. Hyperthyroidism was induced with subcutaneous injections of tetraiodothyronine (300 microg/kg/day), and the hypothyroid rats were obtained with 0.03% methimazole via the drinking water. Compared with that in euthyroid rats, a highly significant increase (by 50%) of soluble aspartyl aminopeptidase activity (P < 0.001) was observed in the atrium of hyperthyroid and hypothyroid animals. In membrane fractions, T4 treatment produced an increase in alanyl aminopeptidase (37%; P < 0.05) and aspartyl aminopeptidase activities (30%; P < 0.01). These results suggest higher formation of des-Asp Ang I in both hypothyroid and hyperthyroid rats but also suggest higher metabolism of Ang III to Ang IV in hyperthyroid animals, which is in agreement with the described alterations of cardiac RAS after thyroid dysfunction.
Animals↗
Brain aminopeptidases and hypertension.
The brain aminopeptidases that participate in the enzymatic cascade of the renin-angiotensin system play a major role in blood pressure (BP) control, and their study offers new perspectives for the understanding of central BP control and the treatment of hypertension. In this system, angiotensin II is converted to angiotensin III (Ang III) by glutamyl aminopeptidase (GluAP) and Ang III is further metabolised to angiotensin IV by alanyl aminopeptidase or arginine-aminopeptidase. It is now clear that Ang III is the key active form of the central angiotensins, exerting tonic stimulatory control over BP. Therefore, the development of GluAP inhibitors as potential antihypertensive agents offers new perspectives for therapy. Brain aspartyl aminopeptidase, which converts angiotensin I to angiotensin 2-10, is also a possible target for antihypertensive therapy because of its potential role in BP control. Finally, since changes in BP levels, that paralleled changes in brain and plasma aminopeptidase activities, were observed after unilateral lesions of the nigrostriatal system, brain asymmetry, aminopeptidase activities and BP control appear to be related, resulting their interplay in an asymmetrical neuroendocrine response that differentially affect BP control. The study of this interaction may contribute to our understanding of how the brain controls BP.
Aminopeptidases↗
Plasma aminopeptidase activities in rats after left and right intrastriatal administration of 6-hydroxydopamine.
Asymmetries in the neuroendocrine system extend from central structures to paired endocrine glands and their innervation. In addition to the well-known asymmetry in the function of brain dopamine, there are also asymmetries in the peripheral response to experimental hemi-parkinsonism, performed by means of lesions of the nigrostriatal system with 6-hydroxydopamine (6-OHDA) injections into the left or right hemisphere. Therefore, it is speculated that the neuroendocrine system would also be asymmetrically affected in experimental hemi-parkinsonism. Aminopeptidases (AP) play a major role in the control of peptide concentration at both central and peripheral levels in tissues and blood, thus reflecting the functional status of their endogenous substrates. Therefore, to evaluate the peripheral response of hemi-parkinsonism, we have performed a comprehensive study of plasma AP activities after lesions of the nigrostriatal system with 6-OHDA administered into either left or right striatum of adult male rats. Saline was injected into control groups. AlaAP, CysAP, AspAP and GluAP activities were determined in plasma, using specific arylamides as substrates. Plasma AlaAP activity increased 3-fold (p < 0.001) whereas AspAP activity decreased by 30% (p < 0.05) after lesion of the right hemisphere. In contrast, CysAP and GluAP activities increased significantly after lesion of the left hemisphere by 200 and 50%, respectively (p < 0.05). The main discovery of the present results demonstrates that experimental hemi-parkinsonism affects differentially the plasma AP activities depending on the hemisphere in which the lesion is performed. This suggests that the circulating hormones, susceptible to be hydrolyzed by these enzymatic activities, are also modified.
Aminopeptidases↗
Anti-inflammatory effects of AT1 receptor blockade provide end-organ protection in stroke-prone rats independently from blood pressure fall.
