Ace gene dosage influences the development of renovascular hypertension

1. Clinical and experimental evidence highlights the importance of the renin–angiotensin system in renovascular hypertension. Furthermore, genetic factors affecting angiotensin‐converting enzyme (ACE) could influence the development of renovascular hypertension. 2. To test the effect of small gene perturbations on the development of renovascular hypertension, mice harbouring two or three copies of the Ace gene were submitted to 4 weeks of two‐kidney, one‐clip (2K1C) hypertension. Blood pressure (BP), cardiac hypertrophy, baroreflex sensitivity and blood pressure and heart rate variability were assessed and compared between the different groups. 3. The increase in BP induced by 2K1C was higher in mice with three copies of the Ace gene compared with mice with only two copies (46 vs 23 mmHg, respectively). Moreover, there was a 3.8‐fold increase in the slope of the left ventricle mass/BP relationship in mice with three copies of the Ace gene. Micewith three copies of the Ace gene exhibited greater increases in cardiac and serum ACE activity than mice with only two copies of the gene. Both baroreflex bradycardia and tachycardia were significantly depressed in mice with three copies of the Ace gene after induction of 2K1C hypertension. The variance in basal systolic BP was greater in mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two copies of the gene (106 vs 54%, respectively). In addition, the low‐frequency component of the pulse interval was higher mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two (168 vs 86%, respectively). Finally, in mice with three copies of the Ace gene, renovascular hypertension induced a 6.1‐fold increase in the sympathovagal balance compared with a 3.2‐fold increase in mice with only two copies of the gene. 4. Collectively, these data provide direct evidence that small genetic disturbances in ACE levels per se have an influence on haemodynamic, cardiac mass and autonomic nervous system responses in mice under pathological perturbation.     

Neural control of renal medullary perfusion

There is strong evidence that the renal medullary circulation plays a key role in long-term blood pressure control. This, and evidence implicating sympathetic overactivity in development of hypertension, provides the need for understanding how sympathetic nerves affect medullary blood flow (MBF). The precise vascular elements that regulate MBF under physiological conditions are unknown, but likely include the outer medullary portions of descending vasa recta and afferent and efferent arterioles of juxtamedullary glomeruli, all of which receive dense sympathetic innervation. Many early studies of the impact of sympathetic drive on MBF were flawed, both because of the methods used for measuring MBF and because single and often intense neural stimuli were tested. Recent studies have established that MBF is less sensitive than cortical blood flow (CBF) to electrical renal nerve stimulation, particularly at low stimulus intensities. Indeed, MBF appears to be refractory to increases in endogenous renal sympathetic nerve activity within the physiological range in all but the most extreme cases. Multiple mechanisms appear to operate in concert to blunt the impact of sympathetic drive on MBF, including counter-regulatory roles of nitric oxide and perhaps even paradoxical angiotensin II-induced vasodilatation. Regional differences in the geometry of glomerular arterioles are also likely to predispose MBF to be less sensitive than CBF to any given vasoconstrictor stimulus. Failure of these mechanisms would promote reductions in MBF in response to physiological activation of the renal nerves, which could, in turn, lead to salt and water retention and hypertension.     

Renin and the (pro)renin receptor in the renal collecting duct: Role in the pathogenesis of hypertension

The intrarenal renin–angiotensin system (RAS) plays a critical role in the pathogenesis and progression of hypertension and kidney disease. In angiotensin (Ang) II‐dependent hypertension, collecting duct renin synthesis and secretion are stimulated despite suppression of juxtaglomerular (JG) renin. This effect is mediated by the AngII type I receptor (AT₁R), independent of blood pressure. Although the regulation of JG renin has been extensively studied, the mechanisms by which renin is regulated in the collecting duct remain unclear. The augmentation of renin synthesis and activity in the collecting duct may provide a pathway for additional generation of intrarenal and intratubular AngII formation due to the presence of angiotensinogen substrate and angiotensin‐converting enzyme in the nephron. The recently described (pro)renin receptor ((P)RR) binds renin or prorenin, enhancing renin activity and fully activating the biologically inactive prorenin peptide. Stimulation of (P)RR also activates intracellular pathways related to fibrosis. Renin and the (P)RR are augmented in renal tissues of AngII‐dependent hypertensive rats. However, the functional contribution of the (P)RR to enhanced renin activity in the collecting duct and its contribution to the development of hypertension and kidney disease have not been well elucidated. This review focuses on recent evidence demonstrating the mechanism of renin regulation in the collecting ducts and its interaction with the (P)RR. The data suggest that renin–(P)RR interactions may induce stimulation of intracellular pathways associated with the development of hypertension and kidney disease.     

