Effects of intrarenal angiotensin 1-7 infusion on renal haemodynamic and excretory function in anaesthetised two-kidney one-clip and deoxycorticosterone acetate-salt hypertensive rats.

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 (AT1 R) 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 AT1 R to Mas receptor, which may to a large extent determine the renal excretory response to Ang (1-7) infusion. ABSTRACT: 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 (UNa V) 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, UNa V, 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, UNa V 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.

Correction: Hashmi et al. Hydrogen Sulphide Treatment Prevents Renal Ischemia-Reperfusion Injury by Inhibiting the Expression of ICAM-1 and NF-kB Concentration in Normotensive and Hypertensive Rats. Biomolecules 2021, 11, 1549.

In the published publication [...].

Renal Nano-drug delivery for acute kidney Injury: Current status and future perspectives.

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.

Renal denervation for atrial fibrillation: a comprehensive updated systematic review and meta-analysis.

The study aims to compare clinical outcomes following renal denervation (RDN) in hypertensive patients with atrial fibrillation (AF). Three online databases were searched (MEDLINE, EMBASE and PubMed) for literature related to outcomes of RDN on hypertension and AF, between January 1, 2010, and June 1, 2021. Where possible, risk ratios (RR) and mean differences (MD) were combined using a random effects model. Significance was set at p ≤ 0.05. Seven trials were included that assessed the effect of adding RDN to pulmonary vein isolation (PVI) in patients with hypertension and AF. A total of 711 patients (329 undergoing PVI + RDN and 382 undergoing PVI alone), with an age range of 56 ± 6 to 68 ± 9 years, were included. Pooled analysis showed a significant lowering of AF recurrence in the PVI + RDN (31.3%) group compared to the PVI-only (52.9%) group (p < 0.00001). Pooled analysis of patients with resistant hypertension showed a significant mean reduction of systolic blood pressure (SBP) (-9.42 mm Hg, p = 0.05), but not diastolic blood pressure (DBP) (-4.11 mm Hg, p = 0.16) in favor of PVI + RDN. Additionally, the pooled analysis showed that PVI + RDN significantly improved estimated glomerular filtration rate (eGFR) (+10.2 mL/min per 1.73 m2, p < 0.001) compared to PVI alone. RDN procedures in these trials have proven to be both safe and efficacious with an overall complication rate of 6.32%. Combined PVI and RDN is beneficial for patients with hypertension and AF. Combined therapy showed improvement in SBP and eGFR, reducing the risk of AF recurrence. RDN may serve as an innovative intervention in the treatment of AF.

Hydrogen Sulphide Treatment Prevents Renal Ischemia-Reperfusion Injury by Inhibiting the Expression of ICAM-1 and NF-kB Concentration in Normotensive and Hypertensive Rats.

Our main objective was to investigate the effect of chronic administration of hydrogen sulphide donor (sodium hydrosulphide) on the expression of intercellular adhesion molecule-1 (ICAM-1) and concentration of nuclear factor-kappa B (NF-kB) in a renal ischemia-reperfusion injury (IRI) model of WKY and L-nitro-arginine-methyl-ester (L-NAME)-induced hypertensive rats. Sodium hydrosulphide (NaHS) was administered intraperitoneally (i.p.) for 35 days while cystathionine gamma lyase (CSE) inhibitor dL-propargylglycine (PAG) was administered at a single dose of 50 mg/kg. Animals were anesthetised using sodium pentobarbitone (60 mg/kg) and then prepared to induce renal ischemia by clamping the left renal artery for 30 min followed by 3 h of reperfusion. Pre-treatment with NaHS improved the renal functional parameters in both WKY and L-NAME-induced hypertensive rats along with reduction of blood pressure in hypertensive groups. Oxidative stress markers like malondialdehyde (MDA), total superoxide dismutase (T-SOD) and glutathione (GSH) were also improved by NaHS treatment following renal IRI. Levels of ICAM-1 and NF-kB concentration were reduced by chronic treatment with NaHS and increased by PAG administration after renal IRI in plasma and kidney. Treatment with NaHS improved tubular morphology and glomerulus hypertrophy. Pre-treatment with NaHS reduced the degree of renal IRI by potentiating its antioxidant and anti-inflammatory mechanism, as evidenced by decreased NF-kB concentration and downregulation of ICAM-1 expression.

The renal excretory responses to acute renal interstitial angiotensin (1-7) infusion in anaesthetised spontaneously hypertensive rats.

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%), UNa V (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 UNa V 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.

Effects of intracerebroventricular leptin and orexin-A on the baroreflex control of renal sympathetic nerve activity in conscious rats fed a normal or high-fat diet.

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.

