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New Findings What is the topic of this review? Reports that bilateral renal denervation in resistant hypertensive patients results in a long-lasting reduction in blood pressure raise the question of the underlying mechanisms involved and how they may be deranged in pathophysiological states of hypertension and renal failure., What advances does it highlight? The renal sensory afferent nerves and efferent sympathetic nerves work together to exert an important control over extracellular fluid volume, hence the level at which blood pressure is set. This article emphasizes that both the afferent and the efferent renal innervation may contribute to the neural dysregulation of the kidney that occurs in chronic renal disease and resistant hypertension., Autonomic control is central to cardiovascular homeostasis, and this is exerted not only at the level of the heart and blood vessels but also at the kidney. At the kidney, the sympathetic neural regulation of renin release and fluid reabsorption may influence fluid balance and, in the longer term, the level at which blood pressure is set. The role of the renal innervation in the regulation of blood pressure has received renewed attention over the past few years, following the reports that bilateral renal denervation of resistant hypertensive patients resulted in a marked reduction in blood pressure, which has been maintained for several years. Such has been the interest that this approach of renal denervation is being applied in other patient groups with diabetes, obesity and renal failure, with the hope that there may be a sustained reduction in blood pressure as well as the amelioration of some aspects of the metabolic syndrome. However, the factors that come into play to cause the rise in blood pressure in these patient groups, particularly the resistant hypertensive patients, are far from clear. Moreover, the mechanisms leading to the fall in blood pressure following renal denervation of resistant hypertensive patients currently elude our understanding and is therefore an area that requires much more investigation to enhance our insight. [ABSTRACT FROM AUTHOR]

There is evidence that in cardiac failure, there is defective baroreceptor reflex control of sympathetic nerve activity. Often, cardiac failure is preceded by a state of cardiac hypertrophy in which there may be enhanced performance of the heart. This study investigated whether in two different models of cardiac hypertrophy, there was an increased contribution of nitric oxide (NO) to the low-pressure baroreceptor regulation of renal sympathetic nerve activity (RSNA) and nerve-dependent excretory function. Administration of a volume load, 0.25* body wt/min saline for 30 min, in normal rats decreased RSNA by 40* and increased urine flow by some 9-fold. Following nitro-l-arginine methyl ester (l-NAME) administration, 10 μg·kg-1·min-1 for 60 min, which had no effect on blood pressure, heart rate, or RSNA, the volume load-induced renal sympathoinhibitory and excretory responses were markedly enhanced. In cardiac hypertrophy states induced by 2 wk of isoprenaline/caffeine or 1 wk thyroxine administration, the volume challenge failed to suppress RSNA, and there were blunted increases in urine flow in the innervated kidneys, but following l-NAME infusion, the volume load decreased RSNA by 30-40* and increased urine flow by some 20-fold in the innervated kidneys, roughly to the same extent as observed in normal rats. These findings suggest that the blunted renal sympathoinhibition and nerve-dependent diuresis to the volume load in cardiac hypertrophy are related to a heightened production or activity of NO within either the afferent or central arms of the reflex. [ABSTRACT FROM AUTHOR]

Pathophysiological states, including cardiovascular and renal diseases, are characterized by oxidative stress but what is less clear is whether physiological challenges incur a degree of altered oxidative metabolism. To this end, this study examined whether exposure to a high dietary sodium intake could cause an oxidative stress at the kidney. Animals, placed on either 0.3% or 3% sodium diets for 2 wk, were given a lethal dose of anesthetic, and kidneys were removed to analyze both NAD(P)H oxidase (NOX) and superoxide dismutase (SOD) expression and activities in the cortex and medulla. Placing animals on the high-sodium diet raised sodium and water excretion and caused an ∼14-fold increase in urinary excretion of 8-isoprostane, a marker of oxidative stress, which was attenuated by chronic treatment with apocynin to prevent NAD(P)H oxidase activity. The protein expression of the NAD(P)H oxidase subunits NOX2 and p47phox and overall NAD(P)H oxidase activity were approximately doubled in the cortex of the rats on the high-sodium diet compared with those on the normal sodium intake while both SOD activity and expression were unchanged. By contrast, neither NOX nor SOD protein expression or activity were altered in the medulla when the rats were placed on the high-sodium intake. These data suggest that an elevation in dietary sodium intake can lead to increased generation of reactive oxygen species and a state of oxidative stress in the cortex but not to such a degree that it extends to the medulla. [ABSTRACT FROM AUTHOR]

1. Acute renal failure develops as a result of periods of renal ischaemia during cardiovascular surgery or hypovolaemic shock. The present study investigated the importance of endogenous prostaglandin production and nitric oxide (NO) in the renal haemodynamic and excretory responses to ischaemia–reperfusion both normally and in the hypertensive state by chronic administration of cyclo-oxygenase (COX) inhibitors. 2. Male Wistar and stroke-prone spontaneously hypertensive rats (SHRSP) were subjected to 30 min renal ischaemia and 2 h reperfusion following 7 day treatment with vehicle, aspirin, NO–aspirin or celecoxib. 3. Renal blood flow was higher in the SHRSP treatment groups. Renal ischaemia increased blood pressure in all Wistar groups except that given aspirin, had no effect in the SHRSP and did not change renal blood flow in any group. Glomerular filtration rate was reduced throughout the reperfusion period in both rat strains. The postischaemic diuresis in the Wistar was enhanced by COX-2 inhibition, but not by aspirin or NO–aspirin. Urine flow increased in SHRSP during the postischaemic period, which was blunted by aspirin and NO–aspirin, but not by celecoxib. There was a postischaemic increase in fractional sodium excretion, the magnitude of which was unaltered by any drug in the Wistar rats, but was blunted by aspirin, NO–aspirin and celecoxib in SHRSP. 4. These results suggest that products of COX activity contribute to the renal responses to ischaemia–reperfusion injury, but in different ways, in SHRSP, which may reflect variations in renal prostaglandin and NO production in the hypertensive state. [ABSTRACT FROM AUTHOR]

The processes involved in the renal damage resulting from ischemia-reperfusion injury are poorly understood. This study examined the contribution of prostaglandins and nitric oxide (NO) in the vascular responses to ischemia-reperfusion injury in the kidneys of normotensive and hypertensive rats. Groups of Wistar and stroke-prone spontaneously hypertensive rats (SHRSP) were dosed with polyethylene glycol vehicle, aspirin (53.5 mg·kg-1·day-1), NO-aspirin (100 mg·kg-1·day-1), or celecoxib (10 mg·kg-1·day-1) for 7 days. On day 7, rats were anesthetized with chloralose/urethane and the left kidney was exposed to a 30-min period of ischemia followed by 90-min reperfusion. Renal cortical and medullary perfusions were monitored throughout using laser-Doppler flowmetry. In the vehicle- and celecoxib-treated Wistar rats, cortical and medullary postischemic perfusion was reduced to 66 and 62% and 53 and 62%, respectively (all P < 0.05), of baseline. The ischemia-induced reductions in cortical and medullary flux were ameliorated in the aspirin and NO-aspirin groups where flux fell to 96 and 78% and 105 and 83%, respectively (P < 0.05). There was a fall in cortical and medullary flux in the postischemic period in the vehicle-treated SHRSP to 82 and 77% (P < 0.05). These findings show that nonselective cyclooxygenase (COX) inhibition, and to an even greater extent NO donation, provided protection to the renal vasculature from ischemic injury in the Wistar rat but not in the SHRSP. This would suggest that prostaglandins are less important in the development of renal ischemia-repei-fusion injury during hypertension and both COX isoforms must be inhibited to offset the decrease in renal hemodynamics. [ABSTRACT FROM AUTHOR]

The kidney plays a central role in ensuring cardiovascular homeostasis, in that it functions to ensure that the variation in fluid intake is matched to that lost through normal everyday metabolism. The autonomic nervous system, via the renal sympathetic nerves, allows kidney function to be adjusted dynamically in response to changes in sensory information arising from the cardiovascular system, the soma, viscera and the higher cortical centres. At the level of the kidney, the sympathetic nerves innervate the vascular and tubular components, thereby regulating renal haemodynamics and fluid reabsorption. The processing of sensory information by the central nervous system involves nuclei associated with cardiovascular control and it is these nuclei which are influenced by angiotensin II generated locally in the brain. The angiotensin II appears to act in a neuromodulatory fashion or as a neurotransmitter. There is now sound evidence that the baroreflex control of sympathetic outflow to the kidney, at least, is under tonic inhibitory control by brain angiotensin II, which also facilitates the impact of the somatosensory system in mediating sympatho-excitation. The significance of brain angiotensin II in mediating reflex activation of the sympathetic nerves from other sensory systems has not yet been defined and needs to be resolved. Interestingly, it may be that deficits in the production of brain angiotensin II at these nuclei could contribute in part to the genesis of hypertension. [ABSTRACT FROM AUTHOR]

