Reduction In Renal Blood Flow Research Articles

TRPs in the kidney - location, location, location

TRPs in the kidney - location, location, location

Abstract 524: Renal Hemodynamic and Excretory Responses to Infusion of Tyrosine Kinase Inhibitor, Imatinib in Anesthetized Mice

Systemic administration of a tyrosine kinase inhibitor, imatinib has been shown to have potent vasodilator activity in pulmonary and systemic vascular beds in rats. Chronic treatment with imatinib was also shown to cause marked attenuation of the renal injury in AngII induced hypertensive rats. However, the involvement of tyrosine kinases in the regulation of renal hemodynamics and excretory function is not yet clearly defined. To examine the role of constitutively active tyrosine kinases in the kidney, we have examined the renal effects of intravenous infusion of imatinib mesylate (Novartis Pharma, AG, Basel, Switzerland) at incremental doses (0.02, 0.2 and 2 mg/min/kg bw) as well as its interaction with nitric oxide (NO) activity in anesthetized mice. Systemic blood pressure (SBP) was recorded from a cannula placed in the left carotid artery. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by renal clearances of PAH and inulin respectively. From a control SBP value of 91 ± 3 mmHg in one group of mice (n=5), imatinib caused minimal changes in SBP at lower doses (87 ± 4 and 86 ± 5mmHg; n=5) but caused significant reduction (75 ± 4 mmHg; P<0.01) at the highest dose. During infusion of imatinib doses, there were no significant changes in RBF (from control value of 9.2 ± 0.9 to 9.2 ± 1.1, 9.9 ± 1.8 and 8.7 ± 2.2 mL/min/g kw respectively), but interestingly, there were dose-depended reductions in GFR (from a control value of 1.8 ± 0.2 to 1.7 ± 0.3, 1.5 ± 0.3, and 1.1 ± 0.3 mmHg). However, only at the highest dose, there were significant reductions in urine flow (from 6.5 ± 0.9 to 4.6 ± 0.5 μL/min/g) and sodium excretion (from 0.42 ± 0.09 to 0.17 ± 0.03 μmol/min/g) but not in fractional excretion of sodium (0.16 ± 0.04 to 0.13 ± 0.04 % ) indicating that the excretory changes were mostly dependent on hemodynamic changes. It is also observed that the usual responses (reductions in RBF, GFR etc) to the infusion of NO synthase inhibitor, nitro-L-arginine (L-NAME; 200mg/min/kg) remain intact in mice (separate group; n=5) pretreated with imatinib (0.2 mg/min/kg). These data suggest that a constitutively active tyrosine kinase pathway plays a regulatory role in maintaining glomerular filtration rate and excretory function in the kidney which seems independent of NO activity.

Renal medullary cyclooxygenase-2 and (pro)renin receptor expression during angiotensin II-dependent hypertension

The (pro)renin receptor [(P)RR] upregulates cyclooxygenase-2 (COX-2) in inner medullary collecting duct (IMCD) cells through ERK1/2. Intrarenal COX-2 and (P)RR are upregulated during chronic ANG II infusion. However, the duration of COX-2 and (P)RR upregulation has not been determined. We hypothesized that during the early phase of ANG II-dependent hypertension, membrane-bound (P)RR and COX-2 are augmented in the renal medulla, serving to buffer the hypertensinogenic and vasoconstricting effects of ANG II. In Sprague-Dawley rats infused with ANG II (0.4 μg·min(-1)·kg(-1)), systolic blood pressure (BP) increased by day 7 (162 ± 5 vs. 114 ± 10 mmHg) and continued to increase by day 14 (198 ± 15 vs. 115 ± 13 mmHg). Membrane-bound (P)RR was augmented at day 3 coincident with phospho-ERK1/2 levels, COX-2 expression, and PGE2 in the renal medulla. In contrast, membrane-bound (P)RR was reduced and COX-2 protein levels were not different from controls by day 14. In cultured IMCD cells, ANG II increased secretion of the soluble (P)RR. In anesthetized rats, COX-2 inhibition decreased the glomerular filtration rate (GFR) and renal blood flow (RBF) during the early phase of ANG II infusion without altering BP. However, at 14 days of ANG II infusions, COX-2 inhibition decreased mean arterial BP (MABP), RBF, and GFR. Thus, during the early phase of ANG II-dependent hypertension, the increased (P)RR and COX-2 expression in the renal medulla may contribute to attenuate the vasoconstrictor effects of ANG II on renal hemodynamics. In contrast, at 14 days the reductions in RBF and GFR caused by COX-2 inhibition paralleled the reduced MABP, suggesting that vasoconstrictor COX-2 metabolites contribute to ANG II hypertension.