Tacrolimus restores the high- and low-pressure baroreflex control of renal sympathetic nerve activity in cisplatin-induced renal injury rats.

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. ABSTRACT: 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.

Interaction between nitric oxide and renal α1-adrenoreceptors mediated vasoconstriction in rats with left ventricular hypertrophyin Wistar Kyoto rats.

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.

Intrarenal Mas and AT1 receptors play a role in mediating the excretory actions of renal interstitial angiotensin-(1-7) infusion in anaesthetized rats.

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.

Effect of tempol and tempol plus catalase on intra-renal haemodynamics in spontaneously hypertensive stroke-prone (SHSP) and Wistar rats

Vasoconstriction within the renal medulla contributes to the development of hypertension. This study investigated the role of reactive oxygen species (ROS) in regulating renal medullary and cortical blood perfusion (MBP and CBP respectively) in both stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar rats. CBP and MBP were measured using a laser-Doppler flow meter before and after intra-renal infusion of tempol, the superoxide dismutase (SOD) mimetic or tempol plus catalase, the hydrogen peroxide-degrading enzyme. Tempol infusion significantly elevated blood perfusion within the renal medulla (MBP) in both SHRSP (by 43 ± 7%, P < 0.001) and Wistar rats (by 17 ± 2%, P < 0.05) but the magnitude of the increase was significantly greater in the SHRSP (P < 0.01). When the enzyme catalase and tempol were co-infused, MBP was again significantly increased in SHRSP (by 57 ± 6%, P < 0.001) and Wistar rats (by 33 ± 6%, P < 0.001), with a significantly greater increase in perfusion being induced in the SHRSP relative to the Wistar rats (P < 0.01). Notably, this increase was significantly greater than in those animals infused with tempol alone (P < 0.01). These results suggest that ROS plays a proportionally greater role in reducing renal vascular compliance, particularly within the renal medulla, in normotensive and hypertensive animals, with effects being greater in the hypertensive animals. This supports the hypothesis that SHRSP renal vasculature might be subjected to elevated level of oxidative stress relative to normotensive animals (AU)

No disponible

Renal targeting potential of a polymeric drug carrier, poly-l-glutamic acid, in normal and diabetic rats.

BACKGROUND AND PURPOSE: Poly-l-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier. EXPERIMENTAL APPROACH: 3H-deoxycytidine-labeled PGs (17 or 41 kDa) and 3H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF). RESULTS: In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular tissues at 2 and 6 h after an intravenous administration. In the diabetic (oxidative stress-induced) kidneys, 41 kDa PG-Tr showed the greatest renal accumulation of 8-fold higher than the free compound 24 h post dose. Meanwhile, the synthesized PG-AEBSF was found to inhibit intracellular nicotinamide adenine dinucleotide phosphate oxidase (a reactive oxygen species generator) at an efficiency that is comparable to that of free AEBSF. This indicates the preservation of the anti-oxidative stress properties of AEBSF in the conjugated state. CONCLUSION/IMPLICATIONS: The favorable accumulation property of 41 kDa PG in normal and oxidative stress-induced kidneys, along with its capabilities in conserving the pharmacological properties of the conjugated renal protective drugs, supports its role as a potential renal targeting drug carrier.

The role of brain angiotensin II (type 2) receptors and nitric oxide in the renal sympathoinhibitory response to acute volume expansion in conscious rats.

OBJECTIVE: The study was performed to investigate the role of angiotensin II type 2 (AT2) receptors and nitric oxide in the renal sympathoinhibitory response to volume expansion (VEP). METHOD: Conscious rats were subjected to volume expansion (VEP) [0.25% body weight/min saline for 10 min intravenously (i.v.)] following intracerebroventricular (i.c.v.) infusion of either saline or angiotensin II (Ang II), or a combination of Ang II with either losartan, PD123319, or N-nitro-L-arginine methyl ester (L-NAME). RESULTS: Intracerebroventricular losartan, PD123319, or L-NAME did not change baseline mean arterial pressure, heart rate, or renal sympathetic nerve activity (RSNA). However, i.c.v. Ang II increased mean arterial pressure and decreased heart rate and RSNA baselines (113 ±â€Š2 vs. 107 ±â€Š2 mmHg, 365 ±â€Š7 vs. 379 ±â€Š5 beats/min, 1.03 ±â€Š0.13 vs. 1.29 ±â€Š0.15 µV.s, respectively, all P < 0.05). During i.c.v. saline infusion, VEP decreased RSNA by 27 ±â€Š2% (P < 0.05) after 10 min and the magnitude of this response was unchanged during i.c.v. infusion of Ang II, losartan, or PD123319 but was decreased by L-NAME compared with that obtained with i.c.v. saline (14 ±â€Š3 vs. 30 ±â€Š5%, P < 0.05). i.c.v. Ang II in combination with losartan enhanced (41 ±â€Š3 vs. 29 ±â€Š5%) but with PD123319 decreased (15 ±â€Š2 vs. 28 ±â€Š4%, P < 0.05) the renal sympathoinhibition compared with Ang II alone. The renal sympathoinhibitory response was enhanced (43 ±â€Š5 vs. 29 ±â€Š1%, P < 0.05) by i.c.v. infusion of an AT2 agonist, CGP42112 the magnitude of which was unchanged when combined with L-NAME. The sympathoinhibitory response to VEP following Ang II plus L-NAME was similar to Ang II alone. CONCLUSION: These findings suggest that activation of central AT2 receptors enhances the renal sympathoinhibitory response to VEP but this effect is not dependent on nitric oxide.