This study investigated the role of nitric oxide (NO) and superoxide anions in modulating the renal nerve-dependent increases in proximal tubular fluid reabsorption (Jva). Renal nerve stimulation at 0.75 and 1.0 Hz (15 V, 0.2 ms) in anaesthetized Wistar rats had no effect on glomerular filtration rate but decreased urine flow and sodium excretion in a frequency-related manner, reaching 39 and 49% at 1.0 Hz, respectively (P < 0.01) and increased Jva by 11 and 31% (P < 0.01). In the stroke prone spontaneously hypertensive rats (SHRSP), basal mean blood pressure was higher (123 ± 2 versus 99 ± 2 mmHg, P < 0.001), glomerular filtration rate, urine flow, sodium excretion and proximal tubular fluid reabsorption (Jva) were lower (all P < 0.001) than in the Wistar rats. Renal nerve stimulation in the SHRSP did not change glomerular filtration rate but decreased urine flow, and sodium excretion by 18 and 34% (P < 0.05) at 1.0 Hz which was less (P < 0.05) than that in the Wistar rats. Under these conditions, Jva was increased at 0.75 Hz by 27%, and to a comparable extent at 1.0 Hz, which was a pattern very different from the frequency related rises reported in the Wistar rats. In the SHRSP, intratubular Nω-nitro-L-arginine methyl ester (L-NAME) had no effect on baseline Jva or the pattern of response to renal nerve stimulation which contrasted with earlier reports in the Wistar rat. Intraluminal superoxide dismutase (SOD) had no effect on basal Jva in the Wistar rats but increased it in the SHRSP (P < 0.05) while the pattern of change in Jva during nerve stimulation was unaltered in both rat strains. By contrast, in the SHRSP, intraluminal sodium nitroprusside (SNP) resulted in a frequency related increase in Jva comparable to that obtained in the vehicle treated Wistar rats. These data suggest that in the hypertensive rats, superoxide anion production is raised which depresses Jva and interacts with NO preventing a normal Jva... [ABSTRACT FROM AUTHOR]

Summary 1. The present study explored the impact of endothelin (ET) and its interaction with renal sympathetic nerves in the control of volume homeostasis in obesity. 2. Groups of lean and obese Zucker rats with innervated and denervated kidneys were subjected to an acute isotonic saline volume expansion (VE), 10% bodyweight and renal haemodynamics and excretory function were evaluated following administration of SB209670 (a non-selective ET antagonist) or UK 350 926 (a selective ET[sub A] receptor antagonist). 3. Volume expansion in untreated obese rats resulted in a blunted cumulative urine sodium excretion (CuU[sub Na] V) after 40 min, VE compared with untreated lean rats being 36 and 51% in the denervated and innervated kidneys, respectively (both P < 0.001). 4. In lean rats, both SB209670 and UK 350 926 caused a depressed ability to excrete the saline load and CuU[sub Na] V after 40 min, VE compared with untreated being decreased by 51 and 60% in the denervated and innervated kidneys, respectively (both P < 0.001). 5. SB209670 and UK 350 926 given to obese rats reduced (both P < 0.001) CuU[sub Na] V after VE by 43% in denervated kidneys compared with untreated obese rats, whereas they were without effect on the magnitude of the excretory response in innervated kidneys. 6. These findings show that the blunted renal excretory responses to VE present in obese rats were not mediated by ET. Conversely, ET, acting through ET[sub A] receptors, plays a role as a diuretic and natriuretic factor in maintaining volume homeostasis by, at least in lean rats, renal nerve-independent mechanisms. [ABSTRACT FROM AUTHOR]

1 The study investigated whether endothelin (ET) contributed to the diabetes-associated alterations in volume reflex and characterised the receptor subtype that might be involved. The influence of renal sympathetic nerves on these aspects of ET was also examined. 2 Groups of nondiabetic and streptozotocin-induced diabetic rats were subjected to an acute isotonic saline volume expansion (VE), 10% body wt in the presence and absence of ET antagonists. 3 Cumulative urine sodium excretion (CuN[SUBNa]V) after VE in diabetic rats reached values of 116±10 in the denervated and 74±6μmolmin[SUP-1]g kidney wt[SUP-1] in the innervated kidneys, which were both less (both P&lt0.001) than those achieved in the nondiabetic rats, at 267±9 in the denervated and 183±10 μmolmin[SUP-1] g kidney wt[SUP-1] in the innervated kidney, respectively. 4 Diabetic rats pretreated with a nonselective Et[SUBA]/ET[SUBB] antagonist had an enhanced CuN[SUBNa] V in the denervated kidneys by 37% (P<0.01) compared to that of untreated diabetic rats. At both does of SB 209670 these increments were less than the values obtained previously in nondiabetic rats (both P<0.01). The ET[SUBA]/ET[SUBB] antagonist had no meaningful effect on CuN[SUBNa]V in the innervated kidneys of the diabetic rats, whereas previous studies in nondiabetic rats showed the response to be depressed. The Cu Na[SUBNa]V responses to VE in diabetic rats given the selective ET[SUBA] antagonist were not different from those observed in untreated diabetic rats, irrespective of whetehr or not the renal nerves were present. IN nondiabetic rats, the ET[SUBA] antagonist had an action similar to the mixed antagonist. 5 These findings demonstrate that activation of ET[SUBB] receptors contributes to the depressed ability to excrete a saline load in diabetes mellitus, but its impact is obscured by the influence of the renal nerves. [ABSTRACT FROM AUTHOR]

Previous findings indicated that cAMP had an inhibitory effect of on tumour necrosis factor (TNF)-alpha production. Angiotensin II (Ang II) may activate the cAMP-protein kinase A (PKA) pathway in renal mesangial cells through synthesis of prostaglandins (PGs) and the possibility arises that inhibition of Ang II-induced cAMP formation might result in the overproduction of TNF-alpha in the cell and this hypothesis was tested in the present study. Rat mesangial cells were exposed to Ang II in the presence or absence of cyclooxygenase inhibitor (indomethacin) or cAMP-PKA inhibitor (H-89). Exposure of mesangial cell to Ang II (10−6 M–10−8 M) significantly increased intracellular cAMP level through type 1 Ang II receptor but had no effect on TNF-alpha protein release, transcriptional activity, or mRNA. However, following the addition of indomethacin or H-89, Ang II significantly increased TNF-alpha release, transcriptional activity, and mRNA level. These data suggested that in mesangial cells after blockade of cAMP-PKA by PG inhibition, Ang II was capable of stimulating TNF-alpha transcription which subsequently increased TNF-alpha mRNA accumulation and protein release. [Copyright &y& Elsevier]

Examines the role of brain angiotensin (ANG) II in the somatosensory induced antinatriuresis in the anaesthetized rat. Ability of the brain to modulate autonomic reflexes; Attempts to block the generation of ANGII within the brain by giving captopril i.c.v.; Analysis on the effect of ANGII with captopril into the central nervous system.

Modulation of interleukin-6 by β2-adrenoceptor in endotoxin-stimulated renal macrophage cells. Background. Activation of the cAMP signaling pathway by means of β2-adrenoceptor agonists has been shown to up-regulate interleukin-6 (IL-6) gene expression and to stimulate IL-6 production in macrophage cells. However, whether β2-adrenoceptor activation can also modify the rate of IL-6 production in macrophage cells activated by the bacterial endotoxins has not yet been determined. Using renal resident macrophage cells treated with endotoxin, lipopolysaccharide (LPS), and β2-adrenoceptor agonist, terbutaline, we investigated the role of cAMP pathway, tumor necrosis factor (TNF)-α and mitogen-activated protein kinase (MAPK) pathway (p42/p44) in regulating IL-6 production. Methods. IL-6 protein, mRNA, and promoter activity were measured in these cells exposed to LPS (1 μg/ml) and/or terbutaline (10-9 to 10-6 m). Furthermore, the time course effects of terbutaline on cAMP, MAPK (p42/p44), and TNF-α release were evaluated in the cells. Results. Terbutaline at high concentrations (10-6 m) significantly up-regulated IL-6 by approximately 25% (P < 0.05), whereas at a lower concentration (10-8 m), it down-regulated IL-6 production by 42% (P < 0.05). Terbutaline (10-8 and 10-6 m) caused a concentration- and time-dependent stimulation of cAMP (P < 0.05) and TNF production (P < 0.05) and a time-dependent decrease in MAPK activity (P < 0.05). Following the addition of a cAMP inhibitor, IL-6 promoter activity was correlated with TNF-α levels and MAPK activity. Conclusions. A biphasic effect of β2-adrenoceptor agonist on IL-6 production in renal resident macrophage cells became apparent when LPS was exposed to the cells. The terbutaline-induced down-regulation of IL-6 gene production was mediated by an inhibitory... [ABSTRACT FROM AUTHOR]

Presents information on a study that examines the renal nerve-dependent renal hemodynamic and tubular responses to somatosensory stimulation in the anesthetized rat by use of subcutaneously applied capsaicin. Causes of the activation of skin somatosensory receptors; Role of renal nerves; Reflex regulation of renal sympathetic nerve; Somatosensory system.