Renal endothelial dysfunction in acute kidney ischemia reperfusion injury.

Acute kidney injury is associated with alterations in vascular tone that contribute to an overall reduction in GFR. Studies in animal models indicate that ischemia triggers alterations in endothelial function that contribute significantly to the overall degree and severity of a kidney injury. Putative mediators of vasoconstriction that may contribute to the initial loss of renal blood flow and GFR are highlighted. In addition, there is discussion of how intrinsic damage to the endothelium impairs homeostatic responses in vascular tone as well as promotes leukocyte adhesion and exacerbating the reduction in renal blood flow. The timing of potential therapies in animal models as they relate to the evolution of AKI, as well as the limitations of such approaches in the clinical setting are discussed. Finally, we discuss how acute kidney injury induces permanent alterations in renal vascular structure. We posit that the cause of the sustained impairment in kidney capillary density results from impaired endothelial growth responses and suggest that this limitation is a primary contributing feature underlying progression of chronic kidney disease.

Increased Activation of the Rho-A/Rho-Kinase Pathway in the Renal Vascular System Is Responsible for the Enhanced Reactivity to Exogenous Vasopressin in Endotoxemic Rats*

We evaluated the role of the renal vascular system and the Rho-A/Rho-kinase pathway in the maintenance of the pressor effects of vasopressin in endotoxemic rats. In vitro and in vivo animal study. University research laboratory. Male Wistar rats (200-300 g). Rats received either saline or lipopolysaccharide (10 mg/kg, intraperitoneal) 6 or 24 hours before the experiments. The effects of vasopressin on isolated aortic rings, cardiac function, mean arterial pressure, and both the renal vascular perfusion pressure of perfused kidneys in vitro and renal blood flow in situ were evaluated. The role of Rho-kinase in the renal and systemic effects of vasopressin was investigated through administration of the selective inhibitor Y-27632 and Western blot analysis. The effect of vasopressin on mean arterial pressure was unaltered and that on renal vascular perfusion pressure enhanced in endotoxemic rats at both 6 and 24 hours after lipopolysaccharide, despite reduced contractile responses in aortic rings and the lack of effect on cardiac function. Vasopressin (3, 10, and 30 pmol/kg, IV) produced increased reduction in renal blood flow in endotoxemic rats. In perfused kidneys from lipopolysaccharide groups, administration of Y-27632 reverted the hyperreactivity to vasopressin. Treatment with Y-27632 partially inhibited the effects of vasopressin on mean arterial pressure and significantly reduced the effects of vasopressin on renal blood flow in control but not in endotoxemic rats. Although the protein levels of Rho-A and Rho-kinase I and II had not been impaired, the levels of phosphorylated myosin phosphatase-targeting subunit 1, the regulatory subunit of myosin phosphatase that is inhibited by Rho-kinase, were increased in both the renal cortex and the renal medulla of endotoxemic rats. Our data suggest that activation of Rho-kinase potentiates the vascular effects of vasopressin in the kidneys, contributing to the maintenance of the hypertensive effects of this agent during septic shock.

Decongestive therapy and renal function in acute heart failure: time for a new approach?

Outcomes after admission for acute heart failure (AHF) remain extremely poor, especially for patients with decreased renal function or those in whom worsening renal function (WRF) develops during treatment. The Table shows the baseline estimated glomerular filtration rate (GFR) with 30- and 60-day mortality from the Dose Optimization Strategies Evaluation trial in acute Heart Failure (DOSE HF), the CArdioRenal REScue Study in acute Heart Failure (CARRESS HF), and the Renal Optimization Strategies Evaluation trial in acute Heart Failure (ROSE HF).1–3 GFR at randomization in each of these trials was significantly decreased, and the 60-day mortality of 14.7% in CARRESS HF (the only study to date requiring documentation of WRF before randomization) is one of the highest yet reported. View this table: Table. Baseline Estimated Glomerular Filtration Rate and 30- and 60-Day Mortality Rates From the DOSE Trial, the ROSE Trial, and the CARRESS in Acute Heart Failure Trial Recently Conducted by the National Heart, Lung, and Blood Institute Heart Failure Network WRF may have many causes in the setting of AHF.4 These include underdiuresis (which may lead to persistent increases in central venous pressure, thereby adversely affecting GFR), direct renal damage from the effects of drugs or procedures, progression of underlying disease, and overdiuresis leading to volume depletion with the subsequent engagement of baroreflex mechanisms and, as a result, a reduction in renal blood flow, GFR, and a fall in cardiac output. WRF may also be caused by a transient reduction in intravascular volume such that the rate at which intravascular volume is replenished from the extravascular space (the so-called plasma refill rate) is exceeded. This can occur despite persistent systemic congestion, as suggested by the results from CARRESS HF in which serum creatinine increased further during treatment with ultrafiltration, despite clinical evidence of ongoing congestion. Regardless of cause, outcomes …

