Angiotensin II, dopamine and nitric oxide. An asymmetrical neurovisceral interaction between brain and plasma to regulate blood pressure.

Vital functions, such as blood pressure, are regulated within a framework of neurovisceral integration in which various factors are involved under normal conditions maintaining a delicate balance. Imbalance of any of these factors can lead to various pathologies. Blood pressure control is the result of the balanced action of central and peripheral factors that increase or decrease. Special attention for blood pressure control was put on the neurovisceral interaction between Angiotensin II and the enzymes that regulate its activity as well as on nitric oxide and dopamine. Several studies have shown that such interaction is asymmetrically organized. These studies suggest that the neuronal activity related to the production of nitric oxide in plasma is also lateralized and, consequently, changes in plasma nitric oxide influence neuronal function. This observation provides a new aspect revealing the complexity of the blood pressure regulation and, undoubtedly, makes such study more motivating as it may affect the approach for treatment.

Cystinyl and pyroglutamyl-beta-naphthylamide hydrolyzing activities are modified coordinately between hypothalamus, liver and plasma depending on the thyroid status of adult male rats.

The hypothalamus determinates metabolic processes in liver through endocrine and autonomic control. Hypothalamic neuropeptides, such as thyrotropin releasing hormone or vasopressin, have been involved in liver metabolism. The thyroid status influences metabolic processes including liver metabolism in modulating those hypothalamic peptides whose functional status is regulated in part by aminopeptidase activities. In order to obtain data for a possible coordinated interaction between hypothalamus, plasma and liver, of some aminopeptidase activities that may partially reflect the hydrolysis of those peptides, pyroglutamyl- (pGluAP) and cystinyl- (CysAP) beta-naphthylamide hydrolyzing activities were determined fluorimetrically, both in their soluble and membrane-bound forms, in eu- hypo- and hyperthyroid adult male rats. Hyperthyroidism and hypothyroidism were induced with daily subcutaneous injections of tetraiodothyronine (300 µg/kg/day) or with 0.03% methimazole in drinking water for 6 weeks. Results demonstrated significant changes depending on the type of enzyme and the thyroid status. The most striking changes were observed for CysAP in liver where it was reduced in hypothyroidism and increased in hyperthyroidism. Significant intra- and inter-tissue correlations were observed. While there were positive inter-tissue correlations between liver, plasma and hypothalamus in eu-and hypothyroid rats, a negative correlation between hypothalamus and liver was observed in hyperthyroidism. These results suggest the influence of thyroid hormones and an interactive role for these activities in the control of liver metabolism. The present data also suggest a role for CysAP and pGluAP activities in liver function linked to their activities in hypothalamus.

Bidirectional asymmetry in the neurovisceral communication for the cardiovascular control: New insights.

The cardiovascular control involves a bidirectional functional connection between the brain and heart. We hypothesize that this connection could be extended to other organs using endocrine and autonomic nervous systems (ANS) as communication pathways. This implies a neuroendocrine interaction controlling particularly the cardiovascular function where the enzymatic cascade of the renin-angiotensin system (RAS) plays an essential role. It acts not only through its classic endocrine connection but also the ANS. In addition, the brain is functionally, anatomically, and neurochemically asymmetric. Moreover, this asymmetry goes even beyond the brain and it includes both sides of the peripheral nervous and neuroendocrine systems. We revised the available information and analyze the asymmetrical neuroendocrine bidirectional interaction for the cardiovascular control. Negative and positive correlations involving the RAS have been observed between brain, heart, kidney, gut, and plasma in physiologic and pathologic conditions. The central role of the peptides and enzymes of the RAS within this neurovisceral communication, as well as the importance of the asymmetrical distribution of the various RAS components in the pathologies involving this connection, are particularly discussed. In conclusion, there are numerous evidences supporting the existence of a neurovisceral connection with multiorgan involvement that controls, among others, the cardiovascular function. This connection is asymmetrically organized.

Handedness and gender influence blood pressure in young healthy men and women: A pilot study.

