Changes In Renal Vascular Resistance Research Articles

Relaxin mechanistic effects on renal hemodynamics and natriuresis: a mathematical modeling approach

Relaxin (RLX) is a hormone that stimulates renal vasodilation during early pregnancy. Recombinant RLX may have potential as a treatment for heart failure and chronic kidney disease, but its application has been limited in part due to uncertainties about its mechanism of action, and particularly its effect on glomerular capillary hydrostatic pressure (P gc ) and fluid status. The objective of this study was to couple mathematical modeling with experimental observations of the renal hemodynamic and natriuretic response to RLX, in order to quantitatively describe the mechanistic effects of relaxin on the kidney, and to predict its effect on clinically difficult-to-measure variables such as P gc . Utilizing a previously developed mathematical model of kidney function and hemodynamics, we began by hypothesizing a minimum set of RLX mechanisms (afferent/efferent vasodilation), fitting the available hemodynamic/natriuretic response in two previously published rat studies (GFR, renal plasma flow (RPF), mean arterial pressure (MAP), sodium and water excretion), and adding additional RLX mechanisms to the model only when the minimal set could not explain available data. We found that changes in renal vascular resistances alone were sufficient to reproduce observed changes in RPF, but insufficient to explain other data features. Experimental studies reported much larger increases in sodium excretion relative to water excretion with RLX, and this effect could only be reproduced if an effect of RLX on the osmotic setpoint for vasopressin release was included in the model – a mechanism that has previously been reported in ovariectomized rats treated with RLX. A small effect of RLX on heart rate was necessary to produce observed changes in MAP.In addition, the single experimental study in which P gc has been measured with RLX reported a rise in GFR but fall in P gc , and this difference could not be explained mathematically by relative afferent/efferent dilation or by downstream shifting of the filtration equilibrium with increased RPF; it could only be reproduced mathematically if RLX was assumed to large positive effect on glomerular membrane permeability. However, the magnitude of this effect is difficult to justify physiologically. Thus, while the model can be forced to fit this limited data, further study is needed to understand whether and how RLX might have such large permeability effects.The fitted model was then able to make predictions consistent with observed renal responses in human subjects, and these effects were better predicted when the RLX effect on permeability was excluded, further suggesting that this effect may not be real. In these simulations, RLX had no net effect on P gc . In conclusion, while some uncertainty remains, this analysis suggests that RLX acts primarily by dilating the afferent and efferent arterioles and shifting the osmotic setpoint for vasopressin release. AstraZeneca and Eli Lilly This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Elastin haploinsufficiency accelerates age-related structural and functional changes in the renal microvasculature and impairment of renal hemodynamics in female mice.

Age-related decline in functional elastin is associated with increased arterial stiffness, a known risk factor for developing cardiovascular disease. While the contribution of elastin insufficiency to the stiffening of conduit arteries is well described, little is known about the impact on the structure and function of the resistance vasculature, which contributes to total peripheral resistance and the regulation of organ perfusion. In this study, we determined how elastin insufficiency impinges on age-related changes in the structure and biomechanical properties of the renal microvasculature, altering renal hemodynamics and the response of the renal vascular bed to changes in renal perfusion pressure (RPP) in female mice. Using Doppler ultrasonography, we found that resistive index and pulsatility index were elevated in young Eln +/- and aged mice. Histological examination showed thinner internal and external elastic laminae, accompanied by increased elastin fragmentation in the medial layer without any calcium deposits in the small intrarenal arteries of kidneys from young Eln +/- and aged mice. Pressure myography of interlobar arteries showed that vessels from young Eln +/- and aged mice had a slight decrease in distensibility during pressure loading but a substantial decline in vascular recoil efficiency upon pressure unloading. To examine whether structural changes in the renal microvasculature influenced renal hemodynamics, we clamped neurohumoral input and increased renal perfusion pressure by simultaneously occluding the superior mesenteric and celiac arteries. Increased renal perfusion pressure caused robust changes in blood pressure in all groups; however, changes in renal vascular resistance and renal blood flow (RBF) were blunted in young Eln +/- and aged mice, accompanied by decreased autoregulatory index, indicating greater impairment of renal autoregulation. Finally, increased pulse pressure in aged Eln +/- mice positively correlated with high renal blood flow. Together, our data show that the loss of elastin negatively affects the structural and functional integrity of the renal microvasculature, ultimately worsening age-related decline in kidney function.