Angiotensin AT1 receptor activation mediates high glucose‐induced epithelial–mesenchymal transition in renal proximal tubular cells

1. Renal tubular epithelial cells can undergo epithelial to mesenchymal transition (EMT) under hyperglycaemic conditions, which is associated with renal interstitial fibrosis. Activation of the renin–angiotensin system (RAS) is involved in diabetic nephropathy. The present study investigated the positive role of angiotensin AT₁ receptors in high glucose‐induced EMT in cultured tubular epithelial cells. 2. A rat kidney proximal tubular epithelial cell line (NRK‐52E) was used in the present study. Levels of EMT makers, namely E‐cadherin and vimentin, were estimated using fluorescence immunocytochemistry, mRNA levels of angiotensinogen (AGT), angiotensin‐converting enzyme (ACE) and AT₁ receptors were determined by real‐time polymerase chain reaction, protein levels of E‐cadherin, vimentin, fibronectin, matrix metallopeptidase (MMP)‐9 and phosphorylated extracellular signal‐regulated kinase (ERK) 1/2 were analysed by western blotting and the concentrations of angiotensin (Ang) II and transforming growth factor (TGF)‐β1 in the culture medium were determined by enzyme immunoassay and ELISA. 3. High glucose (30 mmol/L) induced EMT and increased the synthesis of fibronectin and MMP‐9. Furthermore, high glucose increased AGT, ACE and AT₁ receptor mRNA levels, as well as AngII and TGF‐β1 concentrations in the culture medium and ERK1/2 phosphorylation. Pretreatment of cells for 15 min with the AT₁ receptor antagonist losartan (10^?5 mol/L) attenuated high glucose‐induced increases in TGF‐β1 and ERK1/2 phosphorylation and reduced EMT, as well as the consequent synthesis of fibronectin and MMP‐9. 4. The results of the present study suggest that the activated local RAS mediates high glucose‐induced EMT. By activating AT₁ receptors and stimulating TGF‐β1 synthesis, the elevated local RAS participates in high glucose‐induced EMT and increased extracellular matrix secretion.     

(Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation

1. (Pro)renin receptor (PRR) binding to renin or prorenin mediates angiotensin (Ang) II‐dependent and ‐independent effects. Expression of the PRR is increased in kidneys of diabetic rats, but its role in diabetic nephropathy is unknown. In the present study, we investigated the contribution of the PRR to the development of diabetic nephropathy through enhancement of renal production of tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β. 2. Normoglycaemic control and streptozotocin‐diabetic Sprague‐Dawley rats were used in the study. The urine albumin : creatinine ratio (UACR), renal interstitial fluid (RIF) levels of AngII, TNF‐α and IL‐1β and renal expression of TNF‐α and IL‐1β were evaluated in control, untreated diabetic and diabetic rats treated with either a PRR blocker (PRRB; 0.2 mg/kg per day NH3‐RILLKKMPSV‐COOH), the AT₁ receptor antagonist valsartan (2 mg/kg per day) or combined therapy, administered directly into the renal cortical interstitium for 14 days via osmotic minipumps. 3. Compared with values in normoglycaemic control rats, UACR and RIF AngII, TNF‐α and IL‐1β were significantly higher in untreated diabetic rats. Treatment of diabetic rats with the PRRB or valsartan alone and in combination significantly reduced UACR and RIF TNF‐α and IL‐1β levels. Renal expression of TNF‐α and IL‐1β was higher in untreated diabetic rats than in control rats, but was reduced significantly following treatment with PRRB or valsartan alone and in combination. Renal PRR expression was increased in untreated and PRRB‐treated diabetic rats and reduced in rats receiving valsartan alone or combination therapy. The PRRB had no effect on RIF AngII levels, whereas valsartan alone and in combination with the PRRB significantly increased AngII levels. 4. In conclusion, the PRR is involved in the development and progression of kidney disease in diabetes by enhancing renal production of the inflammatory cytokines TNF‐α and IL‐1β, independent of renal AngII effects.     