Early determinants of acute kidney injury during experimental intra-abdominal sepsis

Sepsis-induced acute kidney injury (AKI) is an early and frequent organ dysfunction, associated with increased mortality. To evaluate the impact of macrohemodynamic and microcirculatory changes on renal function and histology during an experimental model of intra-abdominal sepsis. In 18 anaesthetized pigs, catheters were installed to measure hemodynamic parameters in the carotid, right renal and pulmonary arteries. After baseline assessment and stabilization, animals were randomly divided to receive and intra-abdominal infusion of autologous feces or saline. Animals were observed for 18 hours thereafter. In all septic animals, serum lactate levels increased, but only eight developed AKI (66%). These animals had higher creatinine and interleukin-6 levels, lower inulin and para-aminohippurate clearance (decreased glomerular filtration and renal plasma flow), and a negative lactate uptake. Septic animals with AKI had lower values of mean end arterial pressure, renal blood flow and kidney perfusion pressure, with an associated increase in kidney oxygen extraction. No tubular necrosis was observed in kidney histology. The reduction in renal blood flow and renal perfusion pressure were the main mechanisms associated with AKI, but were not associated with necrosis. Probably other mechanisms, such as microcirculatory vasoconstriction and inflammation also contributes to AKI development.

Exogenous L‐arginine attenuates the effects of angiotensin II on renal hemodynamics and the pressure natriuresis–diuresis relationship

Administration of exogenous L-arginine (L-Arg) attenuates angiotensin-II (AngII)-mediated hypertension and kidney disease in rats. The present study assessed renal hemodynamics and pressure diuresis-natriuresis in anaesthetized rats infused with vehicle, AngII (20 ng/kg per min i.v.) or AngII + L-Arg (300 μg/kg per min i.v.). Experiments in isolated aortic rings were carried out to assess L-Arg effects on the vasculature. Increasing renal perfusion pressure (RPP) from ~100 to 140 mmHg resulted in a nine- to tenfold increase in urine flow and sodium excretion rate in control animals. In comparison, AngII infusion significantly reduced renal blood flow (RBF) and glomerular filtration rate (GFR) by 40-42%, and blunted the pressure-dependent increase in urine flow and sodium excretion rate by 54-58% at elevated RPP. Supplementation of L-Arg reversed the vasoconstrictor effects of AngII and restored pressure-dependent diuresis to levels not significantly different from control rats. Dose-dependent contraction to AngII (10(-10) mol/L to 10(-7) mol/L) was observed with a maximal force equal to 27 ± 3% of the response to 10(-5) mol/L phenylephrine. Contraction to 10(-7) mol/L AngII was blunted by 75 ± 3% with 10(-4) mol/L L-Arg. The influence of L-Arg to blunt AngII-mediated contraction was eliminated by endothelial denudation or incubation with nitric oxide synthase inhibitors. Furthermore, the addition of 10(-3) mol/L cationic or neutral amino acids, which compete with L-Arg for cellular uptake, blocked the effect of L-Arg. Anionic amino acids did not influence the effects of L-Arg on AngII-mediated contraction. These studies show that L-Arg blunts AngII-mediated vascular contraction by an endothelial- and nitric oxide synthase-dependent mechanism involving cellular uptake of L-Arg.

Extending the role of peritoneal dialysis: can we win hearts and minds?