Favorable effect of renal denervation on elevated renal vascular resistance in patients with resistant hypertension and type 2 diabetes mellitus.

To assess the effect of renal denervation (RDN) on renal vascular resistance and renal function in patients with drug-resistant hypertension (HTN) and type 2 diabetes mellitus (T2DM). Fifty-nine patients (mean age 60.3 ± 7.9 years, 25 men) with resistant HTN [mean 24-h ambulatory blood pressure (BP) 158.0 ± 16.3/82.5 ± 12.7 mmHg, systolic/diastolic] and T2DM (mean HbA1c 7.5 ± 1.5%) were included in the single-arm prospective study and underwent RDN. Renal resistive index (RRI) derived from ultrasound Doppler; estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration formula), office and 24-h ambulatory BP were measured at baseline, 6, and 12 months after RDN to evaluate the respective changes in renal vascular resistance, renal function, and BP during treatment. Forty-three patients completed 12 months follow-up. The RRI changed depending on the baseline value. Specifically, the RRI decreased significantly in patients with elevated baseline RRI values ≥ 0.7 {n = 23; -0.024 [95% confidence interval (CI): -0.046, -0.002], p = 0.035} and did not change in those with baseline RRI < 0.7 [n = 36; 0.024 (95% CI: -0.002, 0.050), p = 0.069]. No significant change was observed in eGFR whereas BP was significantly reduced at 12 months after RDN by -10.9 (95% CI: -16.7, -5.0)/-5.5 (95% CI: -8.7, -2.4) mmHg, systolic/diastolic. No relationship was found between the changes in RRI and BP. Our study shows that RDN can decrease elevated renal vascular resistance (RRI > 0.7) and stabilize kidney function in patients with RHTN and T2DM independently of its BP-lowering effect.

Glucagon-like peptide-1 receptors in the kidney: impact on renal autoregulation.

Glucagon-like peptide-1 (GLP-1) and strategies based on this blood sugar-reducing and appetite-suppressing hormone are used to treat obesity and type 2 diabetes. However, the GLP-1 receptor (GLP-1R) is also present in the kidney, where it influences renal function. The effect of GLP-1 on the kidney varies between humans and rodents. The effect of GLP-1 on kidney function also seems to vary depending on its concentration and the physiological or pathological state of the kidney. In studies with rodents or humans, acute infusion of pharmacological doses of GLP-1 stimulates natriuresis and diuresis. However, the effect on the renal vasculature is less clear. In rodents, GLP-1 infusion increases renal plasma flow and glomerular filtration rate, suggesting renal vasodilation. In humans, only a subset of the study participants exhibits increased renal plasma flow and glomerular filtration rate. Differential status of kidney function and changes in renal vascular resistance of the preglomerular arterioles may account for the different responses of the human study participants. Because renal function in patients with type 2 diabetes is already at risk or compromised, understanding the effects of GLP-1R activation on kidney function in these patients is particularly important. This review examines the distribution of GLP-1R in the kidney and the effects elicited by GLP-1 or GLP-1R agonists. By integrating results from acute and chronic studies in healthy individuals and patients with type 2 diabetes along with those from rodent studies, we provide insight into how GLP-1R activation affects renal function and autoregulation.

Renal and segmental artery hemodynamics during whole body passive heating and cooling recovery.