OBJECTIVE: The type and level of sex steroids influence blood pressure (BP). It has been suggested that functional brain asymmetries may be influenced by sex hormones. In addition, there are inter-arm differences in BP not yet related with handedness. In this study, we hypothesize a possible association between sex hormones, handedness, and inter-arm differences in blood pressure. METHODS: To analyze this hypothesis, we measured BP in the left and right arm of the left and right handed adult young men and women in menstrual and ovulatory phase and calculated their mean arterial pressure (MAP). RESULTS: Significant differences depending on sex, arm, handedness or phase of the cycle were observed. MAP was mostly higher in men than in women. Remarkably, in women, the highest levels were observed in the left handed in menstrual phase. Interestingly, the level of handedness correlated negatively with MAP measured in the left arm of right-handed women in the ovulatory phase but positively with the MAP measured in the right arm of right-handed women in the menstrual phase. CONCLUSIONS: These results may reflect an asymmetrical modulatory influence of sex hormones in BP control.

Relationship of angiotensinase and vasopressinase activities between hypothalamus, heart, and plasma in L-NAME-treated WKY and SHR.

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.

The renin-angiotensin system: new insight into old therapies.

Although the renin-angiotensin system (RAS) is already an old acquaintance, there are often exciting discoveries that improve our knowledge of it and open new therapeutic possibilities. Moreover, well-established drugs, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), or beta-blockers, show that their mechanism of action may be the result of parallel pathways other than the ones initially established. A detailed analysis of the RAS can be carried out in part through the study of the enzymes, named angiotensinases, involved in its cascade, whose activity is a reflection of the functionality of their peptide substrates. The study of these enzymes offers the possibility of controlling the effects of angiotensins through various pharmacological manipulations. For example, angiotensinase inhibitors or activators are being used or have been proposed as antihypertensive agents. They have also been suggested as analgesic and antidepressant drugs or targets for drug development against different pathologies such as Alzheimer's disease, epilepsy or ischemia. On the other hand, the analysis of brain asymmetry has revealed surprising results about the laterality of central and peripheral components of the RAS. Such studies indicate that the neurovisceral integration, already proposed by Claude Bernard (1867) should also be analyzed from a bilateral perspective. In this review, the RAS and the role of various angiotensinases implicated in the cascade are revisited. Therapeutic strategies involving some components of the RAS with an unusual vision resulting from a bilateral perspective added to their study are discussed.

Effects of antihypertensive drugs on angiotensinase activities in the testis of spontaneously hypertensive rats.

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.

Angiotensinase and vasopressinase activities in hypothalamus, plasma, and kidney after inhibition of angiotensin-converting enzyme: basis for a new working hypothesis.

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.

Blood pressure increased dramatically in hypertensive rats after left hemisphere lesions with 6-hydroxydopamine.

Plasma angiotensinase activity, nitric oxide and systolic blood pressure (SBP) were differently affected after unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), depending on the brain hemisphere injured. Moreover, normotensive and hypertensive rats responded differently suggesting an asymmetry in the organization of the autonomic nervous system of the vessels. The aim of this study was to investigate the evolution of SBP and heart rate (HR) over time after nigrostriatal lesions in normotensive and hypertensive rat strains. Unilateral depletions of brain dopamine were performed by injecting 6-OHDA into the left or right striatum of normotensive and hypertensive rats. Vehicle without 6-OHDA was unilaterally injected in control (sham) groups. SBP and heart rate (HR) were measured in un-anesthetised animals 10 and 3 days before administration of 6-OHDA or vehicle and 3 and 25 days after treatment. In normotensive rats, at the end of study, SBP increased significantly from pre-lesioned values in left-lesioned animals but no differences were observed in right-lesioned or sham groups. Before sacrifice, there was a significant reduction from pre-lesion values in HR. In hypertensive animals, there was a highly significant increase of SBP in left-lesioned and sham left rats and a slight increase in right-lesioned but no differences were observed in sham right group. No differences in HR were observed throughout the study in the groups studied. The present results represent direct experimental evidence of an asymmetrical cardiovascular response to unilateral brain lesions, suggesting that left injury may have a worst prognosis.