Compares the cardiovascular and renal nerve activity responses to somatosensory stimulation with capsaicin in normotensive and hypertensive rats. Importance of cardiopulmonary receptors; Capsaicin increased blood pressure, heart rate and renal nerve activity; Somatosensory modulation of RNA.

Examines the renal nerve-dependent renal hemodynamic and tubular responses to somatosensory stimulation in the anesthetized rat by use of subcutaneously applied capsaicin when the action of angiotensin G (ANG) III was blocked peripherally or selectively within the brain. Increase in blood pressure upon activation of skin somatosensory receptors; Blockage of the reductions in urine flow and sodium excretion.

Compares cardiovascular and renal nerve activity responses to somatosensory stimulation with capsaicin in normotensive and hypertensive Wistar rats. Description of protocols and animal groups; Cardiovascular and renal nerve responses to capsaicin; Effect of capsaicin and phenylbiguanide (PBG) on blood pressure (BP) and integrated nerve activity.

Determines the influence of renal nerve activity on renal function, plasma renin activity (PRA) and the corresponding expression of renin and angiotensinogen genes in the kidney. Stimulation of left renal nerves in pentobarbitone-anesthetized rats; PRA levels in control rats; Angiotensin messenger RNA levels.

Develops an approach whereby the high-dimensional signal of renal sympathetic nerve activity (RSNA) was reduced to a low-dimensional one by extracting the peak interval sequence in order to allow the use of non-linear dynamics analysis. Effect of brachial nerves stimulation on the blood pressure and heart rate of Wistar rats; Description of the renal sympathetic innervation process.

The author comments on a study published in "The Lancet," a follow-up on a 2009 study which examined the blood-pressure-lowering action of renal denervation (RDN) in patients with resistant hypertension. The study found no evidence of serious cardiovascular events related to RDN or an overall worsening of renal function. He finds it disappointing that even after three years since the first study, there was no indication that the number of drugs taken by the patients could be reduced.

New Findings What is the central question of this study? Dietary sodium manipulation alters the magnitude of angiotensin-(1-7) [Ang-(1-7)]-induced natriuresis. The present study sought to determine whether this was related to relative changes in the activity of intrarenal Mas and/or AT1 receptors., What is the main finding and its importance? Angiotensin-(1-7)-induced diuresis and natriuresis is mediated by intrarenal Mas receptors. However, intrarenal AT1 receptor blockade also had an inhibitory effect on Ang-(1-7)-induced natriuresis and diuresis. Thus, Ang-(1-7)-induced increases in sodium and water excretion are dependent upon functional Mas and AT1 receptors., We investigated whether angiotensin-(1-7) [Ang-(1-7)]-induced renal haemodynamic and excretory actions were solely dependent upon intrarenal Mas receptor activation or required functional angiotensin II type 1 (AT1) receptors. The renin-angiotensin system was enhanced in anaesthetized rats by prior manipulation of dietary sodium intake. Angiotensin-(1-7) and AT1 and Mas receptor antagonists were infused into the kidney at the corticomedullary border. Mas receptor expression was measured in the kidney. Mean arterial pressure, urine flow and fractional sodium excretion were 93 ± 4 mmHg, 46.1 ± 15.7 μl min−1 kg−1 and 1.4 ± 0.3%, respectively, in the normal-sodium group and 91 ± 2 mmHg, 19.1 ± 3.3 μl min−1 kg−1 and 0.7 ± 0.2%, respectively, in the low-sodium group. Angiotensin-(1-7) infusion had no effect on mean arterial pressure in rats receiving a normal-sodium diet but decreased it by 4 ± 5% in rats receiving a low-sodium diet ( P < 0.05). Interstitial Ang-(1-7) infusion increased urine flow twofold and fractional sodium excretion threefold ( P < 0.05) in rats receiving a normal-sodium diet and to a greater extent, approximately three- and fourfold, respectively, in rats receiving the low-sodium diet (both P < 0.05). Angiotensin-(1-7)-induced increases in urine flow and fractional sodium excretion were absent in both dietary groups during intrarenal AT1 or Mas receptor inhibition after either losartan or A-779, respectively. Thus, AT1 receptor activation, as well as Mas receptor activation, plays an essential role in mediating Ang-(1-7)-induced natriuresis and diuresis. Whether this is because Ang-(1-7) partly antagonizes AT1 receptors or whether Ang-(1-7)-induced natriuresis is mediated through AT1-Mas receptor dimerization remains unclear. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Are renal functional responses to intrarenal angiotensin 1–7 (Ang (1–7)) infusion dependent on the level of the endogenous renin–angiotensin system (RAS) in the two‐kidney one‐clip (2K1C) and deoxycorticosterone acetate (DOCA)‐salt animal models of hypertension?What is the main finding and its importance?The renal actions of Ang (1–7) are dependent on the relative endogenous levels of each arm of the classical angiotensin II–angiotensin II type 1 receptor (AT1R) axis and those of the Ang (1–7)–Mas receptor axis. These findings support the hypothesis that a balance exists between the intrarenal classical and novel arms of the RAS, and in particular the relative abundance of AT1R to Mas receptor, which may to a large extent determine the renal excretory response to Ang (1–7) infusion. This study investigated the action of angiotensin 1–7 (Ang (1–7)) on renal haemodynamic and excretory function in the two‐kidney one‐clip (2K1C) and deoxycorticosterone acetate (DOCA)‐salt rat models of hypertension, in which the endogenous renin–angiotensin system (RAS) activity was likely to be raised or lowered, respectively. Rats were anaesthetised and prepared for the measurement of mean arterial pressure and kidney function during renal interstitial infusion of Ang (1–7) or saline. Kidney tissue concentrations of angiotensin II (Ang II) and Ang (1–7) were determined. Intrarenal infusion of Ang (1–7) into the clipped kidney of 2K1C rats increased urine flow (UV), absolute (UNaV) and fractional sodium (FENa) excretions by 110%, 214% and 147%, respectively. Renal Ang II concentrations of the clipped kidney were increased with no major changes in Ang (1–7) concentration. By contrast, Ang (1–7) infusion decreased UV, UNaV, and FENa by 27%, 24% and 21%, respectively in the non‐clipped kidney in which tissue Ang (1–7) concentrations were increased, but renal Ang II concentrations were unchanged compared to sham animals. Ang (1–7) infusion in DOCA‐salt rats had minimal effects on glomerular filtration rate but significantly decreased UV, UNaV and FENa by ∼30%. Renal Ang (1–7) concentrations were higher and Ang II concentrations were lower in DOCA‐salt rats compared to sham rats. These findings demonstrate that the intrarenal infusion of exogenous Ang (1–7) elicits different renal excretory responses the magnitude of which is dependent on the balance between the endogenous renal Ang II–AT1 receptor axis and Ang (1–7)–Mas receptor axis. [ABSTRACT FROM AUTHOR]

The article reviews the article about the role of adrenergic on the development of renin cells in nephrogenesis.