Role of angiotensin AT2 receptors in natriuresis: Intrarenal mechanisms and therapeutic potential

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Effects of prostaglandins and nitric oxide on the renal effects of angiotensin II in the anaesthetized rat

1. The potential influences of nitric oxide (NO) and prostaglandins on the renal effects of angiotensin II (Ang II) have been investigated in the captopril-treated anaesthetized rat by examining the effect of indomethacin or the NO synthase inhibitor, N^ω-nitro-L-arginine methyl ester (L-NAME), on the renal responses obtained during infusion of Ang II directly into the renal circulation.
2. Intrarenal artery (i.r.a.) infusion of Ang II (1–30 ng kg⁻¹ min⁻¹) elicited a dose-dependent decrease in renal vascular conductance (RVC; −38±3% at 30 ng kg⁻¹ min⁻¹; P<0.01) and increase in filtration fraction (FF; +49±8%; P<0.05) in the absence of any change in carotid mean arterial blood pressure (MBP). Urine output (Uv), absolute (UNaV) and fractional sodium excretion (FENa), and glomerular filtration rate (GFR) were unchanged during infusion of Ang II 1–30 ng kg⁻¹ min⁻¹ (+6±17%, +11±17%, +22±23%, and −5±9%, respectively, at 30 ng kg⁻¹ min⁻¹). At higher doses, Ang II (100 and 300 ng kg⁻¹ min⁻¹) induced further decreases in RVC, but with associated increases in MBP, Uv and UNaV.
3. Pretreatment with indomethacin (10 mg kg⁻¹ i.v.) had no significant effect on basal renal function, or on the Ang II-induced reduction in RVC (−25±7% vs −38±3% at Ang II 30 ng kg⁻¹ min⁻¹). In the presence of indomethacin, Ang II tended to cause a dose-dependent decrease in GFR (−38±10% at 30 ng kg⁻¹ min⁻¹); however, this effect was not statistically significant (P=0.078) when evaluated over the dose range of 1–30 ng kg⁻¹ min⁻¹, and was not accompanied by any significant changes in Uv, UNaV or FENa (−21±12%, −18±16% and +36±38%, respectively).
4. Pretreatment with L-NAME (10 μg kg⁻¹ min⁻¹ i.v.) tended to reduce basal RVC (control −11.8±1.4, +L-NAME −7.9±1.8 ml min⁻¹ mmHg⁻¹×10⁻²), and significantly increased basal FF (control +15.9±0.8, +L-NAME +31.0±3.7%). In the presence of L-NAME, renal vasoconstrictor responses to Ang II were not significantly modified (−38±3% vs −35±13% at 30 ng kg⁻¹ min⁻¹), but Ang II now induced dose-dependent decreases in GFR, Uv and UNaV (−51±11%, −41±14% and −31±17%, respectively, at an infusion rate of Ang II, 30 ng kg⁻¹ min⁻¹). When evaluated over the range of 1–30 ng kg⁻¹ min⁻¹, the effect of Ang II on GFR and Uv were statistically significant (P<0.05), but on UNaV did not quite achieve statistical significance (P=0.066). However, there was no associated change in FENa observed, suggesting a non-tubular site of interaction between Ang II and NO.
5. In contrast to its effects after pretreatment with L-NAME alone, Ang II (1–30 ng kg⁻¹ min⁻¹) failed to reduce renal vascular conductance in rats pretreated with the combination of L-NAME and the selective angiotensin AT₁ receptor antagonist, {"type":"entrez-nucleotide","attrs":{"text":"GR117289","term_id":"238364164","term_text":"GR117289"}}GR117289 (1 mg kg⁻¹ i.v.). This suggests that the renal vascular effects of Ang II are mediated through AT₁ receptors. Over the same dose range, Ang II also failed to significantly reduce GFR or Uv.
6. In conclusion, the renal haemodynamic effects of Ang II in the rat kidney appear to be modulated by cyclooxygenase-derived prostaglandins and NO. The precise site(s) of such an interaction cannot be determined from the present data, but the data suggest complex interactions at the level of the glomerulus.