Effect of tempol and tempol plus catalase on intra-renal haemodynamics in spontaneously hypertensive stroke-prone (SHSP) and Wistar rats.

Vasoconstriction within the renal medulla contributes to the development of hypertension. This study investigated the role of reactive oxygen species (ROS) in regulating renal medullary and cortical blood perfusion (MBP and CBP respectively) in both stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar rats. CBP and MBP were measured using a laser-Doppler flow meter before and after intra-renal infusion of tempol, the superoxide dismutase (SOD) mimetic or tempol plus catalase, the hydrogen peroxide-degrading enzyme. Tempol infusion significantly elevated blood perfusion within the renal medulla (MBP) in both SHRSP (by 43 ± 7%, P < 0.001) and Wistar rats (by 17 ± 2%, P < 0.05) but the magnitude of the increase was significantly greater in the SHRSP (P < 0.01). When the enzyme catalase and tempol were co-infused, MBP was again significantly increased in SHRSP (by 57 ± 6%, P < 0.001) and Wistar rats (by 33 ± 6%, P < 0.001), with a significantly greater increase in perfusion being induced in the SHRSP relative to the Wistar rats (P < 0.01). Notably, this increase was significantly greater than in those animals infused with tempol alone (P < 0.01). These results suggest that ROS plays a proportionally greater role in reducing renal vascular compliance, particularly within the renal medulla, in normotensive and hypertensive animals, with effects being greater in the hypertensive animals. This supports the hypothesis that SHRSP renal vasculature might be subjected to elevated level of oxidative stress relative to normotensive animals.

INCREASED OXIDATIVE STRESS AND DOWN REGULATION OF ENDOTHELIAL NITRIC OXIDE SYNTHASE (ENOS) IN THE KIDNEY ATTEN- UATE THE RESPONSIVENESS OF (XlB ADRENERGIC RECEPTORS IN THE KIDNEY OF RATS WITH LEFT VENTRICULAR HYPERTROPHY.

Present study explored endothelial nitric oxide synthase/nitric oxide (eNOS/NO) pathway in the kidney and role of αIB adrenergic receptor in the regulation of renal vasculature in the rats with left ventricular hypertrophy (LVH). LVH was induced by administering isoprenaline 5 mg/kg (s.c. 72 h. apart) and caffeine (62 mg/L in drinking water) for 14 days. Quantification of molecular expression of eNOS in kidney was performed by quantitative Real Time Polymerase Chain Reaction (qPCR). Renal vasoconstrictor responses were measured by administering noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) in pre-drug phase, low dose and high dose phases of chloroethylelonidine (CEC), a selective of (αIB adrenergic receptor antagonist. In the kidney of LVH male Wistar Kyoto (WKY) rats eNOS was significantly down regulated (p < 0.05) by 74% relative to Control WKY (taken as 100%). The high dose 5 CEC attenuated the vasoconstrictor responses to NA by 41%, PE by 43% and ME by 33% in the LVH-WKY when compared to the same dose phase in Control WKY group. In LVH, increased oxidative stress in kidney and increased ACE activity in the plasma resulted in down regulation of eNOS/NO in the kidney. The renal vasoconstrictor responses to adrenergic agonist are blunted in LVH and (αIB adrenergic receptor is functional subtype in renal vasculature in LVH.

A CRITICAL REVIEW ON PHARMACOLOGICAL SIGNIFICANCE OF HYDROGEN SULFIDE (H2S) ON NF-κB CONCENTRATION AND ICAM-1 EXPRESSION IN RENAL ISCHEMIA REPERFUSION INJURY.