This study investigated the effect of tempol (a superoxide dismutase mimetic) on renal vasoconstrictor responses to angiotensin II (Ang II) and adrenergic agonists in fructose-fed Sprague-Dawley rats (a model of metabolic syndrome). Rats were fed 20% fructose in drinking water (F) for 8 weeks. One fructose-fed group received tempol (FT) at 1 mmol·L-1 in drinking water for 8 weeks or as an infusion (1.5 mg·kg-1·min-1) intrarenally. At the end of the treatment regimen, the renal responses to noradrenaline, phenylephrine, methoxamine, and Ang II were determined. F rats exhibited hyperinsulinemia, hyperuricemia, hypertriglyceridemia, and hypertension. Tempol reduced blood glucose and insulin levels (all p < 0.05) in FT rats compared with their untreated counterparts. The vasoconstriction response to all agonists was lower in F rats than in control rats by about 35%-65% (all p < 0.05). Vasoconstrictor responses to noradrenaline, phenylephrine, and methoxamine but not Ang II were about 41%-75% higher in FT rats compared with F rats (all p < 0.05). Acute tempol infusion blunted responses to noradrenaline, methoxamine, and Ang II in control rats by 32%, 33%, and 62%, while it blunted responses to noradrenaline and Ang II in F rats by 26% and 32%, respectively (all p < 0.05), compared with their untreated counterparts. Superoxide radicals play a crucial role in controlling renal vascular responses to adrenergic agonists in insulin-resistant rats. Chronic but not acute tempol treatment enhances renal vascular responsiveness in fructose-fed rats. [ABSTRACT FROM AUTHOR]

ANGII infused ICV in rats on a normal Na+ (NNa+) diet leads to a pressor response and a fall in renal sympathetic nerve activity (RSNA) while rats fed a high Na+ (HNa+) diet also express a later rise in RSNA. This study investigated the impact of peripheral V1 receptor blockade (V1B) on these responses. Male Wistar rats fed a NNa+ (0.3% Na+) or HNa+ (3.0%, Na+) diet for 6 weeks were anaesthetized, cannulae inserted into the femoral artery/vein and right ICV and RSNA recorded from the left kidney. Blood pressure (BP) and RSNA were measured after ICV ANGII (50-100ng in 2µL; NNa+ n=7-10) and during V1 blockade (V1B, Manning compound, 10µg/0.2mL IV; n=6). Data (mean±SE) were compared by ANOVA. P<0.05 indicated significance. Basal BP (mmHg) was similar between groups (ANGII: NNa+ 89±4, HNa+ 95±4; ANGII + V1B: NNa+ 89±4 , HNa+84±4). The 30 min area under the curve (AUC) BP response (ΔmmHg*min) was less during V1B in NNa+ (ANGII: 232±47 vs ANGII+ V1B: 60±29, P<0.05) and HNa+ (ANGII: 237±66 vs ANGII+ V1B: 73±i3, P<0.05). RSNA fell immediately after ICV ANGII in NNa+ (ANGII: 94±3%, ANGII+ V1B: 94±2, P<0.05) and HNa+ (ANGII: 84±6%, ANGII + V1: 91±3%, P<0.05 vs baseline) with no effect of V1B. The rise in RSNA in the HNa+rats 30 min after ICV ANGII was not present during V1B (ANGII:112±2%, ANGII + V1B: 96±6%, P<0.05). The results suggest that V1 receptor activation contributes to the BP and long term rise in RSNA to ICV ANGII. [ABSTRACT FROM AUTHOR]

This study determined the impact of AT1 receptor antisense ODN given icv on the baroreflex control of RSNA in conscious rats. Male Wistar and SHR (n=5-6) were chronically instrumented with cannulae in the femoral artery and jugular vein, electrodes sealed onto the left renal nerve and a cannula implanted into the right lateral cerebroventricle. Three days later, blood pressure (BP) was manipulated by iv phenylephrine and nitroprusside (both at 10µg) to generate baroreflex curves for RSNA (Huang et al 2006, J Physiol 574: 597-604) before and 1 day after the icy administration of 25µg AT1 receptor antisense ODN or 25µg sense ODN dissolved in 20µl lipofectin (1 µg/µl). Means ±SEM were subjected to Student's t test and significance taken at P<0.05. In Wistar rats, BP was 115±5mmHg and was unchanged after the ATI receptor antisense ODN, but there was a significant (P<0.05) increase in the sensitivity of the baroreflex curve of 86.0%. BP in the SHR, at 172±5mmHg, was decreased after the antisense ODN to 148±6mmHg (P<0.05), while the sensitivity of the baroreflex curve increased by 55.1% (P<0.05). Administration of the sense ODN had no effect on BP or the baroreflex curves in either Wistar or SHR. The data showed that whereas the ATI receptor antisense ODN decreased BP only in the SHR, it increased the sensitivity of the baroreflex control of RSNA in both conscious Wistar and SHR. [ABSTRACT FROM AUTHOR]

The article presents a study on the link between the kidney and the brain. According to the author, kidney disease renal sensory receptors cause a sympatho-excitation contributing to the associated hypertension. A hypersensitive rat was studied using nephrectomy and showed that the two systems can be modulated independently of each other. The results showed that the kidney can determine the level of sympathetic outflow to the periphery.

Acute kidney injury (AKI) causes considerable morbidity and mortality, particularly in the case of post-cardiac infarction or kidney transplantation; however, the site-specific accumulation of small molecule reno-protective agents for AKI has often proved ineffective due to dynamic fluid and solute excretion and non-selectivity, which impedes therapeutic efficacy. This article reviews the current status and future trajectories of renal nanomedicine research for AKI management from pharmacological and clinical perspectives, with a particular focus on appraising nanosized drug carrier (NDC) use for the delivery of reno-protective agents of different pharmacological classes and the effectiveness of NDCs in improving renal tissue targeting selectivity and efficacy of said agents. This review reveals the critical shift in the role of the small molecule reno-protective agents in AKI pharmacotherapy - from prophylaxis to treatment - when using NDCs for delivery to the kidney. We also highlight the need to identify the accumulation sites of NDCs carrying reno-protective agents in renal tissues during in vivo assessments and detail the less-explored pharmacological classes of reno-protective agents whose efficacies may be improved via NDC-based delivery. We conclude the paper by outlining the challenges and future perspectives of NDC-based reno-protective agent delivery for better clinical management of AKI. Nanosized drug carrier (NDC) – based targeting of small molecular reno-protective agents (SMRA) to kidneys with acute injury were increasingly attempted and reported effective in vivo. This review critically appraised such in vivo reports and (i) uncovered the advantageous transition in the role of SMRA in managing acute kidney injury (AKI) from prophylaxis-orientated to therapeutic orientated (outer ring) when they are delivered to the kidney by the NDCs; and (ii) highlights the less-explored pharmacological classes of SMRA (middle ring) whose efficacies may be improved via NDC-based renal drug delivery. (* outer ring : intended use of NDC-SMRA for AKI, middle ring : SMRA of various pharmacological classes integrated into NDCs and tested in vivo). [Display omitted] [ABSTRACT FROM AUTHOR]

This study investigated the impact of intrarenal angiotensin 1–7 (Ang [1–7]) infusion on renal excretory function in a rat model of hypertension. Eleven‐week‐old spontaneously hypertensive rats (SHRs, n = 7) and Han Wistar controls (NCR, n = 7) were anaesthetised with sodium pentobarbital (60 mg/kg i.p.) and prepared for the measurement of mean arterial pressure (MAP) and left renal function during renal interstitial infusion of Ang (1–7) (50 ng/min). The kidneys were harvested, the renal cortex and medulla separated, prepared for measurement of Ang II and Ang (1–7) and Western blot determination of AT1 and Mas receptor protein expression. MAP, glomerular filtration rate (GFR), urine flow (UF) and absolute sodium excretion (UNaV) were 109 ± 16 mmHg, 4.4 ± 1.0 mL/min/kg, 102 ± 16 µL/min/kg and 16 ± 3 µmol/min/kg, respectively in the NCR and 172 ± 24 mmHg, 3.4 ± 0.7 mL/min/kg, 58 ± 30 μL/min/kg and 8.6 ± 4.8 μmol/min/kg respectively in the SHR. Ang (1–7) increased UF (31%), UNaV (50%) and fractional sodium excretion (FENa+) (22%) in the NCR group (all p < 0.05) but had no effect on GFR in either group. The magnitudes of the Ang (1–7)‐induced increases in UF and UNaV were significantly blunted in the SHR group (model × drug p < 0.05). The renal cortical AT1: Mas receptor expression ratio was significantly higher in the SHR group (p < 0.05) but renal Ang II and Ang (1–7) levels were not statistically different between groups. The Ang (1–7)‐induced increases in sodium and water excretion were impaired in the SHR group in the context of an unstimulated RAS. The decrease in responsiveness of the SHR kidney to Ang (1–7) appears to be associated with higher levels of AT1 receptor expression in the renal cortex. [ABSTRACT FROM AUTHOR]

