Utilization of Deep Learning for Subphenotype Identification in Sepsis-Associated Acute Kidney Injury.

BACKGROUND AND OBJECTIVES: Sepsis-associated AKI is a heterogeneous clinical entity. We aimed to agnostically identify sepsis-associated AKI subphenotypes using deep learning on routinely collected data in electronic health records. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used the Medical Information Mart for Intensive Care III database, which consists of electronic health record data from intensive care units in a tertiary care hospital in the United States. We included patients ≥18 years with sepsis who developed AKI within 48 hours of intensive care unit admission. We then used deep learning to utilize all available vital signs, laboratory measurements, and comorbidities to identify subphenotypes. Outcomes were mortality 28 days after AKI and dialysis requirement. RESULTS: We identified 4001 patients with sepsis-associated AKI. We utilized 2546 combined features for K-means clustering, identifying three subphenotypes. Subphenotype 1 had 1443 patients, and subphenotype 2 had 1898 patients, whereas subphenotype 3 had 660 patients. Subphenotype 1 had the lowest proportion of liver disease and lowest Simplified Acute Physiology Score II scores compared with subphenotypes 2 and 3. The proportions of patients with CKD were similar between subphenotypes 1 and 3 (15%) but highest in subphenotype 2 (21%). Subphenotype 1 had lower median bilirubin levels, aspartate aminotransferase, and alanine aminotransferase compared with subphenotypes 2 and 3. Patients in subphenotype 1 also had lower median lactate, lactate dehydrogenase, and white blood cell count than patients in subphenotypes 2 and 3. Subphenotype 1 also had lower creatinine and BUN than subphenotypes 2 and 3. Dialysis requirement was lowest in subphenotype 1 (4% versus 7% [subphenotype 2] versus 26% [subphenotype 3]). The mortality 28 days after AKI was lowest in subphenotype 1 (23% versus 35% [subphenotype 2] versus 49% [subphenotype 3]). After adjustment, the adjusted odds ratio for mortality for subphenotype 3, with subphenotype 1 as a reference, was 1.9 (95% confidence interval, 1.5 to 2.4). CONCLUSIONS: Utilizing routinely collected laboratory variables, vital signs, and comorbidities, we were able to identify three distinct subphenotypes of sepsis-associated AKI with differing outcomes.

Aminopeptidases in Cardiovascular and Renal Function. Role as Predictive Renal Injury Biomarkers.

Aminopeptidases (APs) are metalloenzymes that hydrolyze peptides and polypeptides by scission of the N-terminus amino acid and that also participate in the intracellular final digestion of proteins. APs play an important role in protein maturation, signal transduction, and cell-cycle control, among other processes. These enzymes are especially relevant in the control of cardiovascular and renal functions. APs participate in the regulation of the systemic and local renin-angiotensin system and also modulate the activity of neuropeptides, kinins, immunomodulatory peptides, and cytokines, even contributing to cholesterol uptake and angiogenesis. This review focuses on the role of four key APs, aspartyl-, alanyl-, glutamyl-, and leucyl-cystinyl-aminopeptidases, in the control of blood pressure (BP) and renal function and on their association with different cardiovascular and renal diseases. In this context, the effects of AP inhibitors are analyzed as therapeutic tools for BP control and renal diseases. Their role as urinary biomarkers of renal injury is also explored. The enzymatic activities of urinary APs, which act as hydrolyzing peptides on the luminal surface of the renal tubule, have emerged as early predictive renal injury biomarkers in both acute and chronic renal nephropathies, including those induced by nephrotoxic agents, obesity, hypertension, or diabetes. Hence, the analysis of urinary AP appears to be a promising diagnostic and prognostic approach to renal disease in both research and clinical settings.

Combination therapy with vitamin C and DMSA for arsenic-fluoride co-exposure in rats.