Spontaneously hypertensive stroke-prone rats (SHRSP) develop hypertension and systemic inflammation, with subsequent brain and renal disorders and early death. We tested the hypothesis that valsartan, an angiotensin II type 1 (AT1) receptor antagonist, exerts protective effects in SHRSP through its anti-inflammatory properties, even in the absence of a blood pressure-lowering effect. SHRSP fed a high-salt diet were treated with vehicle or valsartan (1-10 mg/kg/day). The vehicle-treated rats developed hypertension, proteinuria, progressive kidney disease, and, 40 +/- 5 days from the beginning of the treatment, brain damage as visualized by magnetic resonance imaging. Rats treated with 1 mg/kg/day valsartan developed brain damage after 61 +/- 3 days (p <0.01 versus vehicle-treated rats). No damage showed after 100 days in 80% of the rats treated with 10 mg/kg/day. Valsartan treatment preserved renal structure, by preventing the infiltration of inflammatory cells, and lowered renal expression of monocyte chemoattractant protein-1, transforming growth factor-beta1, and interleukin-1beta, compared with vehicle-treated SHRSP. Urinary excretion of acute-phase proteins increased in the latter but remained negligible in the drug-treated animals. Furthermore, valsartan exerted protective effects also when given after established proteinuria. In SHRSP, blockade of AT1 receptor with valsartan prevents the development of proteinuria, delays the appearance of brain damage, preserves renal structure, and increases survival under stressful conditions. Valsartan exerts its beneficial effects independently of any blood pressure fall and by means of broad anti-inflammatory actions both at local and at systemic levels. These observations indicate that the administration of AT1 receptor antagonists may be useful in pathological situations in which an anti-inflammatory effect is required.
Angiotensin II Type 1 Receptor Blockers↗
Neuropeptides, neuropeptidases and brain asymmetry.
Brain asymmetry is understood as an anatomical, functional or neurochemical difference between the two hemispheres. It is not a static but rather a dynamic phenomenon in which both environmental and endogenous factors act as modulators. Aging modifies brain asymmetry, and an imbalance in specific asymmetries characterizes some brain disorders such as schizophrenia, depression, infantile autism or Alzheimer's disease. However, it is not clear whether these changes are a cause or a consequence of these disorders. Although this phenomenon has been extensively studied, its functional significance is not yet clear, and the neurochemical basis underlying anatomical or functional asymmetries in the brain is still poorly understood. In recent decades intensive research on the behaviour of neuropeptides has revealed asymmetries in their distribution in the brain, and there is evidence that the lateralized patterns of distribution are involved in the regulatory control of some neuropeptidase activities. Therefore, if these enzymatic activities are distributed asymmetrically, their endogenous substrates would presumably be affected in an asymmetrical way, as would the functions they are involved in. Here we review the most significant literature regarding human and animal brain asymmetry involving neuropeptides such as corticotropin-releasing hormone, cholecystokinin, luteinizing hormone-releasing hormone, thyrotropin-releasing hormone and angiotensin II, as well as their neuropeptidases.
Aminopeptidases↗
Angiotensinase activities in the kidney of renovascular hypertensive rats.
In spite of the well-known contribution of angiotensin II (Ang II) in the pathogenesis of Goldblatt two-kidney one clip (G2K1C) hypertension, the importance of other Ang peptides, such as Ang III, Ang IV or Ang 2-10, is scarcely understood. The functional status of these peptides depends on the action of several aminopeptidases called angiotensinases. The metabolism of Ang III to Ang IV by aminopeptidase M (AlaAP) and of Ang I to Ang 2-10 by aspartyl aminopeptidase (AspAP) was evaluated in the renal cortex and medulla of normotensive (Sham-operated) and hypertensive (G2K1C) rats, treated or not with the AT(1) receptor antagonist valsartan. The results demonstrated a highly significant increase of membrane-bound (MEMB) AlaAP in the cortex of the non-ischemic kidney of G2K1C rats compared with the kidney of normal rats and with the clipped kidney of G2K1C rats. This suggests an increased formation of Ang IV in the non-clipped kidney of G2R1C rats. Valsartan reduced MEMB AlaAP and AspAP activities in the renal cortex of normotensive and in the clipped kidney of hypertensive rats. The reduced metabolism of Ang III may prolong its half-life in valsartan-treated animals. These results suggest a role for AlaAP in renovascular hypertension. In addition, the higher AspAP activity of the renal cortex compared to medulla reflects its relative functional difference between both locations.