High environmental temperatures are associated with increased risk of acute kidney injury, which may be related to reductions in renal blood flow. The susceptibility of the kidneys may be increased because of heat stress-induced changes in renal vascular resistance (RVR) to sympathetic activation. We tested the hypotheses that, compared with normothermia, increases in RVR during the cold pressor test (CPT, a sympathoexcitatory maneuver) are attenuated during passive heating and exacerbated after cooling recovery. Twenty-four healthy adults (22 ± 2 yr; 12 women, 12 men) completed CPTs at normothermic baseline, after passive heating to a rise in core temperature of ~1.2°C, and after cooling recovery when core temperature returned to ~0.2°C above normothermic baseline. Blood velocity was measured by Doppler ultrasound in the distal segment of the right renal artery (Renal, n = 24 during thermal stress, n = 12 during CPTs) or the middle portion of a segmental artery (Segmental, n = 12). RVR was calculated as mean arterial pressure divided by renal or segmental blood velocity. RVR increased at the end of CPT during normothermic baseline in both arteries (Renal: by 1.0 ± 1.0 mmHg·cm-1·s, Segmental: by 2.2 ± 1.2 mmHg·cm-1·s, P ≤ 0.03), and these increases were abolished with passive heating (P ≥ 0.76). At the end of cooling recovery, RVR in both arteries to the CPT was restored to that of normothermic baseline (P ≤ 0.17). These data show that increases in RVR to sympathetic activation during passive heating are attenuated and return to that of normothermic baseline after cooling recovery.NEW & NOTEWORTHY Our data indicate that increases in renal vascular resistance to the cold pressor test (i.e., sympathetic activation) are attenuated during passive heating, but at the end of cooling recovery this response returns to that of normothermic baseline. Importantly, hemodynamic responses were assessed in arteries going to (renal artery) and within (segmental artery) the kidney, which has not been previously examined in the same study during thermal and/or sympathetic stressors.

538-P: Copeptin and Renin Angiotensin Aldosterone System (RAAS) Activation in Long-Standing Type 1 Diabetes (T1D)

It remains unclear why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). Vasopressin and its surrogate copeptin have been implicated in the pathogenesis of DKD. We hypothesized that DKD resistors would be distinguished from those with DKD by copeptin concentrations. Renal hemodynamic function, including renal vascular resistance (RVR), was measured by inulin and para-aminohippurate clearance at baseline and after intravenous infusion of angiotensin II as a measure of RAAS activation in 75 participants (65±8 years, HbA1c 7.4±0.8%) with prolonged T1D durations (≥50 years) and in equal numbers of nondiabetic controls (66±8 years). Copeptin was measured by B·R·A·H·M·S proAVP copeptin KRYPTOR assay. Participants with T1D were categorized as DKD resistors (n=50) if they had eGFR ≥60 ml/min/1.73 m2 and 24-hour urine albumin excretion (UAE) &amp;lt;30 mg/d, and as DKD (n=25) if they had eGFR &amp;lt;60 ml/min/1.73 m2 or 24-hour UAE &amp;gt;30 mg/d at their screening visit. Multivariable linear regression (adjusted for age, sex and HbA1c) was used to evaluate the relationships with copeptin. DKD resistors had lower copeptin (least square geometric means, 95% CI: 4.0 [3.4-4.8] pmol/l) compared to those with DKD (5.8 [4.5-7.6] pmol/l, p=0.02) and the nondiabetic controls (4.8 [4.1-5.5] pmol/l, p=0.01) adjusting for age, sex and HbA1c. In T1D, copeptin inversely associated with GFR (adjusted β±SE: -8.0±3.2, p=0.02) and positively with renin concentration (50.3±24.9, p=0.049) after multivariable adjustments. These relationships were not evident in nondiabetic controls. Further, copeptin inversely associated with change in RVR following exogenous angiotensin II only in participants with T1D (adjusted β±SE: -6.9±3.4, p=0.04). In longstanding T1D, copeptin associated with intrarenal RAAS activation and renal hemodynamic function, suggesting a possible interplay between vasopressin and RAAS in the pathogenesis of DKD. Disclosure P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. J.A. Lovshin: Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics, Inc., Prometic Life Sciences Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Y. Lytvyn: None. P. Wiromrat: None. L.T. Chung: None. C.L. Vinovskis: None. L. Lovblom: None. G. Boulet: Other Relationship; Self; Medtronic. V.S. Lai: None. J.M. Tse: None. L. Cham: None. A. Orszag: None. A. Weisman: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. M.H. Brent: Advisory Panel; Self; AbbVie Inc., Bayer Canada, Novartis Canada. Research Support; Self; Bayer Canada, Novartis Canada, Roche Canada. N. Paul: Consultant; Self; Bayer AG. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. Funding JDRF (17-2013-312, 2-SRA-2018-627-M-B)

Measurement of Renal Hemodynamics by Doppler Ultrasound during Sympathetic Activation while Heat Stressed

