apyrase and Hypertension

Diabetes mellitus (DM) and hypertension are highly prevalent worldwide health problems and frequently associated with severe clinical complications, such as diabetic cardiomyopathy, nephropathy, retinopathy, neuropathy, stroke, and cardiac arrhythmia, among others. Despite all existing research results and reasonable speculations, knowledge about the role of purinergic system in individuals with DM and hypertension remains restricted. Purinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the recognition and degradation of extracellular nucleotides and adenosine. The main components of this system that will be presented in this review are: P1 and P2 receptors and the enzymatic cascade composed by CD39 (NTPDase; with ATP and ADP as a substrate), CD73 (5'-nucleotidase; with AMP as a substrate), and adenosine deaminase (ADA; with adenosine as a substrate). The purinergic system has recently emerged as a central player in several physiopathological conditions, particularly those linked to inflammatory responses such as diabetes and hypertension. Therefore, the present review focuses on changes in both purinergic P1 and P2 receptor expression as well as the activities of CD39, CD73, and ADA in diabetes and hypertension conditions. It can be postulated that the manipulation of the purinergic axis at different levels can prevent or exacerbate the insurgency and evolution of diabetes and hypertension working as a compensatory mechanism.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Animals; Antigens, CD; Apyrase; Cell Communication; Diabetes Mellitus; Diet, Healthy; Exercise; Humans; Hypertension; Purinergic P1 Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purines; Receptors, Purinergic P1; Receptors, Purinergic P2; Signal Transduction

: Background: Central nervous system function has been emerging as an approach to understand hypertension-mediated memory dysfunction, and chronic exercise is able to modulate the purinergic system.. Herein, we investigated the effect of chronic swimming training on the purinergic system in cortex and hippocampus of L-NAME-induced hypertensive rats. Male Wistar rats were divided into four groups: Control, Exercise, L-NAME and Exercise L-NAME. Inhibitory avoidance test was used to assess memory status. NTPDase, CD73 and adenosine deaminase activities and expression, and P2 receptors expression were analyzed. Data were analyzed using two-way ANOVA and Kruskal-Wallis tests, considering P less than 0.05.. Physical exercise reduced the blood pressure and prevented memory impairment induced by L-NAME model of hypertension. L-NAME treatment promoted an increase in NTPDase1, NTPDase3 and CD73 expression and activity in the cortex. A2A expression is increased in hippocampus and cortex in the hypertension group and exercise prevented this overexpression.. These changes suggest that hypertension increases adenosine generation, which acts through A2A receptors, and exercise prevents these effects. These data may indicate a possible mechanism by which exercise may prevent memory impairment induced by L-NAME.

Topics: 5'-Nucleotidase; Animals; Antigens, CD; Apyrase; Cerebral Cortex; Disease Models, Animal; Hypertension; Memory; NG-Nitroarginine Methyl Ester; Physical Conditioning, Animal; Rats; Receptor, Adenosine A2A; Swimming

Ectonucleoside triphosphate diphosphohydrolase-1, the major vascular/immune ectonucleotidase, exerts anti-thrombotic and immunomodulatory actions by hydrolyzing extracellular nucleotides (danger signals). Hypertension is characterized by vascular wall remodeling, endothelial dysfunction, and immune infiltration. Here our aim was to investigate the impact of arterial hypertension on CD39 expression and activity in mice. Arterial expression of CD39 was determined by reverse transcription quantitative real-time PCR in experimental models of hypertension, including angiotensin II (AngII)-treated mice (1 mg/kg/day, 21 days), deoxycorticosterone acetate-salt mice (1% salt and uninephrectomy, 21 days), and spontaneously hypertensive rats. A decrease in CD39 expression occurred in the resistance and conductance arteries of hypertensive animals with no effect on lymphoid organs. In AngII-treated mice, a decrease in CD39 protein levels (Western blot) was corroborated by reduced arterial nucleotidase activity, as evaluated by fluorescent (etheno)-ADP hydrolysis. Moreover, serum-soluble ADPase activity, supported by CD39, was significantly decreased in AngII-treated mice. Experiments were conducted in vitro on vascular cells to determine the elements underlying this downregulation. We found that CD39 transcription was reduced by proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor alpha on vascular smooth muscle cells and by IL-6 and anti-inflammatory and profibrotic cytokine transforming growth factor beta 1 on endothelial cells. In addition, CD39 expression was downregulated by mechanical stretch on vascular cells. Arterial expression and activity of CD39 were decreased in hypertension as a result of both a proinflammatory environment and mechanical strain exerted on vascular cells. Reduced ectonucleotidase activity may alter the vascular condition, thus enhancing arterial damage, remodeling, or thrombotic events.