Angiotensin II at the kidney regulates renal hemodynamic and excretory function, but the actions of an alternative metabolite, angiotensin (1-7), are less clear. This study investigated how manipulation of dietary sodium intake influenced the renal hemodynamic and excretory responses to intrarenal administration of angiotensin (1-7). Renal interstitial infusion of angiotensin (1-7) in anesthetized rats fed a normal salt intake had minimal effects on glomerular filtration rate but caused dose-related increases in urine flow and absolute and fractional sodium excretions ranging from 150 to 200%. In rats maintained for 2 wk on a low-sodium diet angiotensin (1-7) increased glomerular filtration rate by some 45%, but the diuretic and natriuretic responses were enhanced compared with those in rats on a normal sodium intake. By contrast, renal interstitial infusion of angiotensin (1-7) in rats maintained on a high-sodium intake had no effect on glomerular filtration rate, whereas the diuresis and natriuresis was markedly attenuated compared with those in rats fed either a normal or low-sodium diet. Plasma renin and angiotensin (1-7) were highest in the rats on the low-sodium diet and depressed in the rats on a high-sodium diet. These findings demonstrate that the renal hemodynamic and excretory responses to locally administered angiotensin (1-7) is dependent on the level of sodium intake and indirectly on the degree of activation of the renin-angiotensin system. The exact way in which angiotensin (1-7) exerts its effects may be dependent on the prevailing levels of angiotensin II and its receptor expression. [ABSTRACT FROM AUTHOR]

This paper explores the possible relationships between dietary fructose and altered neurohumoral regulation of renal haemodynamic and excretory function in this model of metabolic syndrome. Fructose consumption induces hyperinsulinemia, hypertriglyceridaemia, insulin resistance, and hypertension. The pathogenesis of fructose-induced hypertension is dubious and involves numerous pathways acting both singly and together. In addition, hyperinsulinemia and hypertension contribute significantly to progressive renal disease in fructose-fed rats. Moreover, increased activity of the renin-angiotensin and sympathetic nervous systems leading to downregulation of receptors may be responsible for the blunted vascular sensitivity to angiotensin II and catecholamines, respectively. Various approaches have been suggested to prevent the development of fructose-induced hypertension and/or metabolic alteration. In this paper, we address the role played by the renin-angiotensin and sympathetic nervous systems in the haemodynamic alterations that occur due to prolonged consumption of fructose. [ABSTRACT FROM AUTHOR]

This paper explores the possible relationships between dietary fructose and altered neurohumoral regulation of renal haemodynamic and excretory function in this model of metabolic syndrome. Fructose consumption induces hyperinsulinemia, hypertriglyceridaemia, insulin resistance, and hypertension. The pathogenesis of fructose-induced hypertension is dubious and involves numerous pathways acting both singly and together. In addition, hyperinsulinemia and hypertension contribute significantly to progressive renal disease in fructose-fed rats. Moreover, increased activity of the renin-angiotensin and sympathetic nervous systems leading to downregulation of receptors may be responsible for the blunted vascular sensitivity to angiotensin II and catecholamines, respectively. Various approaches have been suggested to prevent the development of fructose-induced hypertension and/or metabolic alteration. In this paper, we address the role played by the renin-angiotensin and sympathetic nervous systems in the haemodynamic alterations that occur due to prolonged consumption of fructose. [ABSTRACT FROM AUTHOR]

The regulation of blood pressure and sympathetic outflow by the brain renin–angiotensin system in animals subjected to raised or lowered dietary Na+ intake is unclear. This study compared the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to intracerebroventricular (i.c.v.) infusion of angiotensin II (AngII) and III (AngIII) before and after peripheral V1 receptor blockade (V1B) in α-chloralose–urethane-anaesthetized rats fed a low (0.03%, LNa+), normal (0.3%, NNa+) or high Na+ diet (3.0%, HNa+) from 4 to 11 weeks of age. The rise in MAP 2 min post AngIIi.c.v. was greater in HNa+ (14 ± 3 mmHg) versus LNa+ (8 ± 1 mmHg, P < 0.05) and after AngIIIi.c.v. in HNa+ (14 ± 3 mmHg) versus NNa+ (6 ± 1 mmHg, P < 0.05) and LNa+ (7 ± 1 mmHg, P < 0.05). The MAP responses to AngII and AngIIIi.c.v. were abolished after V1B in LNa+, but were only attenuated in HNa+. In NNa+, V1B blunted the MAP responses to AngII and abolished those to AngIII. The MAP remained elevated 30 min after AngII in all groups, but returned to baseline levels 15 min after AngIII in NNa+ and HNa+ ( P < 0.01). Twenty minutes afteri.c.v. AngII, RSNA rose above baseline in HNa+ (112 ± 1%), a response not observed in the LNa+ and NNa+ groups. Twenty minutes post AngIIIi.c.v., RSNA was elevated in both HNa (109 ± 2%) and NNa+ (109 ± 2%). After V1B, RSNA rose only in the HNa+ group 15 min post AngIII infusion (109 ± 1%). Together, these findings: (1) suggest that HNa+ intake augments the MAP and RSNA responses toi.c.v. AngII and AngIII; (2) highlight an important role for peripheral V1 receptors during these responses; and (3) differentiate the effects of AngII and AngIII on blood pressure and RSNA. [ABSTRACT FROM AUTHOR]

This study examined the effect of leptin and orexin‐A on autonomic baroreflex control in conscious Wistar rats exposed to high‐fat (45% fat) or normal (3.4%) diet for 4 weeks. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were monitored during the generation of baroreflex gain curves and acute volume expansion (VEP). Intracerebroventricular (ICV) leptin (1 μg/min) increased RSNA in the normal diet group (0.31 ± 0.04 vs 0.23 ± 0.03 mV/s) and MAP in the high‐fat diet group (115 ± 5 vs 105 ± 5 mm Hg, P <.05). Orexin‐A (50 ng/min) increased RSNA, HR and MAP in the high‐fat diet group (0.26 ± 0.03 vs 0.22 ± 0.02 mV/s, 454 ± 8 vs 417 ± 12 beats/min, 117 ± 1 vs 108 ± 1 mm Hg) and the normal diet group (0.18 ± 0.05 vs 0.17 ± 0.05 mV/s, 465 ± 10 vs 426 ± 6 beats/min, 116 ± 2 vs 104 ± 3 mm Hg). Baroreflex sensitivity for RSNA was increased during ICV leptin by 50% in the normal diet group, compared to 14% in the high‐fat diet group (P <.05). Similarly, orexin‐A increased baroreflex sensitivity by 56% and 50% in the high‐fat and normal diet groups, respectively (all P <.05). During ICV saline, VEP decreased RSNA by 31 ± 5% (P <.05) after 10 minutes and the magnitude of this response was blunted during ICV infusion of leptin (17 ± 2%, P <.05) but not orexin‐A in the normal diet group. RSNA response to VEP was not changed during ICV leptin or orexin‐A in the high‐fat diet group. These findings indicate possible central roles for leptin and orexin‐A in modulating the baroreflexes under normal or increased fat intake in conscious rats and potential therapeutic approaches for obesity associated hypertension. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Does immunosuppression restore the baroreflex control of renal sympathetic nerve activity (RSNA) in an animal model of kidney injury?What is the main finding and its importance?Tacrolimus, a calcineurin inhibitor, restored the high‐ and low‐pressure baroreflex control of RSNA following cisplatin‐induced renal injury. Cisplatin administration causes depression of renal haemodynamic and excretory function and is associated with renal sympatho‐excitation and loss of baroreflex regulation of renal sympathetic nerve activity (RSNA). This study investigated whether administration of the immunosuppressant tacrolimus in this cisplatin‐mediated renal injury model could restore, or the acute intra‐renal infusion of tumour necrosis factor α (TNF‐α) could blunt, the high‐ or low‐pressure baroreflex control of RSNA. Groups of control and cisplatin‐treated (5 mg kg−1, i.p. on day 0) rats received either saline or tacrolimus (0.25 mg kg−1 day−1, i.p.) for 7 days prior to study. Rats were anaesthetised and prepared for measurement of mean arterial pressure (MAP), heart rate (HR) and RSNA. Baroreflex gain curves were generated and the degree of renal sympatho‐inhibition determined (area under the curve (AUC) reported as %RSNA min) during acute volume expansion. Intrarenal TNF‐α infusion (0.3 µg kg−1 h−1) in control rats decreased baroreflex gain by 32% (P < 0.05) compared to intra‐renal saline infusion. In the cisplatin group (MAP: 98 ± 14 mmHg; HR: 391 ± 24beats min−1), the baroreflex gain for RSNA was 39% (P < 0.05) lower than that for the control group (MAP: 91 ± 7 mmHg; HR: 382 ± 29 beats min−1). In cisplatin‐treated rats given daily tacrolimus (MAP: 84 ± 12 mmHg; HR: 357 ± 30 beats min−1), the baroreflex gain and renal sympatho‐inhibition (AUC, 2440 ± 1071 vs. 635 ± 498% min) were restored to normal values. These findings provide evidence for the view that cisplatin administration initiates an injury involving inflammation which may contribute to the deranged baroreflex regulation of RSNA. This phenomenon appears mediated in part via the renal innervation. [ABSTRACT FROM AUTHOR]