P‐aminohippurate clearance demonstrates that passive heat stress increases renal vascular resistance (RVR) in proportion to increases in core temperature. These heat stress evoked elevations in RVR are exacerbated during exercise, a sympathetic stimulus. Passive heat stress attenuates the vascular response to the cold pressor test (CPT), a non‐exercise sympathoexcitatory maneuver. However, the effect of passive heating on renal vascular responsiveness to a non‐exercise sympathoexcitatory stimulus is unknown.PurposeTest the hypothesis that passive heat stress augments increases in RVR during the CPT compared to normothermia.MethodsEight healthy adults (aged 22 ± 1 y, 3 F) completed a CPT by immersing their right hand in an agitated ice slurry mixture for 2 min during normothermia (Normothermia), and after intestinal temperature increased by 1.3 ± 0.1°C following passive heating with a water perfused suit (Heated). Mean arterial pressure (MAP, finger photoplethysmography), heart rate (HR, 3 lead ECG) and renal blood velocity (RBV) were measured at 1 min pre‐CPT, and at 1 and 2 min into the CPT (T1 and T2). RBV was assessed in the distal segment of the right renal artery during the same phase of the respiratory cycle via Doppler ultrasound (GE Vivid 7 Dimension). The coronal approach was utilized using a linear‐array transducer with a 2.5–3.5 MHz pulsed frequency, and participants assumed the left lateral recumbent position. All measurements were obtained by the same sonographer with the focal zone set to the artery's depth, and the transducer held in the same location at an insonation angle &lt;60°. RVR was calculated as MAP/RBV. RBV and RVR were averaged across 2–4 beats. Data are presented as the absolute change from pre‐CPT (mean ± SD) unless otherwise stated.ResultsPre‐CPT, MAP was lower (76 ± 8 vs 84 ± 7 mmHg; P&lt;0.01) and HR was higher (101 ± 14 vs 60 ± 6 bpm; P&lt;0.01) in Heated. RBV was lower (Heated: 31.3 ± 5.0 Normothermia: 34.9 ± 2.4 cm · s−1; P=0.05), but RVR did not differ (Heated: 2.5 ± 0.7, Normothermia: 2.4 ± 0.2 mmHg · cm−1 · s‐1; P=0.67) between Normothermia and Heated pre‐CPT. Elevations in MAP (T1: 22 ± 12; T2: 26 ± 13 mmHg) and HR (T1: 16 ± 8; T2: 13 ± 6 bpm) during Normothermia differed from the MAP (T1: 5 ± 3; T2: 2 ± 2 mmHg) and HR (T1: 3 ± 11; T2: 1 ± 10 bpm) response evoked by the CPT during Heated (P&lt;0.01). Changes in RBV during the CPT did not differ between Heated and Normothermia at T1 (Heated: −2.5 ± 6.2; Normothermia: −4.0 ± 4.9 cm · s−1, P=0.94) or T2 (Heated: 0.9 ± 5.8; Normothermia: −4.0 ± 4.9 cm · s−1, P=0.97). Changes in RVR did not differ between Heated and Normothermia at T1 (Heated: 0.4 ± 0.6, Normothermia: 1.1 ± 1.0 mmHg · cm−1 · s‐1; P=0.10), but were lower in Heated at T2 (0.0 ± 0.4, vs 1.1 ± 1.0 mmHg · cm−1 · s‐1; P&lt;0.02).ConclusionThese data indicate that passive heat stress attenuates Doppler ultrasound derived measures of renal vascular responsiveness to the CPT, a non‐exercising sympathoexcitatory stimulus.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Renin-angiotensin-aldosterone system activation in long-standing type 1 diabetes

In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation. Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation. Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity. In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction. JDRF operating grant 17-2013-312.

Functional vascular changes of the kidney during pregnancy in animals: a systematic review and meta-analysis.