Topics: Animals; Antigens, CD; Apyrase; Arteries; Endothelial Cells; Hypertension; Male; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle

Purinergic signaling plays an important role in inflammation and vascular integrity, but little is known about purinergic mechanisms during the pathogenesis of atherosclerosis in humans.. The objective of this study is to study markers of purinergic signaling in a cohort of patients with peripheral artery disease.. Plasma ATP and ADP levels and serum nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39) and ecto-5'-nucleotidase/CD73 activities were measured in 226 patients with stable peripheral artery disease admitted for nonurgent invasive imaging and treatment. The major findings were that ATP, ADP, and CD73 values were higher in atherosclerotic patients than in controls without clinically evident peripheral artery disease (P<0.0001). Low CD39 activity was associated with disease progression (P=0.01). In multivariable linear regression models, high CD73 activity was associated with chronic hypoxia (P=0.001). Statin use was associated with lower ADP (P=0.041) and tended to associate with higher CD73 (P=0.054), while lower ATP was associated with the use of angiotensin receptor blockers (P=0.015).. Purinergic signaling plays an important role in peripheral artery disease progression. Elevated levels of circulating ATP and ADP are especially associated with atherosclerotic diseases of younger age and smoking. The antithrombotic and anti-inflammatory effects of statins may partly be explained by their ability to lower ADP. We suggest that the prothrombotic nature of smoking could be a cause of elevated ADP, and this may explain why cardiovascular patients who smoke benefit from platelet P2Y12 receptor antagonists more than their nonsmoking peers.

Topics: 5'-Nucleotidase; Adenosine Diphosphate; Adenosine Triphosphate; Adult; Age Factors; Aged; Aged, 80 and over; Alkaline Phosphatase; Angiotensin-Converting Enzyme Inhibitors; Antigens, CD; Apyrase; Artifacts; Atherosclerosis; Biomarkers; Chronic Disease; Comorbidity; Disease Progression; Drug Utilization; Female; Finland; GPI-Linked Proteins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypoxia; Male; Middle Aged; Models, Cardiovascular; Peripheral Arterial Disease; Purinergic P2Y Receptor Antagonists; Risk Factors; Second Messenger Systems; Smoking; Thrombophilia

Hypertension is accompanied by inflammatory process and purinergic system has been recognized as having an important role in modulating immune functions. Physical training is being considered one of the major lifestyle changes that contributes to the cardiovascular health as well as has an important role in regulating purinergic system. Thus, the aim of this study was to investigate the effect of chronic swimming training on lymphocytic purinergic system enzymes activities related to inflammatory process, as well as in lipid profile and classic inflammatory markers in rats that developed hypertension in response to the oral administration of N-nitro-L-arginine methyl ester hydrochloride (L-NAME).. After 6 weeks of training, lymphocytes and serum were separated to be analysed. L-NAME-treated group displayed an increase in SBP as well as in ecto-NTPDase and adenosine deaminase (ADA) activities (P < 0.05). Six weeks of swimming training were able to prevent these alterations and keep the blood pressure and enzymes activities in the same levels of control group. Exercise per se was associated with a decrease in the expression of ecto-NTPDase1 in lymphocytes (-23.4%). Exercise was also efficient in preventing the rise in classic inflammatory markers observed in L-NAME group.. These findings highlight the link between purinergic signalling and inflammatory process and suggest a novel mechanism in which moderate aerobic exercise possesses the potential to attenuate inflammation caused by hypertension.