The profile of fatty acids in frontal cortex of rats depends on the type of fat used in the diet and correlates with neuropeptidase activities.

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.

Hypothalamic and plasmatic angiotensin metabolism in L-NAME treated rats.

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.

The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice.

AIMS/HYPOTHESIS: There is convincing evidence that the endothelin system contributes to diabetic nephropathy and cardiovascular disease. This study aimed to assess the effects of the non-peptidergic endothelin receptor A (ETA) antagonist avosentan in a mouse model of accelerated diabetic nephropathy and atherosclerosis in comparison with the ACE inhibitor, quinapril. METHODS: Apolipoprotein E (Apoe) knockout (KO) mice (n = 20 per group, five groups) were randomised to the following groups: non-diabetic controls and streptozotocin-induced diabetic animals gavaged daily for 20 weeks with placebo, avosentan (high dose: 30 mg/kg, or low dose: 10 mg/kg) or quinapril (given in drinking water, 30 mg/kg). RESULTS: BP was unchanged by avosentan treatment but decreased with quinapril treatment. Diabetes-associated albuminuria was significantly attenuated by high-dose avosentan after 10 and 20 weeks of treatment. Diabetic animals showed a decreased creatinine clearance, which was normalised by avosentan treatment. In diabetic mice, high-dose avosentan treatment significantly attenuated the glomerulosclerosis index, mesangial matrix accumulation, glomerular accumulation of the matrix proteins collagen IV, and renal expression of genes encoding connective tissue growth factor, vascular endothelial growth factor, transforming growth factor beta and nuclear factor kappaB (p65 subunit). Furthermore, high-dose avosentan treatment was also associated with reduced expression of the genes for ETA, ETB and angiotensin receptor 1. The renoprotective effects of avosentan were comparable or superior to those observed with quinapril. High-dose avosentan also significantly attenuated diabetes-associated aortic atherosclerosis in Apoe KO mice and reduced macrophage infiltration and aortic nitrotyrosine expression. CONCLUSIONS/INTERPRETATION: This study demonstrates that ETA blockade with avosentan may provide an alternate therapeutic strategy for the treatment of diabetic micro- and macrovascular complications.

Influence of thyroid disorders on kidney angiotensinase activity.

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.

Angiotensinase activity is asymmetrically distributed in the amygdala, hippocampus and prefrontal cortex of the rat.

There are important asymmetries in brain functions such as emotional processing and stress response in humans and animals. Knowledge of the bilateral distribution of brain neurotransmitters is important to appropriately understand its functions. Some peptides such as those included in the renin-angiotensin system (RAS) and cholecystokinin (CCK) are related to modulation of behavior and stress. However, although angiotensin AT1 and CCK type 2 receptors were found in adult rat brain, there are no studies of their bilateral distribution in stress-related areas. The function of angiotensin peptides is depending on the action of several aminopeptidases (AP) called angiotensinases, some of them being also involved in the metabolism of CCK. We have studied the bilateral distribution of soluble (SOL) and membrane-bound (MEM) alanyl- (AlaAP), cystinyl- (CysAP), glutamyl- (GluAP) and aspartyl- (AspAP) AP activities in stress-related areas such as amygdala, hippocampus and medial prefrontal cortex of adult male rats in resting conditions. These enzymes are involved in the metabolism of angiotensins (AlaAP, CysAP, GluAP, AspAP) and CCK (GluAP, AspAP). In the amygdala, all the activities studied showed a right predominance with a significant difference ranging from 30% for SOL CysAP to 125% for SOL GluAP. In the hippocampus, there was a left predominance for SOL AlaAP, SOL and MEM CysAP and MEM AspAP activities (100, 80, 300 and 100% higher, respectively). In contrast, GluAP predominated remarkably in the right hippocampus (eight-fold for SOL and three-fold for MEM). In the prefrontal cortex, SOL and MEM CysAP and SOL AspAP predominated in the left hemisphere (40, 100 and 40% higher, respectively). These results demonstrated a heterogeneous bilateral pattern of angiotensinase activities in motivation and stress-related areas. This may reflect an uneven asymmetrical distribution of their endogenous substrates depending on the brain location and consequently, it would be also a reflect of the asymmetries in the functions they are involved in.