Renal vascular responses to pregnancy have frequently been studied, by investigating renal vascular resistance (RVR), renal flow, glomerular filtration rate (GFR), and renal artery responses to stimuli. Nonetheless, several questions remain: 1. Which vasodilator pathways are activated and to what extent do they affect RVR, renal flow and GFR across species, strains and gestational ages, 2. Are these changes dependent on renal artery adaptation, 3. At which cellular level does pregnancy affect the involved pathways? In an attempt to answer the questions raised, we performed a systematic review and meta-analysis on animal data. We included 37 studies (116 responses). At mid-gestation, RVR and GFR change to a similar degree across species and strains, accompanied by variable change in renal flow. At least in rats, changes depend on NO activation. At late gestation, changes in RVR, renal flow and GFR vary between species and strains. In rats, these changes are effectuated by sympathetic stimulation. Overall, renal artery responsiveness to stimuli is unaffected by pregnancy, except for Sprague Dawley rats in which pregnancy enhances renal artery vascular compliance and reduces renal artery myogenic reactivity. Our meta-analysis shows that: 1. Pregnancy changes RVR, renal flow and GFR dependent on NO-activation and sympathetic de-activation, but adjustments are different among species, strains and gestational ages; 2. These changes do not depend on adaptation of renal artery responsiveness; 3. It remains unknown at which cellular level pregnancy affects the pathways. Our meta-analysis suggests that renal changes during pregnancy in animals are qualitatively similar, even in comparison to humans, but quantitatively different.

Renal nerves: time for reassessment of their role in hypertension?

Renal nerves: time for reassessment of their role in hypertension?

Renal responses to intra‐arterial infusion of a peroxynitrite scavenging agent with or without angiotensin II in anesthetized rats (1134.4)

Peroxynitrite (OONO‐) is continually formed in the biological tissue by the spontaneous reaction between nitric oxide and superoxide. However, its potential role in the regulation of renal hemodynamics and excretory function in control condition as well as in the condition of elevated angiotensin II (AngII) level is not yet clearly defined. In the present study, we examined the responses to a OONO‐ scavenging agent, mercaptoethyl guanidine (MEG; 5 µg/kg/min for 75 min) infused directly into the left renal artery in anesthetized (Inactin; 100 mg/kg; i.p.) rats pretreated with (n=5) or without (n=5) AngII (1 ng/kg/min). The MEG dose was effective in blocking the increased renal blood flow (RBF) response to a bolus dose infusion of OONO‐ (40 µg/kg). RBF was recorded by the Transonic flow probe placed on the left renal artery and glomerular filtration rate (GFR) was determined by inulin clearance. In control rats (n=5), MEG infusion did not alter renal vascular resistance (RVR), RBF or GFR but caused significant decreases in urine flow (V, 9.5±1.4 to 7.8±1.5 μL/min/g; ‐20.2±6.7%), sodium excretion (UNaV, 1.69±0.38 to 1.34±0.43 μmol/min/g; ‐29.3±14.2%) and in fractional excretion of sodium (FENa, 1.04±0.33 to 0.87±0.36%; ‐29.3±15%). In a separate group (n=5), AngII treatment caused an increase of 18.0±4.1% in RVR (baseline value, b; 14.8±1.9 mmHg/mL/min/g) and the decreases of 14.4±3.6% in RBF (b, 7.2 mL/min/g), 17.1±6.2% in V (b, 6.7±2.3 μL/min/g), 35.6±14.4% in UNaV (b, 1.17±0.61 μmol/min/g) and 37.4±12.5% in FENa (b, 0.9±0.6%) without appreciable change in GFR. However, MEG infusion in these AngII treated rats caused similar decreases in renal excretory parameters (‐19.7±10.9% in V, ‐31.8±13.4% in UNaV and ‐33.3±8.4% in FENa) without significant changes in RVR, RBF or GFR. These data indicate that the endogenous OONO‐ exerts minimal hemodynamic effect but contributes to the maintenance of renal excretory function both in control condition as well as in the condition of elevated AngII level.

Changes in Renal Doppler Ultrasonographic Parameters in Patients Managed with Rigid Ureteroscopy