Topics: Adenosine Deaminase; Animals; Antigens, CD; Apyrase; Blood Pressure; Hypertension; Lymphocytes; Male; NG-Nitroarginine Methyl Ester; Physical Conditioning, Animal; Random Allocation; Rats; Rats, Wistar; Swimming

Hypertension-associated cardiorenal diseases represent one of the heaviest burdens for current health systems. In addition to hemodynamic damage, recent results have revealed that hematopoietic cells contribute to the development of these diseases by generating proinflammatory and profibrotic environments in the heart and kidney. However, the cell subtypes involved remain poorly characterized. Here we report that CD39(+) regulatory T (TREG) cells utilize an immunosuppression-independent mechanism to counteract renal and possibly cardiac damage during angiotensin II (AngII)-dependent hypertension. This mechanism relies on the direct apoptosis of tissue-resident neutrophils by the ecto-ATP diphosphohydrolase activity of CD39. In agreement with this, experimental and genetic alterations in TREG/TH cell ratios have a direct impact on tissue-resident neutrophil numbers, cardiomyocyte hypertrophy, cardiorenal fibrosis, and, to a lesser extent, arterial pressure elevation during AngII-driven hypertension. These results indicate that TREG cells constitute a first protective barrier against hypertension-driven tissue fibrosis and, in addition, suggest new therapeutic avenues to prevent hypertension-linked cardiorenal diseases.

Topics: Angiotensin II; Animals; Antigens, CD; Apoptosis; Apyrase; Cells, Cultured; Fibrosis; Hypertension; Immune Tolerance; Kidney; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Neutrophils; Proto-Oncogene Proteins c-vav; Renal Insufficiency; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

Pomolic acid has recently shown hypotensive effect in rats. The purpose of this investigation was to determine the vascular effects of this triterpenoid and to examine its mode of action. Functional experiments in rat aortic rings precontracted with norepinephrine were performed to evaluate the vasorelaxant effect of pomolic acid. This triterpenoid induced a vasorelaxation (IC₅₀ = 2.45 μM) in a concentration- and endothelium-dependent manner and showed no effect on contractions evoked by KCl (25 mM). Pre-treatment of aortic rings with L-NAME (100 μM), methylene blue (100 μM) or glibenclamide (10 μM), totally prevented the vasorelaxation induced by pomolic acid, while indomethacin (10 μM) had no effect on this response. Additionally, pomolic acid relaxation was unaffected under the muscarinic- and β-adrenergic-receptor blocked ensured for atropine and propanolol respectively (10 μM each). In contrast, the vasorelaxant effect of pomolic acid was abolished under the purinergic-receptor blocked ensured for suramin (10 μM). Finally, apyrase (0.8 U/ml) an enzyme which hydrolyses ATP and ADP did not affect pomolic acid relaxation. In summary, pomolic acid has a potent endothelium-dependent vasorelaxant effect, possibly acting through the direct activation of endothelial purinergic receptors via NO-cGMP signaling pathway, which could be part of the mechanism underlying its hypotensive effect.

Topics: Animals; Antihypertensive Agents; Aorta; Apyrase; Atropine; Chrysobalanaceae; Dose-Response Relationship, Drug; Endothelium, Vascular; Hypertension; Indomethacin; Male; Norepinephrine; Oleanolic Acid; Phytotherapy; Plant Extracts; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Receptors, Muscarinic; Receptors, Purinergic; Signal Transduction; Vasoconstriction; Vasodilator Agents