     

Angiotensin II increases tissue-specific inhibitor of metalloproteinase-2 expression in rat aortic smooth muscle cells in vivo: evidence of a pressure-independent effect

1. Angiotensin (Ang) II plays a major role in vascular remodelling. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in the tissue remodelling processes. The aim of the present study was to investigate whether AngII modulates TIMP-2 expression in rat aortic smooth muscle cells in vivo. 2. Angiotensin II (200 ng/kg per min, s.c.) or AngII + losartan (10 mg/kg per day, s.c.) or normal saline was administered continuously by osmotic minipumps to Sprague-Dawley rats for 1 week. In addition, the effect of endogenous AngII on TIMP-2 expression was evaluated in renovascular hypertensive rats (two kidney, one clip (2K1C) and one kidney, one clip (1K1C) models). Control rats (sham 2K1C and sham 1K1C rats) underwent sham-clipping of the left renal artery. At the end of the treatment, plasma renin activity was measured by radioimmunoassay, aortic TIMP-2 mRNA expression was evaluated by real-time polymerase chain reaction and/or northern blotting and protein expression was evaluated by immunohistochemistry. Systolic blood pressure (SBP) was measured twice a week by the tail-cuff method. 3. Exogenous AngII administration produced the expected increase in SBP (P = 0.02) compared with the control saline-treated group. The increase in SBP was abolished in AngII + losartan-treated rats. Administration of AngII caused a significant increase in TIMP-2 expression (P = 0.01) in rat aortic smooth muscle cells that was abolished in AngII + losartan-treated rats. In renovascular hypertensive rats, SBP was higher (P < 0.0001) in 2K1C and 1K1C rats compared with the corresponding sham-operated rats. Plasma renin activity was higher (P < 0.01) in 2K1C rats compared with the other groups. The expression of TIMP-2 was significantly (P < 0.05) increased only in 2K1C rats. 4. Our in vivo data demonstrate that exogenous and endogenous AngII increases TIMP-2 expression in rat aortic smooth muscle cells. This effect is not dependent on the AngII-induced increase in blood pressure and is mediated by angiotensin AT1 receptors.     

Angiotensin II receptor blockers for the treatment of hypertension

The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.     

Lipoxygenase and cyclo-oxygenase products in the control of regional kidney blood flow in rabbits

1. The aim of the present study was to examine the roles of cyclo-oxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonate signalling cascades in the control of regional kidney blood flow. 2. In pentobarbitone-anaesthetized rabbits treated with NG-nitro-l-arginine and glyceryl trinitrate to 'clamp' nitric oxide, we determined the effects of ibuprofen (a COX inhibitor) and esculetin (a LOX inhibitor) on resting systemic and renal haemodynamics and responses to renal arterial infusions of vasoconstrictors. 3. Ibuprofen increased mean arterial pressure (14 +/- 5%) and reduced medullary laser Doppler flux (MLDF; 26 +/- 6%) when administered with esculetin. A similar pattern of responses was observed when ibuprofen was given alone, although the reduction in MLDF was not statistically significant. Esculetin tended to increase renal blood flow (RBF; 16 +/- 7%) and MLDF (28 +/- 13%) when given alone, but not when combined with ibuprofen. 4. After vehicle, renal arterial infusions of noradrenaline, angiotensin II and endothelin-1 reduced RBF and cortical laser Doppler flux (CLDF), but not MLDF. In contrast, renal arterial [Phe2,Ile3,Orn8]-vasopressin reduced MLDF but not RBF or CLDF. Ibuprofen alone did not significantly affect these responses. Esculetin, when given alone, but not when combined with ibuprofen, enhanced noradrenaline-induced renal vasoconstriction. In contrast, esculetin did not significantly affect responses to [Phe2,Ile3,Orn8]-vasopressin, angiotensin II or endothelin-1. 5. We conclude that COX products contribute to the maintenance of arterial pressure and renal medullary perfusion under 'nitric oxide clamp' conditions, but not to renal haemodynamic responses to the vasoconstrictors we tested. Lipoxygenase products may blunt noradrenaline-induced vasoconstriction, but our observations may, instead, reflect LOX-independent effects of esculetin.     