There has been no study evaluating the intrarenal hemodynamic changes after ureteroscopy in the published literature. To determine preoperative and postoperative intrarenal vascular parameters such as resistive index (RI), pulsatility index (PI), peak systolic velocity (PSV), end-diastolic velocity (EDV), measure changes on these values (ΔRI, ΔPI, ΔPSV, ΔEDV) after ureteroscopy (URS) and compare the outcomes with the results of normal contralateral kidneys, and finally investigate possible parameters that would affect renal vascular resistance changes. We prospectively studied 47 patients who underwent rigid URS. Preoperative gray-scale and Doppler ultrasonography (CDUS) measurements were obtained 24 h before URS. Similarly, postoperative CDUS measurements were done 24 h after the operation. The degree of hydronephrosis and location of stones in the obstructed kidneys, diameters of both kidneys, and thickness of renal parenchyma were evaluated with gray-scale US followed by CDUS with calculation of the intrarenal RI, PI, PSV, and EDV values for each kidney. For the operated kidneys, statistically significant P values were noticed when RI and PI values were considered (P < 0.001). ΔRI and ΔPI of the operated kidneys were also significantly greater than the values for non-operated kidneys (P < 0.001). However, it was not the case for ΔPSV and ΔEDV values. In Spearman correlation coefficient analysis, ΔRI was found to be correlated with the parameters: "operative time" and "irrigation fluid volume". No significant relation was documented between ΔRI and the other parameters: age, gender, side of ureteroscopy, stone location, and degree of hydronephrosis. Significant changes in RI and PI values in patients treated with URS reveal that URS can cause a significant increase in renal vascular resistance. With the increase in operative time and irrigation fluid volume used during the operation, RI seems to be significantly increased.

Dueling nucleosides: cross-regulation of extracellular adenosine by guanosine. Focus on “Extracellular guanosine regulates extracellular adenosine levels”

<i>Dueling nucleosides: cross-regulation of extracellular adenosine by guanosine</i>. Focus on “Extracellular guanosine regulates extracellular adenosine levels”

Impaired myogenic constriction of the renal afferent arteriole in a mouse model of reduced βENaC expression

Previous studies demonstrate a role for β epithelial Na(+) channel (βENaC) protein as a mediator of myogenic constriction in renal interlobar arteries. However, the importance of βENaC as a mediator of myogenic constriction in renal afferent arterioles, the primary site of development of renal vascular resistance, has not been determined. We colocalized βENaC with smooth muscle α-actin in vascular smooth muscle cells in renal arterioles using immunofluorescence. To determine the importance of βENaC in myogenic constriction in renal afferent arterioles, we used a mouse model of reduced βENaC (βENaC m/m) and examined pressure-induced constrictor responses in the isolated afferent arteriole-attached glomerulus preparation. We found that, in response to a step increase in perfusion pressure from 60 to 120 mmHg, the myogenic tone increased from 4.5 ± 3.7 to 27.3 ± 5.2% in +/+ mice. In contrast, myogenic tone failed to increase with the pressure step in m/m mice (3.9 ± 0.8 to 6.9 ± 1.4%). To determine the importance of βENaC in myogenic renal blood flow (RBF) regulation, we examined the rate of change in renal vascular resistance following a step increase in perfusion pressure in volume-expanded animals. We found that, following a step increase in pressure, the rate of myogenic correction of RBF is inhibited by 75% in βENaC m/m mice. These findings demonstrate that myogenic constriction in afferent arterioles is dependent on normal expression of βENaC.

Closure of multiple types of K+ channels is necessary to induce changes in renal vascular resistance in vivo in rats

Inhibition of K(+) channels might mediate renal vasoconstriction. As inhibition of a single type of K(+) channel caused minor or no renal vasoconstriction in vivo in rats, we hypothesized that several classes of K(+) channels must be blocked to elicit renal vasoconstriction. We measured renal blood flow (RBF) in vivo in anesthetized Sprague-Dawley rats. Test agents were infused directly into the renal artery to avoid systemic effects. Inhibition of BK(Ca) and K(ir) channels (with TEA and Ba(2+), respectively) caused small and transient reductions in RBF (to 93 ± 2% and 95 ± 1% of baseline, respectively). K(ATP), SK(Ca) or K(v) channel blockade (with glibenclamide, apamin and 4-aminopyridine, respectively) was without effect. However, a cocktail of all blockers caused a massive reduction of RBF (to 15 ± 10% of baseline). Nifedipine and mibefradil abolished and reduced, respectively, this RBF reduction. The effect of the cocktail of K(+) channel blockers was confirmed in mice using the isolated blood-perfused juxtamedullary nephron preparation. A cocktail of K(+) channel openers (K(+), NS309, NS1619 and pinacidil) had only a minor effect on baseline RBF in vivo in rats, but reduced the vasoconstriction induced by bolus injections of norepinephrine or angiotensin II (by 33 ± 5% and 60 ± 5%, respectively). Our results indicate that closure of numerous types of K(+) channels could participate in the mediation of agonist-induced renal vasoconstriction. Our results also suggest that renal vasoconstriction elicited by K(+) channel blockade is mediated by nifedipine-sensitive Ca(2+) channels and partly by mibefradil-sensitive Ca(2+) channels.