The ability of peritoneal dialysis (PD) to achieve low-molecular weight solute clearance and ultrafiltration at low haemodynamic cost makes it an attractive therapy in situations where more aggressive therapy may be undesirable due to sudden reductions in cerebral, coronary or renal blood flow. We undertook a review of the literature to examine the recent evidence for this in two specific examples: the removal of glutamate following acute stroke and ultrafiltration for the treatment of diuretic resistant heart failure. In acute stroke, glutamate, when released into the extracellular tissues, causes neuronal cell death due to its excitotoxic properties. Experimental evidence from animal models indicates that its removal, including via PD, can reduce infarct size and restore functional brain tissue. PD is effective in removing glutamate in patients treated for renal failure. In heart failure, PD has a number of both theoretical and practical advantages for extending treatment, especially as an established home therapy. Several recent cohort studies describing its use in approaching 300 patients with diuretic resistance show consistent benefits in hospitalization and severity. Both these applications require substantial further clinical evaluation before they can justify wider adoption but their potential to alleviate morbidity on a large and potentially highly cost-effective scale demands further study.

High-NaCl diet impairs dynamic renal blood flow autoregulation in rats with adenine-induced chronic renal failure

This study examined the effects of 2 wk of high-NaCl diet on kidney function and dynamic renal blood flow autoregulation (RBFA) in rats with adenine-induced chronic renal failure (ACRF). Male Sprague-Dawley rats received either chow containing adenine or were pair-fed an identical diet without adenine (controls). After 10 wk, rats were randomized to either remain on the same diet (0.6% NaCl) or to be switched to high 4% NaCl chow. Two weeks after randomization, renal clearance experiments were performed under isoflurane anesthesia and dynamic RBFA, baroreflex sensitivity (BRS), systolic arterial pressure variability (SAPV), and heart rate variability were assessed by spectral analytical techniques. Rats with ACRF showed marked reductions in glomerular filtration rate and renal blood flow (RBF), whereas mean arterial pressure and SAPV were significantly elevated. In addition, spontaneous BRS was reduced by ∼50% in ACRF animals. High-NaCl diet significantly increased transfer function fractional gain values between arterial pressure and RBF in the frequency range of the myogenic response (0.06-0.09 Hz) only in ACRF animals (0.3 ± 4.0 vs. -4.4 ± 3.8 dB; P < 0.05). Similarly, a high-NaCl diet significantly increased SAPV in the low-frequency range only in ACRF animals. To conclude, a 2-wk period of a high-NaCl diet in ACRF rats significantly impaired dynamic RBFA in the frequency range of the myogenic response and increased SAPV in the low-frequency range. These abnormalities may increase the susceptibility to hypertensive end-organ injury and progressive renal failure by facilitating pressure transmission to the microvasculature.

Angiotensin-II induced hypertension and renovascular remodelling in tissue inhibitor of metalloproteinase 2 knockout mice

Sustained hypertension induces renovascular remodelling by altering extracellular matrix (ECM) components. Matrix metalloproteinases (MMPs) are Zn-dependent enzymes that regulate ECM turnover in concert with their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Increased MMP-2 and MMP-9 have been implicated in hypertensive complications; however, the contribution of individual MMPs/TIMPs in renal remodelling has not been fully elucidated. The purpose of this study was to determine the effect of TIMP2 deficiency and thus MMP-2 on angiotensin-II (Ang-II) induced renal remodelling. C57BL/6J (wild-type) and TIMP2 knockout mice were infused with Ang-II at 250 ng/kg per min for 4 weeks. Blood pressure was measured weekly and end-point laser Doppler flowmetry was done to assess cortical blood flow. Immunohistochemical staining was performed for collagen and elastin analyses. The activity of MMP-9 and MMP-2 was determined by Gelatin zymography. Ang-II induced similar elevation in mean blood pressure in TIMP2 and wild-type mice. In TIMP2 mice, Ang-II treatment was associated with a greater reduction in renal cortical blood flow and barium angiography demonstrated decreased vascular density compared with Ang-II treated wild-type mice. Peri-glomerular and vascular collagen deposition was increased and elastin content was decreased causing increased wall-to-lumen ratio in TIMP2 mice compared with wild-type mice receiving Ang-II. Ang-II increased the expression and activity of MMP-9 predominantly in TIMP2 mice than in wild-type mice. These results suggest that TIMP2 deficiency exacerbates renovascular remodelling in agonist-induced hypertension by a mechanism that may, in part, be attributed to increased activity of MMP-9.