Adrenal Cortex↗
Disparate effects of angiotensin II antagonists and calcium channel blockers on albuminuria in experimental diabetes and hypertension: potential role of nephrin.
OBJECTIVE AND DESIGN: To explore the effects of various antihypertensive regimes which achieve similar blood pressure control using a range of agents including the angiotensin II type 1 receptor antagonist, valsartan, as monotherapy or in combination with two subclasses of calcium channel blockers (CCBs) (the dihydropyridine, amlodipine and the phenylalkylamine, verapamil) on the progression of renal disease and the expression of the podocyte slit pore protein, nephrin in an accelerated model of diabetic nephropathy. RESULTS: Valsartan treatment reduced systolic blood pressure as assessed by radiotelemetry (135 +/- 3 versus diabetic 153 +/- 6 mmHg) as well as retarding the increase in albumin excretion rate by approximately 50%. Combination therapy of valsartan with either amlodipine or verapamil was equally effective in reducing blood pressure to valsartan monotherapy (valsartan + amlodipine 129 +/- 4 valsartan + verapamil 133 +/- 6 mmHg;) but was not as effective at reducing albuminuria. A reduction in glomerulosclerosis was observed with valsartan monotherapy with less reduction in injury with the valsartan + amlodipine combination, despite a similar reduction in blood pressure. The decrease in nephrin, in diabetic rats was attenuated by valsartan monotherapy, but not by other treatments. CONCLUSIONS: The results of this study demonstrate that despite a similar reduction in blood pressure, the addition of the CCB amlodipine to the AII antagonist failed to provide similar renoprotection to that observed with an equihypotensive regimen of valsartan as monotherapy. Furthermore, the depletion in glomerular nephrin expression in diabetic animals was only abrogated by valsartan treatment, the therapy which was most effective at retarding the development of albuminuria in this model.
Albuminuria↗
Aminopeptidase activity in renovascular hypertension.
BACKGROUND: Renovascular hypertension is accompanied by increased renin-angiotensin system activity. Angiotensin II (Ang II) is degraded by aminopeptidases into various metabolites. Increased Ang II production and decreased Ang II degradation may have pathological consequences in maintaining high tissue/plasma Ang II levels. MATERIAL/METHODS: We report the effects of renovascular hypertension on alanyl- (AlaAP), arginyl- (ArgAP), cystinyl- (CysAP), aspartyl- (AspAP), glutamyl- (GluAP) and pyroglutamyl- (pGluAP) aminopeptidases, using arylamides as substrates. The enzymatic activities were analyzed in plasma, right atrium, lung, left ventricle and aortic ring of rats, normotensive (sham-operated) and hypertensive (Goldblatt two-kidney one-clip, G2K1C), treated or not with the AT1 receptor antagonist valsartan. All determinations were performed six weeks after surgery. RESULTS: Whereas the atrium exhibited an increase, the lung, ventricle and aorta showed a decrease of aminopeptidases in G2K1C rats. Except in the aorta of normotensive rats, valsartan did not affect aminopeptidases in the groups studied. CONCLUSIONS: The present study may imply reduced metabolism of angiotensin II in the lung and aorta of G2K1C rats. This down-regulation could prolong the half-life of Ang II and contribute to the maintenance of hypertension. Changes in AP activities did not appear to be part of the action mechanism of AT1 receptor blockade in hypertensive rats
Aminopeptidases↗
Angiotensin II and nitric oxide interaction.