RENAL FUNCTION EVALUATION INDUCED BY HIGH SALT INTAKE IN PERFUSED KIDNEYS.

There is a significant association between salt intake and high blood pressure that could be related to alterations in the ability of the kidneys to excrete sodium chloride. Preliminary data from our group showed an increase in blood pressure of 11% in rats with salt added to the drinking water (1%) during 10 days; therefore the aim of this study was to evaluate renal function changes induced in rats by high salt intake. Male Wistar rats (n=5/group) were divided in Control group (CG) and Salt group (SG), (1%, drinking water, 10 days). Isolated kidneys were perfused with Krebs‐Henseleit solution containing 6% (g weight) of previously dialyzed bovine serum albumin. Glomerular filtration rate (GFR), renal vascular resistance (RVR), urinary flow (UF), fractional sodium and potassium tubular absortion (%TNa+ and %TK+) and Clearance osmolar (Cosm) were determined during 120 min. In SG group we observed an increased in GFR, (SG: 1.1 ± 0.04 vs CG: 0.4±0.01 mL/g/min), associated with markedly augments in UF (SG: 0.2±0.05 vs CG: 0.1±0.01 mL/g/min). There were no changes in RVR (SG: 6±1 vs CG: 4±0.4 mmHg/mL/g/min). The %TNa+ (SG: 73±3 vs CG: 74±6, %) was similar between the groups. However, salt intake increased the %TK+ (SG: 75±5 vs CG: 58±4 %) and Cosm (SG: 0.2±0.06 vs CG: 0.1±0.01, mL/g/min). These findings demonstrate that renal alterations observed herein are not related to blood pressure increased.

Water extracts of cigarette smoke elicit smooth muscle dependent relaxation of rat renal arteries

The mechanisms responsible for cigarette smoking‐induced increases in glomerular filtration rate and microalbuminuria in healthy persons are not known. We hypothesized that they may be related to changes in renal vascular resistance elicited by the water‐soluble components of cigarette smoke (wCS). The acute effects of wCS on isometric tension of preconstricted isolated rat renal arteries were examined. Increasing doses of wCS (1‐5‐10% of saturated solution) elicited dose dependent relaxations of renal arteries (wCS‐1%: 41±15%, wCS‐5%: 79±9%, wCS‐10% 90±6%). Endothelium removal did not affect relaxations to wCS (wCS‐1%: 15 ± 9%, wCS‐5%: 62±15%, wCS‐10% 90±7%). Similar results were obtained with nicotine free cigarettes (wCS‐1%: 38 ± 3%, wCS‐5%: 77±15%, wCS‐10% 97±0,2%). Relaxation induced by wCS were not affected by inhibition of soluble guanylate cyclase by ODQ (wCS‐1%: 13 ± 4%, wCS‐5%: 58±15%, CS‐10% 94±4%). Thus water soluble components of cigarette smoke elicit relaxations of isolated renal arteries that are independent of endothelium‐, nicotine‐ and cGMP‐related vasomotor mechanisms (such as NO or CO). Although further studies are necessary to elucidate the mechanisms responsible for renal artery relaxation, we propose that cigarette smoking, by modulating directly the smooth muscle tone of renal microvessels, could increases glomerular filtration rate and microalbuminuria observed in healthy smoking men.(Grants: Hungarian SRF/OTKA T48376, K71591, F68638; HSC/ETT 364/2006, AHA F. Aff. 0855910D, USA)

Hemodynamic effect produced by microinjection of angiotensins at the caudal ventrolateral medulla of spontaneously hypertensive rats