Until recently hydrogen sulfide (H2S) was the least appreciated of the three gasotransmitters but now recognized as 3Y gaseous mediator after nitric oxide(NO) and carbon monoxide (CO). H2S regulates a number of physiological processes like vasorelaxation, prevention of inflammation, leukocyte adhesion, anti-prolifera- tive effects, anti-thrombotic effects, resistance to oxidative stress and protection against ischemia reperfusion injury (IRI). However, considerable amount of research is still needed to evaluate the mechanisms involved in the therapeutic effects of H2S in IRI such as its effects on nuclear factor-kappa B (NF-KB) concentration and intercellular adhesion molecule-1 (ICAM-1) expression in renal IRI and ARF (acute renal failure). More than a decade of good repute among researchers, H2S research has certain results that need to be clarified more such as whether H2S is pro-inflammatory or anti-inflammatory agent. Moreover, pathways adopted by H2S in the protein modification and its effects on cell signalling specially its effect on NF-KB in the process of inflamma- tion are not fully elucidated. H2S has delighted researchers and a great deal of information is being generated every year.The main purpose of the review is to provide an update on the development in the research of H2S in renal IRI due to uncertainty of the exact role of H2S on ICAM-1 expression and NF-KB concentration whether it inhibits or activates them.

Interaction between irbesartan, peroxisome proliferator-activated receptor (PPAR-gamma), and adiponectin in the regulation of blood pressure and renal function in spontaneously hypertensive rats

Adiponectin exerts vasodilatory effects. Irbesartan, an angiotensin receptor blocker, possesses partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity and increases circulating adiponectin. This study explored the effect of irbesartan alone and in combination with adiponectin on blood pressure, renal hemodynamic excretory function, and vasoactive responses to angiotensin II and adrenergic agonists in spontaneously hypertensive rat (SHR). Irbesartan was given orally (30 mg/kg/day) for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Groups of SHR received either irbesartan or adiponectin or in combination. A group of Wistar Kyoto rats (WKY) served as controls. Metabolic data and plasma samples were taken on days 0, 21, and 28. In acute studies, the renal vasoconstrictor actions of angiotensin II (ANGII), noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) were determined. SHR control rats had a higher mean blood pressure than the WKY (132 ± 7 vs. 98 ± 2 mmHg), lower plasma and urinary adiponectin, creatinine clearance, urine flow rate and sodium excretion, and oxidative stress markers compared to WKY (all P < 0.05) which were progressively normalized by the individual drug treatments and to a greater extent by combined treatment. Responses to intrarenal administration of NA, PE, ME, and ANGII were larger in SHR (P < 0.05) than WKY by 20-25 %. Irbesartan enhanced (P < 0.05) responses to NA and PE, while adiponectin blunted responses to all vasoconstrictors (all P < 0.05). Combined treatment in SHR further decreased the renal vascular responses to ANGII. These findings suggest that an interactive relationship may exist between PPAR-γ, alpha adrenoceptors, and ANGII in the renal vasculature of the SHR (AU)

No disponible

Interaction between irbesartan, peroxisome proliferator-activated receptor (PPAR-γ), and adiponectin in the regulation of blood pressure and renal function in spontaneously hypertensive rats.

Adiponectin exerts vasodilatory effects. Irbesartan, an angiotensin receptor blocker, possesses partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity and increases circulating adiponectin. This study explored the effect of irbesartan alone and in combination with adiponectin on blood pressure, renal hemodynamic excretory function, and vasoactive responses to angiotensin II and adrenergic agonists in spontaneously hypertensive rat (SHR). Irbesartan was given orally (30 mg/kg/day) for 28 days and adiponectin intraperitoneally (2.5 µg/kg/day) for last 7 days. Groups of SHR received either irbesartan or adiponectin or in combination. A group of Wistar Kyoto rats (WKY) served as controls. Metabolic data and plasma samples were taken on days 0, 21, and 28. In acute studies, the renal vasoconstrictor actions of angiotensin II (ANGII), noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) were determined. SHR control rats had a higher mean blood pressure than the WKY (132 ± 7 vs. 98 ± 2 mmHg), lower plasma and urinary adiponectin, creatinine clearance, urine flow rate and sodium excretion, and oxidative stress markers compared to WKY (all P < 0.05) which were progressively normalized by the individual drug treatments and to a greater extent by combined treatment. Responses to intrarenal administration of NA, PE, ME, and ANGII were larger in SHR (P < 0.05) than WKY by 20-25 %. Irbesartan enhanced (P < 0.05) responses to NA and PE, while adiponectin blunted responses to all vasoconstrictors (all P < 0.05). Combined treatment in SHR further decreased the renal vascular responses to ANGII. These findings suggest that an interactive relationship may exist between PPAR-γ, alpha adrenoceptors, and ANGII in the renal vasculature of the SHR.