Nitric oxide degradation linked to endothelial dysfunction plays a central role in cardiovascular diseases. Superoxide producing enzymes such as NADPH oxidase and xanthine oxidase are responsible for NO degradation as they generate a variety of reactive oxygen species (ROS). Moreover, superoxide is rapidly degraded by superoxide dismutase to produce hydrogen peroxide leading to the uncoupling of NO synthase and production of increased amount of superoxide. Angiotensin II is an important stimulus of NADPH oxidase. Through its AT(1) receptor, Ang II stimulates the long-term increase of several membrane component of NADPH oxidase such as P(22) phox or nox-1 and causes an increased activity of NADPH oxidase with inactivation of NO leading to impaired endothelium-dependent vasorelaxation, vascular smooth muscle cell hypertrophy, proliferation and migration, extracellular matrix formation, thrombosis, cellular infiltration and inflammatory reaction. Several preclinical and clinical studies have now confirmed the involvement of the AT(1) receptor in endothelial dysfunction. It is proposed that the AT(2) receptor counterbalances the deleterious effect of the Ang II-induced AT(1) receptor stimulation through bradykinin and NOS stimulation. This mechanism could be especially relevant in pathological cases when the NADPH oxidase activity is blocked with an AT(1) receptor antagonist.
Angiotensin II↗
Dietary fatty acid composition affects aminopeptidase activities in the testes of mice.
The autocrine/paracrine control mechanisms of local factors, such as the renin-angiotensin system and the thyrotropin-releasing hormone (TRH), seem to play a relevant role in testicular physiology. It has been proposed that dietary fat composition influences male reproductive function modifying the cholesterol-phospholipid composition of testicular plasma membranes. Modifications in the composition and physical properties of the membranes may lead to alterations in the activities of membrane-bound (M-B) enzymes. We have previously demonstrated that cholesterol and steroid hormones affect aminopeptidase (AP) activities. Dietary fatty acids with different degrees of saturation modified AP activities in the serum of mice and an olive oil supplemented diet influenced the AP activities in the testes of mice. We hypothesized that the modification of dietary fat composition may affect angiotensin- [glutamyl-AP (GluAP), aspartyl-AP (AspAP)] and TRH- [pyroglutamyl-AP (pGluAP)] degrading activities in the testis. In this study, we investigated the effect of diets supplemented with sunflower oil (SFO), fish oil (FO), olive oil (OO), lard (L) or coconut oil (CO) on soluble (Sol) and M-B GluAP, AspAP and pGluAP in mice testis, using arylamides as substrates. Sol GluAP activity did not show differences among groups. However, Sol AspAP and Sol pGluAP progressively decreased with the degree of saturation of the fatty acid used in the diet. In contrast, M-B GluAP progressively increased with the degree of saturation of the fatty acid used in the diet. For M-B AspAP activity, mice fed diets containing FO showed significantly higher levels than those fed diets containing SFO, OO and L but not those containing CO. For M-B pGluAP activity, the highest levels were observed for mice fed diets containing FO and OO. The present data suggest that the type of fat used in the diet may influence the autocrine/paracrine functions of locally synthesized angiotensin peptides and TRH in the testis, and consequently may be important in male reproductive functions.
Aminopeptidases↗
Combination of low-dose valsartan and enalapril improves endothelial dysfunction and coronary reserve in Nomega-nitro-L-arginine methyl ester-treated spontaneously hypertensive rats.