Effect of maturation on renal Na+/K+-atpase and its susceptibility to nitric oxide-deficient hypertension in rats

1. The present study deals with the effect of maturation on the kinetic properties of renal Na(+)/K(+)-ATPase and its susceptibility to nitric oxide (NO)-deficient hypertension induced by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). 2. Immature (4-week-old) and adult (12-week-old) male Wistar rats were administered L-NAME (40 mg/kg per day) in their drinking water for 4 weeks. 3. The properties of the ATP- and Na(+)-binding sites of Na(+)/K(+)-ATPase were investigated by activation of the enzyme with increasing concentrations of the energy substrate ATP and/or cofactor Na(+). Unchanged values of K(m) suggest that energy utilization by the enzyme in the kidney of control rats remains unaffected during maturation. Conversely, the decrease in K(Na) values (the concentration of Na(+) necessary to achieve half-maximal reaction velocity) indicates improved affinity for Na(+) in the older group of control rats. 4. Application of L-NAME to all young animals had no significant effect on the functional properties of Na(+)/K(+)-ATPase. 5. In adult animals, the V(max) values remained unchanged after treatment with L-NAME, but the affinities of the ATP- and Na(+)-binding sites were decreased, as indicated by significant increase in K(m) and K(Na) values. 6. Maturation of control rats was accompanied by an increase in the Na(+) affinity of renal Na(+)/K(+)-ATPase without affecting ATP utilization. However, maturation increased the susceptibility of renal Na(+)/K(+)-ATPase to the harmful effects of L-NAME.     

Function of renal angiotensin AT2 receptors is not enhanced in Lyon hypertensive rats

1. Because we previously observed that angiotensin AT2 receptor stimulation decreased pressure-natriuresis, in the present study we examined the possible involvement of these receptors in altered sodium excretion shown by Lyon hypertensive (LH) rats. 2. In 9-week-old male anaesthetized LH rats and normotensive (LL) controls pretreated with an angiotensin-converting enzyme inhibitor (quinapril; 10 mg/kg) and an AT1 receptor antagonist (losartan; 10 mg/kg), angiotensin (Ang) II was infused (30 ng/kg per min) to stimulate AT2 receptors. In other groups of rats, an AT2 receptor antagonist (PD123319; 50 micro g/kg per min) was added before AngII infusion. 3. During AT2 receptor stimulation, LH differed from LL rats by significantly reduced renal blood flow (RBF), glomerular filtration rate and pressure diuresis and natriuresis. The addition of PD123319 did not change total RBF, whereas it did increase pressure diuresis and natriuresis in both strains. However, the effects of PD123319 were less marked in LH rats than in LL rats. 4. These findings confirm that, under the present experimental conditions, AT2 receptors are antinatriuretic and are not of greater functional importance in hypertensive animals of the Lyon strain.     