Angiotensinase activity in hypothalamus and pituitary of hypothyroid, euthyroid and hyperthyroid adult male rats.

A local renin-angiotensin system (RAS) that may be involved in their regulatory functions has been identified in hypothalamus and pituitary. Altered thyroid status induces modifications in the secretory function of hypothalamus and pituitary. However, few studies have analyzed the role of the RAS in hypothalamus and, to our knowledge, there is no data on the pituitary RAS during thyroid dysfunction. In the present study, angiotensinase activities (glutamyl, aspartyl and alanyl aminopeptidase: GluAP, AspAP and AlaAP, respectively) were studied in hypothalamus and in the anterior and posterior lobes of pituitary of euthyroid, hypothyroid and hyperthyroid adult male rats. In the anterior pituitary, compared with euthyroid and hyperthyroid rats, hypothyroid animals showed a highly significant increase of GluAP and AspAP activities; the percentage increase in GluAP was markedly higher than the percentage increase in AspAP. This suggests an increased metabolism of angiotensin (Ang) I and Ang II to des-Asp 1-Ang I and Ang III, respectively. We also observed an increase of Ang III-degrading activity (AlaAP) in the hypothalamus of hyperthyroid rats in soluble fraction. Increased Ang I and Ang II metabolism in the anterior pituitary of hypothyroid rats and increased metabolism of Ang III in the hypothalamus of hyperthyroid animals may be related to alterations in the secretory function of hypothalamus and pituitary in these thyroid dysfunctions.

Effects of dehydration on renal aminopeptidase activities in adult male and female rats.

Aminopeptidases (APs) are important regulators of peptides directly involved in water homeostasis such as angiotensins (Ang) and vasopressin (AVP). Sex differences in water balance and differences in the effects of gonadal steroids on osmotic stimulation of vasopressin secretion have been reported. Since sex steroids may be involved, the gonadotropin response to osmotic stimuli may be different between males and females. The purpose of this study was to determine the behavior of angiotensinases, vasopressin-degrading activity and gonadotropin-releasing hormone (GnRH)-degrading activity in the cortex and medulla of the kidney of dehydrated male and female rats. In the renal cortex, our results demonstrated an increase in Ang III-degrading activity in dehydrated males but not in females. This response may lead to an increased formation of Ang IV. This occurs with an increase in AspAP activity (which metabolizes Ang I to des-Asp(1)-Ang I), with no changes in Ang II-degrading activity and also with increased levels of AVP-degrading activity in dehydrated animals. These results may suggest an increased cortical blood flow due to enhanced formation of Ang IV together with reduced availability of the vasoconstrictor agents Ang II and AVP in the renal cortex of dehydrated males. The results obtained in the renal medulla suggest the inhibition of the metabolism of Ang I to des-Asp(1)-Ang I, together with a reduced metabolism of Ang II and AVP in dehydrated males but not in females. These results suggest a prolonged action of Ang II and AVP, which could stimulate sodium and water reabsorption in the medulla of dehydrated males. Changes in APs after dehydration occur preferentially in males, which may explain in part the reported sex differences in water homeostasis. The present results suggest a physiologically relevant role for AP activities in water homeostasis.

Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury.