Combination of nonhypotensive doses of valsartan and enalapril markedly improved survival (+87%) compared with untreated animals (37%) in spontaneously hypertensive rats (SHRs) with endothelial dysfunction. However, the combination had no effect on kidney function, and proteinuria persisted over the 12 weeks of the study. It was hypothesized that the greater survival was due to improvement in endothelial function or coronary vasculature despite blockade of nitric oxide synthase and high blood pressure. Therefore, endothelial function was evaluated in isolated aortic ring and maximal coronary blood flow was studied in isolated perfused SHR hearts (20-24 weeks) treated with -nitro-l-arginine methyl ester (L-NAME) (50 mg/l) for 4 weeks. The animals received vehicle, valsartan 5 mg/kg/d, enalapril 1 mg/kg/d, valsartan 50 mg/kg/d, or the combination valsartan 5 mg/kg/d with enalapril 1 mg/kg/d in drinking water. Normotensive Wistar-Kyoto (WKY) rats were used as control. Blood pressure was measured by telemetry. Histopathology was performed on heart, kidney (hematoxylin-eosin), and aorta (Masson trichrome). L-NAME elevated blood pressure by 50 mm Hg after vehicle (199 +/- 5 mm Hg). Valsartan 50 mg/kg/d completely abolished this increase (150 +/- 4 mm Hg) whereas the valsartan-enalapril combination synergistically decreased blood pressure (-37 mm Hg at 162 +/- 7 mm Hg) compared with monotherapy (valsartan 5 mg/kg/d -10 mm Hg; enalapril 1 mg/kg/d -15 mm Hg). All treatments improved the histopathology, most markedly in those receiving the valsartan-enalapril combination. The severity mean grades for lesions were 2.1, 1.9, 1.7, 1.1, and 0.9 in vehicle-treated SHRs, enalapril 1 mg/kg/d, valsartan 5 mg/kg/d, valsartan 5 or 50 mg/kg/d, and the valsartan-enalapril combination, respectively, compared with 0.02 in WKY rats. Acetylcholine-induced relaxation was significantly greater in treated SHRs than after vehicle (-40% at 0.1 mmol acetylcholine) but the combination induced the maximal relaxation (-85%). The ratio of maximal tension induced by serotonin in rings with and without endothelium was 1.4 and 1.3 in vehicle and valsartan 5 mg/kg/d-treated rats whereas it did not differ from 1 in WKY rats and all other treated groups. The cardiac hypertrophy (+27%) was prevented by valsartan 50 mg/kg/d and the valsartan-enalapril combination. Coronary reserve was significantly increased by valsartan 50 mg/kg/d (+85% at 7.8 +/- 0.7 ml/min/g) and the valsartan-enalapril combination (+42% at 6.0 +/- 0.4 ml/min/g) compared with 4.2 +/- 0.5 (vehicle). This was not different of 8.8 +/- 0.5 (WKYs). Despite the maintenance of a high blood pressure, low-dose valsartan-enalapril significantly improved endothelial function and histopathology and increased coronary reserve in SHRs chronically receiving L-NAME.
Angiotensin-Converting Enzyme Inhibitors↗
Effect of angiotensin II type 1 receptor blockade on cardiac remodeling in angiotensin II type 2 receptor null mice.
To clarify the possible involvement of uninhibited angiotensin II (Ang II) type 2 (AT(2)) receptor stimulation in the effects of an Ang II type 1 (AT(1)) receptor blocker, valsartan, we examined the cardiovascular remodeling induced by aortic banding with the use of wild-type (Agtr2+) and AT(2) receptor null (Agtr2-) mice. Aortic banding caused cardiac hypertrophy in Agtr2+ and Agtr2- mice to a similar degree 6 weeks after surgery, whereas coronary arterial thickening and perivascular fibrosis were more exaggerated in Agtr2- mice. The AT(2) receptor was observed predominantly in the coronary arteries and perivascular region of Agtr2+ mice. Valsartan at a dose of 1 mg/kg per day, which did not influence systolic blood pressure, suppressed cardiac hypertrophy similarly in both strains. Valsartan inhibited coronary arterial thickening and perivascular fibrosis in both groups; however, the inhibitory effects of valsartan were significantly weaker in Agtr2- mice. The inhibitory effects of a nonselective Ang II receptor antagonist, [Sar(1),Ile(8)]-Ang II, on cardiac hypertrophy, coronary artery thickening, and perivascular fibrosis were not significantly different in Agtr2+ and Agtr2- mice. These results suggest that the improvement by valsartan of coronary arterial thickening and perivascular fibrosis after pressure overload is caused by uninhibited AT(2) receptor stimulation in addition to AT(1) receptor blockade.
Angiotensin Receptor Antagonists↗