INTRODUCTION: Arsenic and fluoride are recognized globally as the most serious inorganic contaminants in drinking water. As there is no safe and effective treatment for the cases of fluoride poisoning and combined arsenic-fluoride toxicity, the present study was planned to assess (i) the mechanism of combined exposure to arsenic and fluoride via biochemical and spectroscopic data; (ii) the effect of a thiol chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA), either individually or in combination with the antioxidant vitamin C in reversing arsenic-fluoride toxicity; and (iii) whether combination therapy enhances arsenic and fluoride removal from blood and soft tissues. METHODS: Rats were exposed to arsenic (50 mg l-1) and fluoride (50 mg l-1) individually and in combination for 9 months and later administered DMSA (50 mg kg-1) via an i.p. route and vitamin C (25 mg kg-1) orally for 5 days. Biochemical parameters suggestive of alterations in the heme synthesis pathway, oxidative stress in blood, the liver and the kidneys, and concentrations of arsenic and fluoride in blood and soft tissues were studied. We also studied the infrared (IR) spectra of DNA extracted from the livers and kidneys of the normal and exposed animals. RESULTS: It was found that chronic arsenic and fluoride exposure led to an increased oxidative stress condition and impaired heme synthesis (67% inhibition in δ-aminolevulinic acid dehydratase activity and 38% increase in δ-aminolevulinic acid synthetase activity). The decreased antioxidant defense mechanism was marked by a 2.25 fold increased concentration of Reactive Oxygen Species (ROS) and a 28% decrease in the Glutathione (GSH) level. Interestingly, concomitant exposure to arsenic and fluoride did not lead to antagonistic effects as the toxic effects were the same as those seen during the individual exposure to both the toxicants. It suggests that toxicity depends on the dose and duration of exposure. Combination therapy with DMSA and vitamin C showed a better efficacy than monotherapy in terms of reducing the arsenic and fluoride burden (more than 70% in blood and soft tissues) as well as reversal in the altered biochemical variables indicative of oxidative stress and tissue damage (80-85%). The infrared (IR) spectra of DNA isolated from the liver and kidneys suggested that the treatment with vitamin C and DMSA had no beneficial effects in terms of reversing DNA damage. CONCLUSION: On the basis of the above observations, we suggest that the combinational therapy of DMSA and vitamin C would be more effective in arsenic and/or fluoride toxicity; however, more detailed studies are required to address recoveries in DNA damage.

Liver Enzymes, Fatty Liver and Type 2 Diabetes Mellitus in a Jinchang Cohort: A Prospective Study in Adults.

OBJECTIVES: It is unclear whether liver enzymes or the interactions of various liver enzymes is a predictor of type 2 diabetes mellitus (T2DM), which is independent of fatty liver. METHODS: A total of 48,001 subjects participated in baseline examinations. Among the subjects, 33,355 were followed for an average of 2.2 years. Cox proportional hazard models were used to examine the adjusted associations of AST, GGT and ALT with T2DM. RESULTS: The cumulative incidence of T2DM was 8.05% to 9.02% for fatty liver and 2.25% to 4.10% for non-fatty liver, both showing statistically significant differences. Compared with the normal liver enzyme levels in the group with fatty liver, the adjusted incident hazard ratios in T2DM were: ALT 1.23 (95% CI 1.10 to 1.50); AST 1.30 (95% CI 1.07-1.59); and GGT 1.34 (95% CI 1.08 to 1.65). In addition, compared with the normal liver enzyme levels in the group with non-fatty liver, the adjusted incident hazard ratios in type 2 diabetes were: ALT 1.27 (95% CI 1.02 to 1.59); AST 1.33 (95% CI 1.02 to 1.59); and GGT 1.53 (95% CI 1.19 to 1.98). There are significant interactions of T2DM hazard ratios between GGT and ALT and between GGT and AST in addition to ALT and AST. CONCLUSIONS: Our results suggest that the incidence of T2DM in the group with fatty liver is significantly higher than that in the normal population, and the rise of serum AST, GGT and ALT levels are risk factors independent of fatty liver for the development of T2DM after adjusting for confounding factors.

Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort.