Demonstration of the existence of nitric oxide-independent as well as nitric oxide-dependent vasodilator mechanisms in the in situ renal circulation in near term pregnant rats

1. We have investigated the role of endogenous nitric oxide on renal vascular reactivity in late pregnancy in in situ blood perfused kidneys of α-chloralose anaesthetized Wistar-Kyoto rats. Nitric oxide synthesis inhibition was achieved by intravenous administration of N^G-nitro-L-arginine or N^G-nitro-L-arginine methyl ester.
2. Intra-arterial mean blood pressure was lower in pregnancy compared with nonpregnant controls. Following nitric oxide synthesis inhibition mean blood pressure increased in both pregnant and nonpregnant groups, but remained lower in pregnant animals.
3. Basal renal perfusion pressure was similar in pregnant and nonpregnant groups. Intravenous administration of N^G-nitro-L-arginine resulted in dose-dependent increases in renal perfusion pressure but responses were substantially depressed in pregnancy.
4. Renal vasoconstrictor responses to regional angiotensin II (AII) were decreased in pregnancy, whereas those to noradrenaline (NA) did not differ from nonpregnant controls. N^G-nitro-L-arginine (5 mg kg⁻¹) potentiated renal responses to regional AII and NA in both groups, but AII responses remained lower in pregnancy. Blunted renal AII responses in pregnancy were still evident following large doses of N^G-nitro-L-arginine methyl ester (100 mg kg⁻¹).
5. The results demonstrate that nitric oxide synthesis inhibition increases renal perfusion pressure to a lesser extent in pregnant compared with nonpregnant rats, and that reduced renal pressor responses to AII are still evident in pregnancy after nitric oxide synthesis inhibition.
6. These results suggest that although endogenous nitric oxide synthesis modulates renal vasoconstrictor responses in both pregnant and nonpregnant animals, this mechanism does not fully account for the blunted renal vasoconstrictor responses to regional AII or nitric oxide inhibitors in near term pregnant rats. The nature of this important physiological vasodilator mechanism in pregnancy remains to be elucidated.

     

Causal link between neonatal hydronephrosis and later development of hypertension

1. Although congenital ureteral obstruction is a common disorder in infants, its pathophysiology remains poorly understood and its clinical management continues to be debated. During the past decade, the surgical management of non‐symptomatic hydronephrosis in children has become more conservative, but the long‐term physiological consequences of this new policy are unclear. 2. In experimental models with complete ureteral obstruction, tubular atrophy and interstitial inflammation occur rapidly. Although this type of obstruction is very rare in clinical practice, it is often referred to in clinical discussions. New studies, using a model with chronic partial ureteral obstruction, have demonstrated that hydronephrosis is associated with renal injuries and is causally related to hypertension. 3. The mechanisms underlying the development of hypertension in experimental hydronephrosis are complex and involve changes in both the renin–angiotensin system and renal sympathetic nerve activity. Furthermore, oxidative stress and nitric oxide deficiency in the diseased kidney, with consequent resetting of the tubuloglomerular feedback mechanism, appear to play a pivotal role in the development and maintenance of hyper‐tension. 4. In view of the new knowledge regarding the long‐term effects of partial ureteral obstruction, today’s non‐operative management of hydronephrosis should be reconsidered to prevent obstructive nephropathy and hypertension in later life.     

Role of nitric oxide in the effects of hypoglycemia on the cerebral circulation in awake goats

This study was performed to examine the role of nitric oxide in the effects of hypoglycemia on the cerebral circulation. Hypoglycemia was induced with insulin and its effects on cerebral blood flow (measured with an electromagnetic flow transducer placed on the internal maxillary artery) were studied in awake goats under control conditions and after administration of the nitric oxide synthesis inhibitor N^G-nitro-

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-arginine methyl ester (

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-NAME, 47 mg/kg). Also, cerebrovascular reactivity to vasodilator stimuli was examined during insulin-induced severe hypoglycemia, before and after

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-NAME treatment. In five animals under control conditions (glycemia=90±7 mg/dl, cerebral blood flow=64±4 ml/min, mean systemic arterial pressure=102±4 mmHg, cerebrovascular resistance=1.62±0.11 mmHg/ml per min and heart rate =73±6 beats/min), insulin decreased glycemia: when hypoglycemia was moderate (glycemia=46±2 mg/dl) or severe (glycemia=26±1 mg/dl) cerebral blood flow increased by 25±4% and 47±6%, and cerebrovascular resistance decreased by 18±3% and 34±4%, respectively. Under basal conditions,