English

role of AKI in the ICU is contributed to its association with high mortality, morbidity and economic costs. It develops as a result of the reductions in renal blood flow (RBF), cellular and humoural immune system response to infection, nephrotoxic drugs and cellular injury 1–3 . One important controversy area in the field of AKI is the pathogenesis of AKI. The classification of AKI into prerenal and renal may be questionable today. The pre-renal state is very transient and mild, but when it becomes severe, prolonged and with already compromised kidney, the pre-renal state can lead to renal AKI. In addition, the fact that acute tubular necrosis (ATN) is the main pathological character of AKI seems to be challenged by the recent findings that renal blood flow may not be reduced, at least in sepsis, and other types of cell damage may occur 4 . The early identification of at-risk patients and prevention of acute kidney injury to reduce mortality rate (50%–70%) associated with acute kidney injury in sepsis is essentially required 5 . However, failure of AKI preventive strategies is contributed to the lack of real-time sensitive and specific renal biomarkers and diagnostic tool, which allow the early detection of AKI. One of the research priority today is to find a tool or marker for an early prediction of AKI, to prevent or attenuate persistent AKI in patients with transient AKI 6 . The aims of this review are to discuss briefly recent advance in understanding the pathological changes in sepsis-induced AKI, and the current investigated tools and biomarkers with their advantages and limitations in field of AKI.

Abstract 285: Renal Inflammation and Injury Markers Correlate Directly With Cortical and Fractional Hypoxia Measured With Blood Oxygen Level Dependent (BOLD) MR in Human Atherosclerotic Renal Artery Stenosis

Background: Atherosclerotic renal artery stenosis (ARAS) reduces renal blood flow (RBF) and amplifies regional kidney hypoxia, but their relationship to tissue inflammation and injury markers is poorly understood. We tested the hypothesis that renal injury, reflected by renal vein levels of neutrophil gelatinase associated lipocalin (NGAL) and inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) would be magnified with severe occlusive vascular disease in humans with ARAS. Methods: Inpatient studies performed in patients with ARAS (n=40, 71.3±11% occlusion by CT angiography) or essential hypertension (EH) (n=30), during fixed Na+ intake and ACE/ARB Rx. Single-kidney cortical and medullary perfusion and RBF were measured using multidetector CT, and glomerular filtration rate (GFR) by iothalamate clearance. Tissue deoxyhemoglobin levels (R2*) and fractional kidney hypoxia (% of axial area with R2*&gt;30/s) were measured by BOLD-MRI at 3T. Results: Single kidney RBF, cortical and medullary perfusion were reduced in the post-stenotic kidney, as was GFR. Renal vein NGAL, MCP-1 and fractional hypoxia were higher in patients with ARAS than EH. NGAL and MCP-1 levels correlated directly with cortical R2* and fractional hypoxia (r = 0.52, P &lt;0 .0001 and r = 0.4, P = 0.0006) and with the degree of artey stenosis (r = 0.37, P = 0.04 and r = 0.35, P = 0.05). GFR correlated inversely with NGAL (r= - 0.5, P &lt;0.0001). Conclusions: Our results demonstrate that elevated renal venous markers of kidney inflammation (MCP-1) and injury (NGAL) in ARAS are correlated with the severity of tissue hypoxia as measured by BOLD MR, suggesting a possible link between kidney inflammation and hypoxia.

Abstract 5: Intrarenal Responses to Angiotensin I and Angiotensin (1-7) in the Stroke-Prone Spontaneously Hypertensive Rat Are Y Chromosome Dependent