Serum or plasma proteases have been associated with various diseases including cancer, inflammation, or reno-cardiovascular diseases. We aimed to investigate whether the enzymatic activities of serum proteases are associated with the estimated glomerular filtration rate (eGFR) in patients with different stages of chronic kidney disease (CKD). Our study population comprised 268 participants of the "Greifswald Approach to Individualized Medicine" (GANI_MED) cohort. Enzymatic activity of aminopeptidase A, aminopeptidase B, alanyl (membrane) aminopeptidase, insulin-regulated aminopeptidase, puromycin-sensitive aminopeptidase, leucine aminopeptidase 3, prolyl-endopeptidase (PEP), dipeptidyl peptidase 4 (DPP4), angiotensin I-converting enzyme, and angiotensin I-converting enzyme 2 (ACE2) proteases was measured in serum. Linear regression of the respective protease was performed on kidney function adjusted for age and sex. Kidney function was modeled either by the continuous Modification of Diet in Renal Disease (MDRD)-based eGFR or dichotomized by eGFR < 15 mL/min/1.73 m2 or <45 mL/min/1.73 m2, respectively. Results with a false discovery rate below 0.05 were deemed statistically significant. Among the 10 proteases investigated, only the activities of ACE2 and DPP4 were correlated with eGFR. Patients with lowest eGFR exhibited highest DPP4 and ACE2 activities. DPP4 and PEP were correlated with age, but all other serum protease activities showed no associations with age or sex. Our data indicate that ACE2 and DPP4 enzymatic activity are associated with the eGFR in patients with CKD. This finding distinguishes ACE2 and DPP4 from other serum peptidases analyzed and clearly indicates that further analyses are warranted to identify the precise role of these serum ectopeptidases in the pathogenesis of CKD and to fully elucidate underlying molecular mechanisms. Impact statement • Renal and cardiac diseases are very common and often occur concomitantly, resulting in increased morbidity and mortality. Understanding of molecular mechanisms linking both diseases is limited, available fragmentary data point to a role of the renin-angiotensin system (RAS) and, in particular, Ras-related peptidases. • Here, a comprehensive analysis of serum peptidase activities in patients with different stages of chronic kidney disease (CKD) is presented, with special emphasis given to RAS peptidases • The serum activities of the peptidases angiotensin I-converting enzyme 2 and dipeptidyl peptidase 4 were identified as closely associated with kidney function, specifically with the estimated glomerular filtration rate. The findings are discussed in the context of available data suggesting protective roles for both enzymes in reno-cardiac diseases. • The data add to our understanding of pathomechanisms underlying development and progression of CKD and indicate that both enzymes might represent potential pharmacological targets for the preservation of renal function.

High aminopeptidase A activity contributes to blood pressure control in ob/ob mice by AT2 receptor-dependent mechanism.

Obesity is assumed to be a major cause of human essential hypertension; however, the mechanisms responsible for weight-related increase in blood pressure (BP) are not fully understood. The prevalence of hypertension induced by obesity has grown over the years, and the role of the renin-angiotensin-aldosterone system (RAAS) in this process continues to be elucidated. In this scenario, the ob/ob mice are a genetic obesity model generally used for metabolic disorder studies. These mice are normotensive even though they present several metabolic conditions that predispose them to hypertension. Although the normotensive trait in these mice is associated with the poor activation of sympathetic nervous system by the lack of leptin, we demonstrated that ob/ob mice present massively increased aminopeptidase A (APA) activity in the circulation. APA enzyme metabolizes angiotensin (ANG) II into ANG III, a peptide associated with intrarenal angiotensin type 2 (AT2) receptor activation and induction of natriuresis. In these mice, we found increased ANG-III levels in the circulation, high AT2 receptor expression in the kidney, and enhanced natriuresis. AT2 receptor blocking and APA inhibition increased BP, suggesting the ANG III-AT2 receptor axis as a complementary BP control mechanism. Circulating APA activity was significantly reduced by weight loss independently of leptin, indicating the role of fat tissue in APA production. Therefore, in this study we provide new data supporting the role of APA in BP control in ob/ob mouse strain. These findings improve our comprehension about obesity-related hypertension and suggest new tools for its treatment.NEW & NOTEWORTHY In this study, we reported an increased angiotensin III generation in the circulation of ob/ob mice caused by a high aminopeptidase A activity. These findings are associated with an increased natriuresis found in these mice and support the role of renin-angiotensin-aldosterone system as additional mechanism regulating blood pressure in this genetic obese strain.

The impact of P2X7 receptor antagonist, brilliant blue G on graft-versus-host disease in mice after allogeneic hematopoietic stem cell transplantation.

The purpose of this study was to investigate the role of P2X7 on liver inflammation in mice after HSCT. Hematopoietic stem cells obtained from C57BL/6 mice were administrated into BALB/c mice to establish GVHD model. On day 7, 14, 21 and 28 after HSCT, mice received P2X7R antagonist brilliant blue G (BBG) or not were sacrificed for analysis of weight loss, liver inflammation, cytokine secretion, P2X7, NLRP3 expression as well as caspase-1 activation. Liver inflammation with neutrophils and macrophases infiltration as well as weight loss increase was present after HSCT, but improved after administration with high dose of BBG compared with lower dose. High dose of P2X7R inhibitor administration after HSCT previously reduced levels of IL-1ß, IL-18, caspase-1, NLRP3 as well as P2X7, and the level of alanine transaminase (ALT) and the ratio of aspartate amino transferase (AST)/ALT compared with that receiving low dose of BBG. Meanwhile, P2X7R blockage also reduced infiltration of macrophages and neutrophils and levels of CXCL8 and CCL2 in peripheral blood as well as improved liver function. In conclusion, blockage of P2X7R by BBG exerts a protective effect on GVHD post HSCT and improves liver function suggesting that this receptor could be considered as an attractive target for treatment of GVHD.