Left ventricular hypertrophy (LVH) is associated with decreased responsiveness of renal α1-adrenoreceptors subtypes to adrenergic agonists. Nitric oxide donors are known to have antihypertrophic effects however their impact on responsiveness of renal α1-adrenoreceptors subtypes is unknown. This study investigated the impact of nitric oxide (NO) and its potential interaction with the responsiveness of renal α1-adrenoreceptors subtypes to adrenergic stimulation in rats with left ventricular hypertrophy (LVH). This study also explored the impact of NO donor on CSE expression in normal and LVH kidney. LVH was induced using isoprenaline and caffeine in drinking water for 2 weeks while NO donor (L-arginine, 1.25g/Lin drinking water) was given for 5 weeks. Intrarenal noradrenaline, phenylephrine and methoxamine responses were determined in the absence and presence of selective α1-adrenoceptor antagonists, 5- methylurapidil (5-MeU), chloroethylclonidine (CeC) and BMY 7378. Renal cortical endothelial nitric oxide synthase mRNA was upregulated 7 fold while that of cystathione γ lyase was unaltered in the NO treated LVH rats (LVH-NO) group compared to LVH group. The responsiveness of renal α1A, α1B and α1D-adrenoceptors in the low dose and high dose phases of 5-MeU, CEC and BMY7378 to adrenergic agonists was increased along with cGMP in the kidney of LVH-NO group. These findings suggest that exogenous NO precursor up-regulated the renal eNOS/NO/cGMP pathway in LVH rats and resulted in augmented α1A, α1B and α1D adrenoreceptors responsiveness to the adrenergic agonists. There is a positive interaction between H2S and NO production in normal animals but this interaction appears absent in LVH animals. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to investigate the interaction between H2S and NO (nitric oxide) in the kidney and to evaluate its impact on the functional contribution of α1A and α1B-adrenoreceptors subtypes mediating the renal vasoconstriction in the kidney of rats with left ventricular hypertrophy (LVH). In rats the LVH induction was by isoprenaline administration and caffeine in the drinking water together with intraperitoneal administration of H2S. The responsiveness of α1A and α1B to exogenous noradrenaline, phenylephrine and methoxaminein the absence and presence of 5-methylurapidil (5-MeU) and chloroethylclonidine (CEC) was studied. Cystathione gamma lyase (CSE), cystathione β synthase (CBS), 3-mercaptopyruvate sulphar transferase (3-MST) and endothelial nitric oxide synthase (eNOS) were quantified. There was significant up regulation of CSE and eNOS in the LVH-H2S compared to the LVH group (P<0.05). Baseline renal cortical blood perfusion (RCBP) was increased (P<0.05) in the LVH-H2S compared to the LVH group. The responsiveness of α1A-adrenergic receptors to adrenergic agonists was increased (P<0.05) after administration of low dose 5-Methylurapidil in the LVH-H2S group while α1B-adrenergic receptors responsiveness to adrenergic agonists were increased (P<0.05) by both low and high dose chloroethylclonidine in the LVH-H2S group. Treatment of LVH with H2S resulted in up-regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways in the kidney. These up regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways enhanced the responsiveness of α1A and α1B-adrenoreceptors subtypes to adrenergic agonists in LVH-H2S. These findings indicate an important role for H2S in modulating deranged signalling in the renal vasculature resulting from LVH development. [ABSTRACT FROM AUTHOR]

Hydrogen sulphide (H2S) is an emerging molecule in many cardiovascular complications but its role in left ventricular hypertrophy (LVH) is unknown. The present study explored the effect of exogenous H2S administration in the regression of LVH by modulating oxidative stress, arterial stiffness and expression of cystathione γ lyase (CSE) in the myocardium. Animals were divided into four groups: Control, LVH, Control-H2S and LVH-H2S. LVH was induced by administering isoprenaline (5mg/kg, every 72 hours, S/C) and caffeine in drinking water (62mg/L) for 2 weeks. Intraperitoneal NaHS, 56μM/kg/day for 5 weeks, was given as an H2S donor. Myocardial expression of Cystathione γ lyase (CSE) mRNA was quantified using real time polymerase chain reaction (qPCR).There was a 3 fold reduction in the expression of myocardial CSE mRNA in LVH but it was up regulated by 7 and 4 fold in the Control-H2S and LVH-H2S myocardium, respectively. Systolic blood pressure, mean arterial pressure, pulse wave velocity were reduced (all P<0.05) in LVH-H2S when compared to the LVH group. Heart, LV weight, myocardial thickness were reduced while LV internal diameter was increased (all P<0.05) in the LVH-H2S when compared to the LVH group. Exogenous administration of H2S in LVH increased superoxide dismutase, glutathione and total antioxidant capacity but significantly reduced (all P<0.05) plasma malanodialdehyde in the LVH-H2S compared to the LVH group. The renal cortical blood perfusion increased by 40% in LVH-H2S as compared to the LVH group. Exogenous administration of H2S suppressed the progression of LVH which was associated with an up regulation of myocardial CSE mRNA/ H2S and a reduction in pulse wave velocity with a blunting of systemic hemodynamic. This CSE/H2S pathway exhibits an antihypertrophic role by antagonizing the hypertrophic actions of angiotensin II(Ang II) and noradrenaline (NA) but attenuates oxidative stress and improves pulse wave velocity which helps to suppress LVH. Exogenous administration of H2S augmented the reduced renal cortical blood perfusion in the LVH state. [ABSTRACT FROM AUTHOR]

In the family of gas transmitters, hydrogen sulfide (H2S) is yet not adequately researched. Known for its rotten egg smell and adverse effects on the brain, lungs, and kidneys for more than 300 years, the vasorelaxant effects of H2S on blood vessel was first observed in 1997. Since then, research continued to explore the possible therapeutic effects of H2S in hypertension, inflammation, pancreatitis, different types of shock, diabetes, and heart failure. However, a considerable amount of efforts are yet needed to elucidate the mechanisms involved in the therapeutic effects of H2S, such as nitric oxide-dependent or independent vasodilation in hypertension and regression of left ventricular hypertrophy. More than a decade of good repute among researchers, H2S research has certain results that need to be clarified or reevaluated. H2S produces its response by multiple modes of action, such as opening the ATP-sensitive potassium channel, angiotensin-converting enzyme inhibition, and calcium channel blockade. H2S is endogenously produced from two sulfur-containing amino acids L-cysteine and L-methionine by the two enzymes cystathionine γ lyase and cystathionine β synthase. Recently, the third enzyme, 3-mercaptopyruvate sulfur transferase, along with cysteine aminotransferase, which is similar to aspartate aminotransferase, has been found to produce H2S in the brain. The H2S has interested researchers, and a great deal of information is being generated every year. This review aims to provide an update on the developments in the research of H2S in hypertension amid the ambiguity in defining the exact role of H2S in hypertension because of insufficient number of research results on this area. This critical review on the role of H2S in hypertension will clarify the gray areas and highlight its future prospects. [ABSTRACT FROM AUTHOR]

This study investigated the role of α1D-adrenoceptor in the modulation of renal haemodynamics in rats with left ventricular hypertrophy (LVH). LVH was established in Wistar-Kyoto (WKY) rats with isoprenaline (5.0 mg·(kg body mass)-1, by subcutaneous injection every 72 h) and caffeine (62 mg·L-1 in drinking water, daily for 14 days). Renal vasoconstrictor responses were measured for noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) before and immediately after low or high dose intrarenal infusions of BMY 7378, a selective α1D-adrenoceptor blocker. The rats with LVH had higher mean arterial blood pressure and circulating NA levels, but lower renal cortical blood perfusion compared with the control group (all P < 0.05). In the LVH group, the magnitude of the renal vasoconstrictor response to ME was blunted, but not the response to NA or PE ( P < 0.05), compared with the control group (LVH vs. C, 38% vs. 50%). The magnitude of the drop in the vasoconstrictor responses to NA, PE, and ME in the presence of a higher dose of BMY 7378 was significantly greater in the LVH group compared with the control group (LVH vs. C, 45% vs. 25% for NA, 52% vs. 33% for PE, 66% vs. 53% for ME, all P < 0.05). These findings indicate an impaired renal vasoconstrictor response to adrenergic agonists during LVH. In addition, the α1D-adrenoceptor subtype plays a key role in the modulation of vascular responses in this diseased state. [ABSTRACT FROM AUTHOR]