The Y chromosome accounts for 15-20mmHg difference in arterial pressure; the gene(s) and mechanism(s) underlying this effect remain unknown. One candidate gene, the Sry3 gene, expressed exclusively on the hypertensive SHR Y chromosome has been shown in vitro to interact with the renin angiotensin system (RAS). Using a reciprocal Y consomic rat approach, we investigated the functional consequences of this interaction in vivo ; examining the interaction of the Y chromosome with the renal vasculature. 16 week old normotensive rats (WKY), hypertensive rats (SHRSP) and two reciprocal Y consomic rat strains; one comprising the WKY autosomes and X chromosome with the hypertensive Y chromosome (WKY.SP Gla Y) and vice versa (SP.WKY Gla Y) were examined. We confirmed via radiotelemetry that systolic blood pressure (SBP) was Y chromosome dependent; SP.WKY Gla Y had lower SBP than SHRSP (195±5mmHg vs 227±8mmHg, P&lt;0.03) and was higher in WKY.SP Gla Y compared to WKY (157±3mmHg vs 148±3mmHg, P&lt;0.05). Compared to WKY rats, the vasodilator arm of the RAS was enhanced in SHRSP as evidenced by a higher plasma Ang(1-7):Ang II ratio (WKY:0.13±0.01 vs SHRSP:1.33±0.4, P&lt;0.005) and a blunted renal blood flow (RBF) response to graded intrarenal Ang I and Ang(1-7) infusions. In response to 10ng/kg we observed a reduction in RBF of WKY:58±6% and 16±6% vs SHRSP: 17±6%, P&lt;0.01 and 1±4%, P&lt;0.05 respectively. Introgression of the normotensive Y chromosome into the SHRSP background (SP.WKY Gla Y) resulted in a reduction in plasma Ang(1-7):AngII ratio (SP.WKY Gla Y: 0.24±0.02, P&lt;0.01) and an increased vasoconstrictor response to intrarenal Ang I and Ang(1-7) infusion. In response to 10ng/kg bolus RBF in SP.WKY Gla Y reduced by 45±14%, P&lt;0.01 and 41±18%, P&lt;0.005, respectively compared to SHRSP, demonstrating the blunted responsiveness in the SHRSP is Y chromosome dependent. Investigation of the interlobular arteries via wire myography revealed increased sensitivity to Ang II in SHRSP compared to WKY which was reduced following introgression of the WKY Y chromosome (SP.WKY Gla Y) confirming that the Y chromosome influences the RAS in the renal vasculature. This study provides novel evidence that the Y chromosome influences the vasodilatory arm of the RAS and intrarenal vascular function.

The “nervous” kidney and ventricular fibrillation: A possible game changer?

The “nervous” kidney and ventricular fibrillation: A possible game changer?

Renal angioplasty for treatment of hypertensive patients with fibromuscular dysplasia. No country for old men

Renal angioplasty for treatment of hypertensive patients with fibromuscular dysplasia. No country for old men

Pressor and renal regional hemodynamic effects of urotensin II in neonatal pigs

Renal expression of the peptide hormone urotensin II (UII) and its receptor (UTR) are dependent on kidney maturation and anatomical regions. However, renal regional hemodynamic effects of UII in neonates are unclear. Here, we investigated regional hemodynamic responses to acute intrarenal arterial administration of UII in newborn pigs. Western immunoblotting and immunofluorescence confirmed UTR expression and membrane localization in newborn pig renal afferent arterioles and afferent arteriolar smooth muscle cells respectively. Intrarenal arterial bolus injections of human UII (hUII; 1-100 ng/kg) resulted in a dose-dependent decrease in total renal blood flow (RBF) and an increase in mean arterial pressure (MAP) and renal vascular resistance (RVR) in newborn pigs. Moreover, hUII dose dependently reduced cortical blood flow (CBF) but increased medullary blood flow (MBF) in the piglets. hUII-induced MAP elevation and hemodynamic changes were inhibited by urantide, a UTR antagonist, but not losartan, a type 1 angiotensin II receptor antagonist. U-73122, a phospholipase C (PLC) inhibitor, and 2-aminoethoxydiphenyl borate, an inositol 1,4,5 trisphosphate (IP₃) receptor antagonist, attenuated hUII-induced MAP and RVR elevations, RBF and CBF reductions, but not MBF increase. These findings indicate that intrarenal arterial administration of hUII elevates blood pressure and induces region-selective renal hemodynamic changes in newborn pigs. Our data also suggest that the PLC/IP₃ signaling pathway contributes to hUII-induced alterations in MAP, RBF, RVR, and CBF but not MBF in newborn pigs.

Maternal separation (MS) increases acute and chronic norepinephrine (NE) sensitivity revealing sympatho‐activation