Effect of dystocia on some hormonal and biochemical parameters in the one-humped camel (Camelus dromedarius).

The present study compared some of the hormonal and biochemical constituents of serum from eutocic and dystocic one-humped camels (Camelus dromedarius). Sera were harvested from eutocic (n = 9) and dystocic (n = 20) camels within the first 15 minutes after delivery. Although there were no differences in the concentrations of estradiol-17ß (E2) and prostaglandin F2α (PGF2α) between the eutocic and the dystocic animals, the level of progesterone (P4) and cortisol was significantly higher (P < 0.01) in animals that experienced dystocia than those that had a normal birth. There were no differences between the concentrations of alkaline phosphatase, aspartate aminotransferase, calcium, cholesterol, creatine kinase, creatinine, or magnesium (Mg) in eutocic and dystocic animals. The nitric oxide concentration was significantly higher (P < 0.01) in the serum from animals with dystocia than those that had normal births. By contrast, the serum concentrations of glucose, phosphorus (P), and triglycerides were significantly lower (P < 0.01) in eutocic camels compared with dystocic camels. As the delayed decline of P4 is reported to be the major hormonal difference between eutocic and dystocic camels, we propose that the insensitivity of corpus luteum to luteolytic action may be a cause of dystocia. Moreover, stress and hormonal changes may affect the metabolic traits in dystocia camels.

Influence of thyroid disorders on the kidney expression and plasma activity of aminopeptidase A.

OBJECTIVE: Thyroid disorders may affect blood pressure and renal function modifying factors of the plasmatic and kidney renin-angiotensin system such as aminopeptidase A (AP A) that metabolizes angiotensin II to angiotensin III. We investigated the expression of AP A in the kidney, as well as its enzymatic activity in the plasma of euthyroid, hyperthyroid, and hypothyroid adult male rats. METHODS: Hyperthyroidism was induced by daily subcutaneous injections of tetraiodothyronine. Hypothyroid rats were obtained by administration of methimazole in drinking water. Expression of AP A was determined by Western blot analysis. Plasma AP A activity was measured fluorometrically using glutamyl-ß-naphthylamide as substrate. RESULTS: While hyperthyroid rats exhibited lower levels of plasma AP A activity than controls, the kidney of hyperthyroid animals expressed significantly higher AP A than controls and hypothyroid animals. CONCLUSIONS: A discrepancy between the high expression of AP A in kidney of hyperthyroid rats and the low activity of AP A measured in plasma and kidney of hyperthyroid animals was found. The posttranslational influence of environmental biochemical factors may be in part responsible for that divergence.

Liver disease in the adolescent.

This article discusses common liver diseases in the adolescent. Briefly reviewed is the evaluation of the adolescent with new-onset liver enzyme elevation. Then the article discusses common liver diseases, such as nonalcoholic fatty liver disease, hepatitis, metabolic disease, biliary atresia, cystic fibrosis, and inherited disorders of cholestasis. Finally, a management approach to the adolescent with liver disease is outlined, noting the challenges that must be addressed to effectively care for not only liver disease in the adolescent but also the patient as a whole.

Circulating aminopeptidase activities in men and women with essential hypertension.