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-NAME did not affect glycemia but reduced resting cerebral blood flow by 37±2%, increased mean arterial pressure by 33±2% and decreased heart rate by 28±3%; after

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-NAME, both moderate and severe hypoglycemia did not alter significantly resting cerebral blood flow and cerebrovascular resistance. In five other goats,

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-NAME, administered during severe hypoglycemia, abolished the increase in cerebral blood flow, and increased cerebrovascular resistance and mean arterial pressure over the control (normoglycemic) values. In these animals with severe hypoglycemia, acetylcholine (0.01–1 μg), isoproterenol (0.03–3 μg) and diazoxide (0.3–9 mg), injected into the internal maxillary artery, decreased cerebrovascular resistance in a dose-dependent manner, and this decrease was similar before and after

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-NAME. Therefore, insulin-induced hypoglycemia may produce cerebral vasodilatation by releasing nitric oxide and may diminish the capacity of the cerebral vasculature to release nitric oxide in response to acetylcholine.     

高血压与肾脏疾病中肾脏局部肾素血管紧张素系统的激活及病理生理作用

肾脏存在独立调节的肾素-血管紧张素系统(RAS).多数高血压与肾脏疾病患者均存在肾脏RAS活性的上调,这对维持机体水钠平衡有重要作用,但同时也促进了高血压的发生,并加速了肾损害的进展.本文结合最近一些基础及临床研究结果,着重讨论疾病状态下肾脏RAS激活的机制、后果及RAS阻断剂的干预意义,这对认识肾脏局部RAS功能,探讨延缓慢性肾脏病进展的治疗策略具有重要意义.     

The renin–angiotensin system from conception to old age: the good,the bad and the ugly

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Asymmetric dimethylarginine does not inhibit arginase activity and is pro‐proliferative in pulmonary endothelial cells

Asymmetric dimethylarginine (ADMA) is an endogenously produced nitric oxide synthase (NOS) inhibitor. l ‐Arginine can be metabolised by NOS and arginase, and arginase is the first step in polyamine production necessary for cellular proliferation. We tested the hypothesis that ADMA would inhibit NOS but not arginase activity and that this pattern of inhibition would result in greater l ‐arginine bioavailability to arginase, thereby increasing viable cell number. Bovine arginase was used in in vitro activity assays with various concentrations of substrate (l ‐arginine, ADMA, N^G‐monomethyl‐l ‐arginine (L‐NMMA) and N^G‐nitro‐l ‐arginine methyl ester (l ‐NAME)). Only l ‐arginine resulted in measurable urea production (K_m = 6.9 ± 0.8 mmol/L; V_max = 6.6 ± 0.3 μmol/mg protein per min). We then incubated bovine arginase with increasing concentrations of ADMA, l ‐NMMA and l ‐NAME in the presence of 1 mmol/L l ‐arginine and found no effect of any of the tested compounds on arginase activity. Using bovine pulmonary arterial endothelial cells (bPAEC) we determined the effects of ADMA on nitric oxide (NO) and urea production and found significantly lower NO production and greater urea production (P < 0.003) with ADMA, without changes in arginase protein levels. In addition, ADMA treatment resulted in an approximately 30% greater number of viable cells after 48 h than in control bPAEC. These results demonstrate that ADMA is neither a substrate nor an inhibitor of arginase activity and that in bPAEC ADMA inhibits NO production and enhances urea production, leading to more viable cells. These results may have pathophysiological implications in disorders associated with higher ADMA levels, such as pulmonary hypertension.     

Unmasking the potential of the angiotensin AT2 receptor as a therapeutic target in hypertension in men and women: What we know and what we still need to find out

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Distinct regulation of inner medullary collecting duct nitric oxide production from mice and rats

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