The objective of this work was to evaluate the effect of different glucose levels on the ATP, ADP and AMP hydrolysis in the platelets of diabetic, hypertensive and diabetic/hypertensive participants.. The activities of the enzymes NTPDase (ATP and ADP hydrolysis) and 5'-nucleotidase (AMP hydrolysis), and CD39 expression were analyzed in human blood platelets of diabetic (DM-2), hypertensive (HT) and diabetic/hypertensive (DM-2/HT) patients. To evaluate the interference of glucose and fructose in NTPDase and 5'-nucleotidase activities, experiments were performed with glucose, fructose and mannitol concentrations ranging from 5 to 30 mM in platelet-rich plasma (PRP). Pre-incubation times of 10, 120 min and 24h were used.. NTPDase and 5'-nucleotidase activities increased with increasing glucose and fructose concentrations (P<0.001) and the different times of pre-incubation did not interfere in ectonucleotidases activities (P>0.5). NTPDase and 5'-nucleotidase activities demonstrated a positive correlation between serum glucose levels and ATP and ADP hydrolysis in DM-2 and DM-2/HT patients. CD39 expression demonstrated that DM-2, HT and DM-2/HT groups presented a significant increase when compared to the control group (P<0.004).. The hydrolysis of adenine nucleotides is enhanced in platelets of patients with diabetes and hypertension. We observed that an increasing glucose concentration had a direct effect on ATP, ADP and AMP hydrolysis. Furthermore, CD39 expression was enhanced in all patients groups, indicating that these enzyme activities are related with diabetes and hypertension.

Topics: 5'-Nucleotidase; Adenosine Diphosphate; Adenosine Triphosphate; Adult; Aged; Albuminuria; Antigens, CD; Apyrase; Blood Glucose; Blood Platelets; C-Reactive Protein; Cholesterol; Diabetes Complications; Diabetes Mellitus; Glucose; Humans; Hypertension; Middle Aged; Nucleoside-Triphosphatase

In the present study, we evaluated the effect of low-dose aspirin (acetylsalicylic acid (ASA); 1.0 mg/kg daily) on blood pressure, albumin excretion, glomerular fibrinogen deposits, and glomerular (basement) membrane-bound adenosine diphosphatase (ecto-ADPase) activity, as well as on glomerular inflammation in pregnant rats infused with low-dose endotoxin (1.0 mg/kg). Rats (day 14 of pregnancy) were infused with endotoxin (ET rats) or saline (control rats) and received ASA in their drinking water. These rats were compared with non-ASA-treated rats. Blood pressure and albumin excretion were measured from day 15 to day 21, and glomerular fibrinogen and ecto-ADPase activity were measured at day 21. Glomerular inflammation was evaluated at various times after the start of the infusion. The results show that treatment with ASA had a significant beneficial effect on hypertension and inflammation induced by endotoxin in pregnant rats, whereas it reduced albumin excretion and glomerular fibrinogen deposits in some of the rats.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apyrase; Aspirin; Blood Pressure; Cell Adhesion Molecules; Endotoxins; Female; Glomerular Filtration Rate; Glomerulonephritis; Hypertension; Kidney Glomerulus; Leukocyte Count; Neutrophils; Pregnancy; Pregnancy Complications; Proteinuria; Rats; Rats, Wistar; Serum Albumin

Hypertension is a major risk factor for stroke/myocardial infarction as expression of the atherogenic process. Platelets play a fundamental role in all these disease processes. In physiological conditions there is an equilibrium between pro aggregating and anti aggregating factors. In pathological situations this equilibrium is broken and pro aggregating factors are predominant . Patients with hypertension have an state of hyper-aggregation and dysequilibrium in the production of eicosanoids. Some antihypertensive drugs tend to not only reduce blood pressure to control levels but to reduce platelet aggregation and re-establish the broken equilibrium in eicosanoid production.

Topics: Adult; Aged; Antihypertensive Agents; Apyrase; Cerebrovascular Disorders; Eicosanoids; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Nitric Oxide; Platelet Aggregation; Platelet Aggregation Inhibitors; Risk Factors; Vasodilation; Venezuela