Essential hypertension is one of the major contributors to premature morbidity and mortality due to the incresased risk for coronary heart disease, stroke, renal disease, peripheral vascular disease and vascular dementia for both men and women. However, its basic causes remain unknown. In the present work we studied the activity of several proteolytic regulatory enzymes related to renin-angiotensin-system (RAS) (aminopeptidase A, APA; aminopeptidase N, APN; aminopeptidase B, APB; and insulin-regulated aminopeptidase, IRAP); with oxytocin regulation (oxytocinase); with the metabolism of GnRH and TRH (pyrrolidone carboxypeptidase, Pcp); and with enkephalins metabolism (enkephalindegrading activity, EDA), to elucidate their role in the mechanisms responsible of essential hypertension and to discuss the possible gender differences. Serum samples of 53 individuals with essential hypertension and 60 healthy volunteers were collected and used to assay enzyme activities, gonad hormones testosterone and estradiol, TSH and free thyroxin (fT4). Differences were observed in APA, APN, Pcp and EDA specific activities, and in serum gonad hormone levels between hypertensive and control groups. Only Pcp activity showed gender differences. Regarding the RAS, APA is reduced while APN is increased, suggesting increased levels of angiotensin II and a facilitation of the conversion of angiotensin III in angiotensin IV. Thus, the changes in several RAS-regulating specific activities and other enzyme activities involved in the neuroendocrine modulation of gonad and stress-related functions are related to essential hypertension with minor gender differences. Therefore, aminopeptidases constitute new elements for the knowledge of the causes of essential hypertension and an alternative as therapeutic targets against the illness.

Clinical impact of aspartyl aminopeptidase expression and activity in colorectal cancer.

Aspartyl aminopeptidase (ASP; EC 3.4.11.21) is a widely distributed and abundant cytosolic enzyme that regulates bioactive peptides such as angiotensin II. It has been demonstrated that the expression and activity of this enzyme is modified in tissue and serum of patients with several types of cancer. However, the involvement of ASP in the neoplastic development and survival of patients with colorectal cancer (CRC) has not been analyzed to date. The activity and messenger RNA expression of ASP in tumor tissue (n = 71) and plasma (n = 40) of patients with CRC was analyzed prospectively using fluorometric and quantitative real-time polymerase chain reaction methods. Data obtained from tumor tissue were compared with those from the surrounding normal mucosa. Classic pathologic parameters (grade, stage, nodal invasion, distant metastases and perineural, lymphatic, and vascular invasion) were stratified following ASP data and analyzed for 5-year survival. ASP was upregulated in CRC tissues, and greater activity correlated significantly with the absence of lymph node metastases and with better overall survival. Inversely, greater plasmatic ASP activity was associated with worse overall and disease-free survival. Data suggest that ASP is involved in colorectal neoplasia and point to this enzyme as a potential useful diagnostic tool in clinical practice.

Neoadjuvant chemotherapy modifies serum angiotensinase activities in women with breast cancer.

PURPOSE: The aim of this study was to investigate the putative changes in serum angiotensinase activities (aminopeptidase N, APN; aminopeptidase B, APB; aminopeptidase A, APA; aspartyl aminopeptidase, ASAP) involved in the renin-angiotensin system (RAS) in women with breast cancer treated or not with a neoadjuvant therapy of paclitaxel and anthracycline and in healthy women volunteers. METHODS: We fluorometrically analysed serum APN, APB, APA and ASAP activities using their corresponding aminoacyl-ß-naphthylamides as substrates in women with breast cancer treated with a neoadjuvant therapy of paclitaxel and anthracycline. RESULTS: When compared with healthy controls, women with breast cancer not treated with neoadjuvant chemotherapy, showed a decrease in angiotensinase activity, which support the putative increase of angiotensin II (Ang II) levels, indicating that the tumour process would favour the development of the disease. Also, an increase in APN and APB activities was observed, which support a role for angiotensin IV (Ang IV). In women treated with a neoadjuvant therapy, we described an increase in ASAP and APA activities, supporting the idea that this treatment increases Ang II catabolism. The resulting decrease in Ang II level could lead to an inhibition of the tumour growth. CONCLUSION: Present results show changes in serum angiotensinase activities in women with breast cancer and in women with breast cancer treated with a neoadjuvant therapy of paclitaxel and anthracycline. Therefore, considerable attention should be focused on the development of RAS blockade therapy as a new strategy for breast cancer treatment.

Effects of dietary supplementation with betaine on a nonalcoholic steatohepatitis (NASH) mouse model.