Purpose: To examine the hypothesis that in hypertensive diabetic rats hydrogen sulphide (H2S) reduces blood pressure through diuretic action in addition to its vasodilating effect. Methods: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were used. SHR were divided into three groups: SHR (II), SHR diabetic (III), and SHR diabetic NaHS-Treated (IV) with a group of WKY (I) rats serving as normotensive nondiabetic control. Diabetes was produced in two SHR groups using intraperitoneal streptozotocin (STZ). One diabetic group received NaHS, a donor of H2S (56 μM/kg i.p.) daily for five weeks. Blood pressure was measured in conscious and anesthetized states in surgically prepared animals. Plasma and urinary H2S levels and electrolytes were measured weekly throughout the 35-day period. Results: SHR and diabetic SHR had higher blood pressure and lower plasma and urinary H2S levels compared to WKY controls (p < 0.05). Moreover, the SHR diabetic group had higher plasma sodium, higher absolute and fractional sodium excretions (p < 0.05) but with similar blood pressure compared to SHR controls. NaHS treatment reduced blood pressure and restored H2S and plasma sodium (p < 0.05) levels. Moreover, SHR diabetic-NaHS treated group had higher urine output and absolute urinary sodium excretion compared to the untreated SHR diabetic group (p < 0.05). Conclusion: These results suggest a possible diuretic effect of exogenous H2S in spontaneously hypertensive diabetic rats. [ABSTRACT FROM AUTHOR]

Oxidative stress and suppressed H2S production lead to increased renal vascular resistance, disturbed glomerular hemodynamics, and abnormal renal sodium and water handling, contribute to the pathogenesis and maintenance of essential hypertension in man and the spontaneously hypertensive rat. This study investigated the impact of H2S and tempol alone and in combination on blood pressure and renal hemodynamics and excretory functions in the SHR. Groups of WKY rats or SHR ( n = 6) were treated for 4 weeks either as controls or received NaHS (SHR + NaHS), tempol (SHR + Tempol), or NaHS plus tempol (SHR + NaHS + Tempol). Metabolic studies were performed on days 0, 14, and 28, thereafter animals were anaesthetized to measure renal hemodynamics and plasma oxidative and antioxidant markers. SHR control rats had higher mean arterial blood pressure (140.0 ± 2 vs. 100.0 ± 3 mmHg), lower plasma and urinary H2S, creatinine clearance, urine flow rate and urinary sodium excretion, and oxidative stress compared to WKY (all p < 0.05). Treatment either with NaHS or with tempol alone decreased blood pressure and oxidative stress and improved renal hemodynamic and excretory function compared to untreated SHR. Combined NaHS and tempol therapy in SHRs caused larger decreases in blood pressure (∼20-22% vs. ∼11-15% and ∼10-14%), increases in creatinine clearance, urinary sodium excretion and fractional sodium excretion and up-regulated the antioxidant status compared to each agent alone (all p < 0.05). These findings demonstrated that H2S and tempol together resulted in greater reductions in blood pressure and normalization of kidney function compared with either compound alone. [ABSTRACT FROM AUTHOR]

Reference 1 Hashmi S.F., Rathore H.A., Sattar M.A., Johns E.J., Gan C.Y., Chia T.Y., Ahmad A. Hydrogen Sulphide Treatment Prevents Renal Ischemia-Reperfusion Injury by Inhibiting the Expression of ICAM-1 and NF-kB Concentration in Normotensive and Hypertensive Rats. In addition to affiliation 1, the current address should be: College of Pharmacy, Qatar University, Doha P.O. Box 2713, Qatar. Hydrogen Sulphide Treatment Prevents Renal Ischemia-Reperfusion Injury by Inhibiting the Expression of ICAM-1 and NF-kB Concentration in Normotensive and Hypertensive Rats. [Extracted from the article]

This study investigated the effects of tempol, a superoxide dismutase (SOD) mimetic and L-NAME, a nitric oxide (NO) synthase inhibitor on the renal function and hemodynamics in cyclosporine A (CsA) induced renal insufficiency rats. Male Sprague-Dawley rats were treated with either vehicle (C), tempol (T, 1 mmol/L in drinking fluid), L-NAME (L, 1 mmol/L in drinking fluid), CsA (Cs, 25 mg/kg/day via gavage), CsA plus tempol (TCs), CsA plus L-NAME (LCs) or CsA plus a combination of tempol and L-NAME (TLCs) for 21 consecutive days. At the end of treatment regimen, the renal responses to noradrenaline (NA), phenylephrine (PE), methoxamine and angiotensin II (Ang II) were determined. Cs and LCs rats had lower creatinine clearance (0.7 ± 0.1 and 0.6 ± 0.5 vs. 1.3 ± 0.2 mL/min/kg) and fractional excretion of sodium (0.12 ± 0.02 and 0.17 ± 0.01 vs. 0.67 ± 0.04%) but higher systolic blood pressure (145 ± 2 and 178 ± 4 vs. 116 ± 2) compared to the control (all p < 0.05), respectively. Tempol treatment in TCs or TLCs prevented the increase in blood pressure and improved creatinine clearance and sodium excretion compared to untreated Cs. The renal vasoconstriction in Cs or LCs to NA, PE and Ang II were lower than control by ∼35-48% (all p < 0.05). In TCs or TLCs, there was enhanced renal vasoconstriction to all agonist by ∼39-114% compared to Cs. SOD is important to counterbalance the hypertensive effect of a defective NO system and to allow the normal vasoconstrictor response of the renal vasculature to adrenergic agonists and Ang II in a model of CsA-induced renal insufficiency. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to quantify phenolic acids and flavonoids from Citrullus colocynthis roots (CCR), leaves (CCL) fruits (CCF) and compare the antioxidant and free radical scavenging activities of their extracts and major compounds. Reverse phase high performance liquid chromatography method was developed and validated for the simultaneous quantification of phenolic acids and flavonoids from ethanol and hexane extracts of CCR, CCL and CCF. The antioxidant activity of CCR, CCL and CCF extracts was investigated by measuring total phenolics, total flavonoids contents, DPPH free radical scavenging activity, inhibition of linoleic acid peroxidation and reducing power. The RP-HPLC analysis of C. colocynthis extracts revealed the presence of ferulic acid, vanillic acid, p-coumeric acid, gallic acid, p-hydroxy benzoic acid and chlorogenic acid being the major phenolic acids and quercetin, myricetin and catechin being the most prominent flavonoids compounds. The amounts of TP (3.07–18.6mg/g of dry plant material, measured as gallic acid equivalent) and TF (0.51–13.9mg/g of dry plant material, measured as catechin equivalent) were higher in ethanol extracts of CCL, followed by CCR and CCF. Ethanol extract of CCL exhibited the highest antioxidant and DPPH radical scavenging activities followed by ethanol extracts of CCR and CCF. However, only hexane extract of CCF showed considerable DPPH radical scavenging activity. The results suggested that CCR, CCL and CCF extracts showed a wide variability of their phenolic acids and flavonoids composition and antioxidant activity. [Copyright &y& Elsevier]

The present study compared the cardiovascular and renal actions of γ2-melanocyte-stimulating hormone (γ2 MSH) with those of the synthetic analogue [Nle3, d-Phe6]-γ2 MSH ( NDP-γ2 MSH) and explored the effects of high dietary salt intake on the renal actions of NDP-γ2 MSH., Both peptides were infused systemically (3-1000 nmol/kg) and intrarenally (500 fmol/min) into innervated and renally denervated rats fed either a normal (0.4% NaCl) or high-salt (4% NaCl; HS) diet. Mean arterial pressure ( MAP), glomerular filtration rate ( GFR), urinary sodium excretion ( UNaV), urinary output ( UV) and fractional sodium excretion were determined, as was expression of the melanocortin MC3 receptor in inner medullary collecting duct ( IMCD) epithelial cells., Both renal and systemic infusion of γ2 MSH increased MAP by 23 ± 2% and 54 ± 4%, respectively, but equivalent doses of NDP-γ2 MSH had no significant pressor effects. Both peptides had similar natriuretic and diuretic effects in rats fed a normal salt diet. However, NDP-γ2 MSH increased UNaV and UV by two- to threefold in rats fed the normal salt diet and by six- to sevenfold in rats fed the HS diet. Furthermore, NDP-γ2 MSH induced a 3.5-fold increase in GFR only in rats fed the HS diet. These renal effects of NDP-γ2 MSH were not abolished by prior renal denervation. Rats fed the HS diet also exhibited a 4.5-fold increase in MC3 receptor expression in IMCD epithelial cells., Intrarenal infusion of NDP-γ2 MSH induced the natriuretic but not the cardiovascular effects exhibited by γ2 MSH. The renal activities may be attributed to a direct binding of NDP-γ2 MSH to MC3 receptors expressed in IMCD cells, leading to a potent natriuretic effect that is independent of renal innervation. [ABSTRACT FROM AUTHOR]