BACKGROUND: To investigate the effect of angiotensin (Ang) II type 1 receptor (AT(1)) blocker on vascular remodeling and explore the possibility of the involvement of Ang II type 2 receptor (AT(2)) stimulation in this process, we examined the effects of the selective AT(1) blocker valsartan on the vascular injury in wild-type (Agtr2+) and AT(2)-null (Agtr2-) mice. METHODS AND RESULTS: Neointima formation and the proliferation of vascular smooth muscle cells (VSMCs) induced by cuff placement on the femoral artery were greater in Agtr2- mice than those in Agtr2+ mice. Treatment of mice with valsartan at a dose of 1 mg. kg(-1). d(-1), which did not influence systolic blood pressure, significantly decreased neointima formation and the proliferation of VSMCs, whereas the valsartan was less effective in Agtr2- mice. Moreover, cuff placement increased the expression of monocyte chemoattractant protein-1 (MCP-1); inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta; and infiltration of CD45-positive leukocytes and macrophages in the injured arteries and further enhanced them in Agtr2- mice, suggesting the antagonistic effects of AT(1) and AT(2) for vascular inflammation. Valsartan attenuated the expression of MCP-1, TNF-alpha, IL-6, IL-1beta, and infiltration of leukocytes and macrophages in the injured arteries; however, these effects of valsartan were less prominent in Agtr2- mice. CONCLUSIONS: These results suggest that the stimulation of the AT(2) receptor after AT(1) blockade is important in the improvement of the inflammatory vascular injury.

Effect of valsartan on angiotensin II- and vasopressin-degrading activities in the kidney of normotensive and hypertensive rats.

Valsartan, a selective antagonist of angiotensin II at the AT(1) receptor subtype, is an efficacious, orally active, blood pressure-lowering agent used in hypertensive patients. Given that aminopeptidases (APs) play a major role in the metabolism of local peptides involved in blood pressure control, studying them helped us to understand cardiovascular control. We studied the effect of valsartan on angiotensin II- (GluAP) and vasopressin- (CysAP) degrading activities in the kidney in the rat model of renovascular hypertension, Goldblatt two-kidney one-clip. GluAP and CysAP in renal cortex and medulla exhibited different responses to hypertension and valsartan treatment. In the renal cortex, GluAP decreased in clipped and non-clipped kidneys of hypertensive animals. However, while hypertension did not affect GluAP in the clipped kidney medulla, the non-clipped kidney exhibited an increase in soluble and a decrease in membrane-bound activity. Valsartan decreased soluble GluAP in the medulla of normotensive and hypertensive animals. In the renal cortex, CysAP activity was mainly downregulated following hypertension. Valsartan decreased soluble CysAP activity in sham-operated, but not in hypertensive animals. The renal medulla showed a significant valsartan-related decreased activity in clipped and non-clipped kidneys of both sham-operated and hypertensive animals. These results suggest a functional relationship between the AT(1) receptor and vasopressin-degrading activity.

Combined angiotensin II AT1-receptor blockade and angiotensin I-converting enzyme inhibition on survival and cardiac remodeling in chronic heart failure in rats.

BACKGROUND: Angiotensin I-converting enzyme inhibition (ACEI) and angiotensin II AT(1)-receptor blockade are effective at improving survival and limiting cardiac remodeling in the rat model of postischemic heart failure. Whether their combination yields additive/synergistic effects is unknown. METHODS AND RESULTS: Rats underwent coronary artery ligation and 7 days later were treated orally for 9 months with placebo (controls), 5 mg/kg valsartan, 1 mg/kg enalapril (doses submaximally effective at reducing mortality in the experimental model used), or 5 mg/kg valsartan and 1 mg/kg enalapril combined. Compared with controls, valsartan, enalapril, and their combination decreased mortality by 40% (P =.006), 21% (P =.065), and 33% (P =.032), respectively, but there was no significant difference between the 3 treatments. At the doses used, valsartan, but neither enalapril nor the combination, slightly limited cardiac hypertrophy and fibrosis development and reduced left ventricular end-diastolic pressure as assessed in the surviving animals at 9 months. CONCLUSIONS: In experimental chronic heart failure in rats, valsartan reduces mortality similar to other AT(1)-receptor blockers and a combination of AT(1)-receptor blockade (valsartan) and ACEI (enalapril) at submaximal doses does not exert additive/synergistic beneficial effects on mortality.