We reported that MS, a model of early life stress (ELS), induces a greater drop in blood pressure in response to a ganglion blockade and a reduction in the renal filtration capacity that was normalized by renal denervation. We hypothesized that MS sensitizes the peripheral sympathetic system. The aims of this study were to evaluate 1) NE content in vasculature, kidney, spleen, and adrenal tissues, and 2) vascular tone in response to adrenergic agonists from 12 week old MS and control WKY rats. MS consisted of separating half of the male pups from the dam 3 hr a day from days 2–14 of life. NE was unchanged in plasma, thoracic and abdominal aorta while NE content was significantly increased in renal cortex (331±26 vs. 219±38 ng/g tissue), spleen (473±66 vs. 253±28 ng/g tissue) and adrenal gland (1152±189 vs. 303±99 vs. ng/g tissue) from MS vs. control rats (p&lt;0.05). Rats were injected with NE (2 μg/kg, i.p.) and blood pressure monitored by telemetry. Mean arterial pressure was exacerbated in MS vs. control rats (178±1 vs. 147±10 mmHg, p&lt;0.05) within 15 minutes. In a separate group of anesthetized rats, reduction in renal blood flow in response to phenylephrine was attenuated in MS rats compared to control rats (−1.8±0.2 vs. −2.8±0.2 Δml/min, p&lt;0.05, 100 ug/kg), suggesting an adrenergic desensitization. Thus, ELS sensitizes the sympathetic system impairing the normal acute and chronic vascular tone regulation.

Natriuresis induced by angiotensin II infusion is attenuated in knockout mice lacking tumor necrosis factor‐α receptors

Angiotensin II (AngII) induces the production of tumor necrosis factor‐α (TNF‐α) which causes reduction in renal blood flow (RBF) as well as natriuresis. To assess the contribution of TNF‐α in the renal actions of AngII, the responses to AngII infusion (1 ng/min/g for 30 min, iv) were evaluated in anesthetized knockout mice lacking TNF‐α receptor type 1 (R1KO, n=6) and type 2 (R2KO, n=6) and compared these responses with those in wild type (WT, n=6) mice. Arterial pressure (AP) was recorded from a cannula placed in the carotid artery. RBF and glomerular filtration rate (GFR) were measured by PAH and inulin clearances respectively. Urine was collected from a catheter placed in the bladder. Basal mean AP was lower in R1KO (81±3 mmHg) but not in R2KO (90±4 mmHg) compared to WT (92±4 mmHg). AngII caused similar increases in AP (WT, 37±5%; R1KO, 38±4%; R2KO, 30±4%) in these mice. The AngII induced reductions in RBF (−39±5%) and GFR (−17±7%) in WT were also not significantly different in R1KO (−28±7% and −17±7%) and R2KO (−31±4% and −12±7%). However, despite similar increases in AP, AngII induced natriuresis was significantly attenuated in RIKO (Δ, 2.5±0.9 μmol/min/g) compared to that in WT (Δ, 6.0±0.9 μmol/min/g) and in R2KO (Δ, 4.1±0.4 μmol/min/g). These data indicate that the natriuresis induced by AngII infusion is, at least partly, mediated by concomitant production of TNF‐α acting mainly via the receptor type 1.

Pressor and renal regional hemodynamic effects of urotensin II in neonatal pigs

Renal expression of urotensin II (UII) and its receptor (UTR) are dependent on kidney maturation and anatomical regions. However, renal regional hemodynamic effects of UII in neonates, in whom the kidneys are functionally immature, are unclear. Here, we investigated regional hemodynamic responses to acute intrarenal administration of UII in newborn pigs. Western immunoblotting and immunofluorescence indicated that UTR is expressed in newborn pig renal microvessels and microvascular smooth muscle cells. Intrarenal bolus injections of human UII (hUII; 1–100 ng·kg−1) resulted in a dose‐dependent decrease in total renal blood flow (RBF) and an increase in mean arterial pressure (MAP) and renal vascular resistance (RVR) in newborn pigs. Cortical blood flow (CBF) measured by laser Doppler flowmetry was ~2‐fold higher than medullary blood flow (MBF) in newborn pigs. hUII dose‐dependently reduced CBF, but increased MBF in the pigs. hUII‐induced MAP elevation and hemodynamic changes were inhibited by urantide, a UTR inhibitor, but not losartan, a type 1 angiotensin II receptor inhibitor. U73122, a phospholipase C (PLC) inhibitor and 2‐aminoethoxydiphenyl borate, an inositol 1,4,5 trisphosphate (IP3) receptor blocker attenuated hUII‐induced MAP and RVR elevations, RBF and CBF reductions, but not MBF increase. These findings indicate that intrarenal administration of hUII elevates blood pressure and induces regional‐selective renal hemodynamic changes in newborn pigs. Our data also suggest that PLC/IP3 signaling pathway contributes to hUII‐induced alterations in MAP, RBF, RVR, and CBF, but not MBF in newborn pigs.