To evaluate possible interactions between the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) in the systemic circulation upon the intravenous administration of angiotensin II and a set of adrenergic agonists in normal Sprague-Dawley (SD) rats. Rats were treated with carvedilol, a non-selective β- and selective α1-adrenoceptor blocker, in a dose of (5 mg/kg) orally for 7 days, and on day 8, the animals werepentobarbitone-anaesthetized and prepared for systemic hemodynamic study. Dose-response relationships in terms of elevation in the magnitude of the mean arterial blood pressure in response to intravenous injection of noradrenaline (NA), phenylephrine (PE), methoxamine (ME), and angiotensin II (Ang II) were determined. Data, mean ± S.E.M., were subjected to ANOVA with significance at P < 0.05. Carvedilol blunted the peripheral vascular response to NA, PE, ME, and Ang II (all P < 0.05). It is concluded that peripheral vasoconstriction induced by Ang II is contributed to by adrenergic action. Furthermore, there is a cross-talk relationship between RAS and SNS in determining the responsiveness of the peripheral vasculature to adrenergic agonists and angiotensin II in normal rats. [ABSTRACT FROM AUTHOR]

Background. This study examined the effect of renal sympathetic innervation on adrenergically and angiotensin II (Ang II)- induced renal vasoconstriction in Wistar-Kyoto (WKY) rats. Methods. Forty-eight WKY rats were treated with either losartan (10 mg/kg/day p.o.) or carvedilol (5 mg/kg/day p.o.) or a combination of them (10 mg/kg/day + 5 mg/kg/day p.o.) for 7 days. On day 8, the rats were anaesthetized, and renal vasoconstrictor experiments were carried out. A group of rats was subjected to acute unilateral renal denervation during the acute study. Changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by Ang II, noradrenaline (NA), and methoxamine (ME). Results. In normal animals, losartan decreased (P < 0.05) the renal vasoconstrictor response to Ang II but not to NA or ME. Carvedilol treatment, however, blunted (P < 0.05) the renal vasoconstrictor responses to Ang II and adrenergic agonists. Combination of losartan and carvedilol blunted (P < 0.05) the renal vasoconstrictor response to Ang II but augmented the responses to NA and ME (all P < 0.05). Interestingly, when denervated rats were treated with the same combination, there was a reduction (P < 0.05) in the renal vasoconstrictor responses to Ang II and adrenergic agonists. Conclusions. Data suggest that the renal sympathetic nerve contributes to adrenergic agonist-mediated renal vasoconstrictions in normal rats. The data further indicate an interactive relationship between renin-angiotensin and sympathetic nervous systems in modulating adrenergically and Ang II-induced renal vasoconstriction in WKY rats. [ABSTRACT FROM AUTHOR]

The role of renal sympathetic nerves in the pathogenesis of ischemic acute renal failure (ARF) and the immediate changes in the renal excretory functions following renal ischemia were investigated. Two groups of male Sprague Dawley (SD) rats were anesthetized (pentobarbitone sodium, 60 mg kg−1 i.p.) and subjected to unilateral renal ischemia by clamping the left renal artery for 30 min followed by reperfusion. In group 1, the renal nerves were electrically stimulated and the responses in the renal blood flow (RBF) and renal vascular resistance (RVR) were recorded, while group 2 was used to study the early changes in the renal functions following renal ischemia. In post-ischemic animals, basal RBF and the renal vasoconstrictor reperfusion to renal nerve stimulation (RNS) were significantly lower (all p < 0.05 vs. control). Mean arterial pressure (MAP), basal RVR, urine flow rate (UFR), absolute and fractional excretions of sodium (UNaV and FENa), and potassium (UKV and FEK) were higher in ARF rats (all p < 0.05 vs. control). Post-ischemic animals showed markedly lower glomerular filtration rate (GFR) ( p < 0.05 vs. control). No appreciable differences were observed in urinary sodium to potassium ratio (UNa/UK) during the early reperfusion phase of renal ischemia ( p > 0.05 vs. control). The data suggest an immediate involvement of renal sympathetic nerve action in the pathogenesis of ischemic ARF primarily through altered renal hemodynamics. Diuresis, natriuresis, and kaliuresis due to impaired renal tubular functions are typical responses to renal ischemia and of comparable magnitudes. [ABSTRACT FROM AUTHOR]

Background & objectives: Regulation of renal function and haemodynamics are under a direct control from the renal sympathetic nerves and renal denervation produces overt diuresis and natriuresis in several mammalian species. However, the inter-related series of changes in renal function and haemodynamics following acute renal denervation (ARD) is not fully understood. Thus, we aimed to investigate and relate the changes in renal function and haemodynamics following acute unilateral renal denervation in anaesthetized Sprague Dawley (SD) rats. Methods: Male SD rats were fasted overnight, anaesthetized with sodium pentobarbitone (60 mg/kg ip), denervated by application of phenol to the left renal artery and maintained on an intravenous (iv) infusion of isotonic saline for 2 h. Throughout this period, six urine and plasma samples were taken at 20-min intervals to study kidney function parameters. In a different set of experiments, renal nerve stimulation (RNS) was carried out to characterize the changes in renal vasoconstrictor responses following ARD. Results: Denervated animals showed significantly (P < 0.05 vs. control innervated rats) higher urine flow rate (UFR), absolute sodium excretion (UNa V), fractional sodium excretion (FENa) and glomerular filtration rate (GFR). The renal vasoconstrictor responses to RNS were significantly (P < 0.05) lower in denervated rats as compared to the innervated counterparts. However. no appreciable differences were seen in the mean arterial pressure (MAP), plasma sodium (PNa), basal renal blood flow (RBF) and basal renal vascular resistance (RVR) in both innervated and denervated SD rats. Interpretation & conclusions: Natriuresis, diuresis, enhanced GFR and impaired vasoconstriction in response to RNS are typical and instant responses to ARD in SD rats. Renal sympathetic nerves serve more important role in salt and water conservation than in dynamic autoregulation of RBF under normal sympathetic tone; yet, their effects on renal haemodynamics become more evident in the presence of augmented renal sympathetic nerve activity (RSNA). [ABSTRACT FROM AUTHOR]

Abstract: This study set out to investigate the impact of chronic cumulative blockade of angiotensin II and adrenoceptors in WKY and SHR and to explore how the renovascular responses to adrenergic and angiotensin II receptor agonists may be interdependent. Rats were treated with either losartan, carvedilol or losartan+carvedilol for 7 days and on day eight, animals were pentobarbitone anaesthetized and prepared for renal haemodynamic study. Dose–response relationships were determined in terms of reduction/elevation in the magnitude of renal blood flow in response to intrarenal arterial injection of dopamine, phenylephrine and isoprenaline. Renal vascular responses were blunted in WKY and SHR treated with either losartan or carvedilol as compared to their untreated counterparts (P <0.05). In the combined treated rats, the vascular responses to isoprenaline and phenylephrine were restored to levels observed in the untreated rats, but the renal vasoconstrictor responses to dopamine decreased (P <0.05) in both WKY and SHR. There was a reduction of (P <0.05) in the magnitude of the isoprenaline induced renal vasodilation in all SHR as compared to WKY groups. The data obtained showed that the renal vascular action of dopamine, phenylephrine and isoprenaline depended on an intact renin–angiotensin system (RAS) in WKY and SHR. Treatment with losartan or carvedilol blunted the renal vasoconstrictor/vasodilator responses to sympathomimetics which was attenuated with the combined treatment. These observations using chronic blockade of adrenergic and angiotensin receptors demonstrated that there was a long standing interdependency between the RAS and sympathetic nervous system (SNS) in determining the responsiveness of the renal vasculature of normal and hypertensive rats. [Copyright &y& Elsevier]