The effects of betaine supplementation on non-alcoholic steatohepatitis (NASH) model mice were examined by measuring the accumulation of fat in the livers of NASH model mice compared to a control. Betaine from sugar beets was provided to the model mice as a dietary supplement. After 3 wk of dietary supplementation, there were no significant differences in body weight or liver weight between the groups. However, the liver to body weight ratio in the high-fat diet with betaine (HFB) group was significantly (p<0.05) higher than that in the high-fat diet (HF) group. There were no differences in serum triglyceride (TG) concentrations, AST and ALT activities, or hepatic glutathione concentrations between the groups. Hepatic TG level in the HFB group was significantly (p<0.05) lower than that in the HF group. Hepatic cells obtained from the HF group showed increased occurrence of explosive puff and necrosis as compared with those in the HFB group. Betaine supplementation had an inhibitory effect on fat accumulation in the liver: the Oil red-positive area in the HFB group (0.82 ± 0.85%) was significantly (p<0.001) smaller than that in the HF group (9.06 ± 2.24%). These results indicate the potential of betaine to serve as an agent for amelioration of hepatic steatosis in NASH model mice.

Does the aminopeptidase A have prognostic and diagnostic value in Chagas disease and other dilated cardiomyopathies?

Chagas disease (CD), which is caused by the protozoan Trypanosoma cruzi, is a major cause of heart failure in Latin America. We investigated if plasma activity of one of the enzymes being part of the renin-angiotensin system, aminopeptidase A (APA), has diagnostic and prognostic potency in patients with CD and dilated cardiomyopathies (DCMs) due to other causes. Blood samples were taken from 94 patients with CD, 46 patients with DCM, and 34 healthy control subjects. Plasma APA activity was determined by fluorometry assays. The average follow-up time was 39 months; by the end of study, 33 patients had died and another 13 received heart transplant. There was no significant alteration in plasma APA activity in the patients with CD or DCM, as compared with that in controls. The Pearson correlation of echocardiographic data with plasma APA activity in patients with CD and DCM did not reveal any significant correlation with left-ventricular ejection fraction or other echocardiographic parameters. APA activity was unable to predict mortality or the need for heart transplant. Detection of APA activity in plasma may not prove suitable for prognosis in patients with heart failure and is unable to screen or diagnose asymptomatic patients with CD for early therapy.

Renin angiotensin system-regulating aminopeptidase activities in serum of pre- and postmenopausal women with breast cancer.

Angiotensin peptides regulate vascular tone and natriohydric balance through the renin angiotensin system (RAS) and are related with the angiogenesis which plays an important role in the metastatic pathway. Estrogen influences the aminopeptidases (APs) involved in the metabolism of bioactive peptides of RAS through several pathways. We analyze RAS-regulating AP activities in serum of pre- and postmenopausal women with breast cancer to evaluate the putative value of these activities as biological markers of the development of breast cancer. We observed an increase in aminopeptidase N (APN) and aminopeptidase B (APB) activities in women with breast cancer; however, a decrease in aspartyl-aminopeptidase (AspAP) activity in premenopausal women. These results suggest a slow metabolism of angiotensin II (Ang II) to angiotensin III (Ang III) in premenopausal women and a rapid metabolism of Ang III to angiotensin IV (Ang IV) in pre- and postmenopausal women with breast cancer. An imbalance in the signals activated by Ang II may produce abnormal vascular growth with different response between pre- and postmenopausal women depending on the hormonal profile and the development of the disease.

Asymmetrical response of aminopeptidase A and nitric oxide in plasma of normotensive and hypertensive rats with experimental hemiparkinsonism.

Aminopeptidases and dopamine (DA) exhibit asymmetries in the brain that are reflected in the peripheral response to unilateral striatal DA depletions (experimental hemiparkinsonism). This might be due to asymmetries in the autonomic innervation of the peripheral vessels. Nitric oxide (NO) is released through vascular sympathetic activation. A similar pathway could be postulated for aminopeptidases. Angiotensin II, metabolized by aminopeptidase A (AP A), interacts with NO and dopamine in the control of blood pressure. Moreover, plasma AP A activity and NO concentrations are elevated in hypertensive rats in which sympathetic activity is increased. We hypothesize that plasma AP A activity and NO concentrations may reflect a central asymmetry of the sympathetic activity. Therefore, we analyzed the effect of unilateral depletions of brain DA by injecting 6-hydroxydopamine into the left or right striatum and measuring plasma AP A, NO and systolic blood pressure (SBP) in normotensive and hypertensive rats. Changes in plasma AP A and NO in opposite directions may reflect an asymmetry in the function of the nigrostriatal system. Our results also revealed an inverse correlation between AP A and NO, in normotensive rats lesioned or sham operated in the right side and hypertensive rats lesioned in the left one. We concluded that the observed changes in plasma NO and AP A after left or right striatal DA depletions may be due to asymmetries in the peripheral autonomic innervation of the vessels.