In the present study, the effect of caudal ventrolateral medulla (CVLM) microinjection of angiotensin-(1-7) (Ang-(1-7)) and angiotensin II (Ang II) on mean arterial pressure (MAP), heart rate (HR) and pulsatile vascular blood flow (VBF; Transonic System) of the femoral, renal or mesenteric arteries was evaluated in male Wistar and spontaneously hypertensive rats (SHR) anesthetized with urethane. The vascular resistance (VR) was calculated by the ratio between the changes in MAP and VBF. Ang-(1-7) (40 ng) and Ang II (40 ng) microinjection into the CVLM caused similar depressor effects in Wistar rats and SHR. The hypotensive effect produced by Ang-(1-7) into the CVLM of Wistar rats was accompanied by a decrease in femoral (ΔVR/VRbaseline=−0.12±0.04 vs. 0.001±0.03; after saline) and renal (ΔVR/VRbaseline=−0.10±0.02 vs. −0.003±0.02; after saline) vascular resistance. On the other hand, the Ang II hypotensive effect in Wistar rats produced only changes in renal vascular resistance (ΔVR/VRbaseline=−0.16±0.02 vs. −0.003±0.02; after saline). In SHR, the hypotensive effect produced by Ang-(1-7) and Ang II caused decrease in renal vascular resistance (ΔVR/VRbaseline=−0.18±0.03 and −0.13±0.01, respectively, as compared with saline, ΔVR/VRbaseline=−0.06±0.02), but did not alter the femoral or mesenteric vascular resistance. These data show that Ang II and Ang-(1-7) hypotensive effect at the CVLM involves the participation of different vascular beds. Further, the lack of involvement of the femoral vascular bed in SHR suggests that hypertension may induce alteration in the neural control of the different vascular beds, at least at the CVLM.

Short-term ANG II produces renal vasoconstriction independent of TP receptor activation and TxA2/isoprostane production

The relative contributions of vasoconstrictor and of dilator systems are balanced in health. The balance is reset in disease, often favoring a predominant role of vasoconstrictors, perhaps due to positive interactions between constrictor systems. For example, in hypertension, chronic high levels of angiotensin II (ANG II) stimulate the production of thromboxane (TxA2/PGH2) and/or isoprostane that activate constrictor thromboxane prostanoid (TP) receptors in the vasculature. The present study evaluated a modest concentration of ANG II administered acutely into the renal artery on urinary excretion of TxB2 and isoprostane and possible renal TP receptor activation that might amplify ANG II-induced renal vasoconstriction. TP receptors were blocked with SQ29548 coinfused with ANG II. Results were compared with a time control group of continuous ANG II infusion (40 ng.min(-1).kg body wt(-1)) over 90 min. TP receptor antagonism during 30-60 min had no effect on the reduction in renal blood flow (RBF) produced by ANG II (15.8 +/- 2.8 vs. 13.2 +/- 4.9%) (P > 0.6). Likewise, there was no difference between groups during ANG II-induced renal vasoconstriction between 60-90 min in presence or absence of TP receptor antagonist (RBF -8.6 +/- 4.0 vs. -9.6 +/- 4.5%) (P > 0.8). Systemic arterial pressure was stable throughout, so RBF changes reflected localized changes in renal vascular resistance. Urinary excretion of TxB2 and isoprostane were nearly doubled by ANG II. The present data indicate that short-term intrarenal infusion of ANG II rapidly increases renal production of TxA2 but that the ANG II-induced renal vasoconstriction is independent of TP receptor activation during the initial 90 min of local challenge with ANG II.

Acute changes in renal resistance and arterial stiffness during static exercise

Augmentation index (AI) is used as a measure of arterial stiffness. It represents the augmentation in central aortic pressure due to the effect of returning reflected pulse wave. The aim of the study was to assess the relationship between acute changes in renal vascular resistance (RVR) and arterial stiffness (assessed by AI) during static exercise. Nine subjects (mean age 31.7±9.1 years, 5 males) performed two protocols: First, handgrip (HG) for 15 sec at 30% and 70% of maximum voluntary contraction (MVC). Second, HG to fatigue (HGF) at 40% of MVC followed by post handgrip circulatory arrest (CA) for 2 min. RVR was calculated as the quotient of blood pressure (beat-by-beat) to renal artery velocity (Duplex). AI% was computed by the SphygmoCor software from the aortic pressure waveform, derived from the radial artery waveform recorded by a micromanometer. The AI% was logarithmically transformed and corrected for heart rate. Results: Table 1. The increase in Log AI% accompanied by increase in RVR index was more pronounced in the HGF and CA protocol. Conclusion: During static exercise, renal vascular resistance and arterial stiffness (measured by augmentation index) increase in a parallel way reflecting sympathetic activation. Supported by P01 HL077670.