Effects of chronic dietary salt loading on the renin angiotensin and adrenergic systems of rainbow trout (Oncorhynchus mykiss)

2011 ◽  
Vol 301 (3) ◽  
pp. R811-R821 ◽  
Author(s):  
Steve F. Perry ◽  
Kate Ellis ◽  
Jordan Russell ◽  
Nicholas J. Bernier ◽  
Colin Montpetit
Keyword(s):  
Blood Pressure ◽  
Chromaffin Cells ◽  
Acute Hypoxia ◽  
Ang Ii ◽  
Dietary Salt ◽  
Salt Loading ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Adrenergic Systems

Previous studies have demonstrated that chronic dietary salt loading causes hypertension and a decreased sensitivity of the systemic vasculature to α-adrenergic stimulation and other hypertensive stimuli (e.g. hypercapnia) in rainbow trout ( Oncorhynchus mykiss). This reduced sensitivity to hypertensive stimuli is consistent with a possible blunting of homeostatic responses normally aimed at raising blood pressure. To test this idea, we examined the consequences of long-term salt feeding and the associated hypertension on the interactive capacities of the renin angiotensin system (RAS) and adrenergic systems to elevate blood pressure in trout. Secretion of catecholamines in response to a range of doses of homologous ANG II in vivo and in situ (using a perfused posterior cardinal vein preparation) was reduced in the salt-fed fish. The reduced sensitivity to ANG II could not be explained by alterations in stored catecholamine (adrenaline or noradrenaline) levels or the general responsiveness of the chromaffin cells to depolarizing stimuli (60 mmol/l KCl). Despite the decreased responsiveness of the chromaffin cells to ANG II, plasma catecholamines were increased to a greater extent in the salt-fed fish during acute hypoxia (a condition that activates the RAS). Interestingly, the pressor effects of ANG II in vivo were actually heightened in the salt-fed fish. The increased pressor response to exogenous ANG II was likely attributable to its direct interaction with vascular ANG II receptors because the effect persisted even after blockade of α-adrenergic receptors. Treating fish with the vascular smooth muscle relaxant papaverine caused similar reductions in blood pressure and increases in plasma ANG II levels regardless of diet. Similarly, inhibition of angiotensin converting enzyme with lisinopril reduced blood pressure equally in control and salt-fed fish. These results indicate that, while long-term dietary salt loading blunts the response of trout chromaffin cells to ANG II, the RAS itself appears to be unaffected. Indeed, the capacity of ANG II to elevate blood pressure is not compromised nor do fish exhibit a reduced capacity to mount an acute humoral adrenergic stress response during acute hypoxia.

Salt sensitivity in hypertensive rats with angiotensin II administration

1990 ◽  
Vol 259 (5) ◽  
pp. R1012-R1016 ◽  
Author(s):  
K. Ando ◽  
Y. Sato ◽  
T. Fujita
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Salt Sensitivity ◽  
Ang Ii ◽  
Short Term ◽  
Salt Loading ◽  
Salt Diet ◽  
Dose Dependent Fashion ◽  
Dose Dependent

We examined the salt sensitivity of blood pressure in angiotensin II (ANG II)-induced hypertension. Wistar rats, salt loaded (0.66, 2, or 8% salt-containing diet) for 4 or 12 days, were infused intravenously with 15 or 60 ng/min of ANG II. Systolic blood pressure (SBP) was not increased by long-term (12 days) salt loading, and SBP was unchanged with ANG II and normal-salt (0.66%) diet. However, when combined with salt loading, ANG II produced hypertension in a dose-dependent fashion; compared with control (120 +/- 2 mmHg), SBP was increased with 15 ng/min of ANG II and 8% salt diet (145 +/- 5 mmHg, P less than 0.05) and with 60 ng/min of ANG II and either 2 or 8% salt diet (149 +/- 8 and 174 +/- 8 mmHg, P less than 0.05, respectively). Na space (exchangeable Na) was increased in a roughly similar pattern and correlated significantly (r = 0.531, P less than 0.05) with SBP. However, with 15 ng/min of ANG II, Na space was not different among rats on either level of salt loading, although the 8% salt diet elevated SBP. Data obtained with short-term (4 days) treatment indicate that an elevated Na space preceded development of hypertension. With 15 ng/min of ANG II and 8% salt diet for 4 days, Na space was markedly (P less than 0.05) increased, but SBP was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and long-term TNF-alpha administration increases pulmonary vascular reactivity in isolated rat lungs

1992 ◽  
Vol 73 (2) ◽  
pp. 708-712 ◽  
Author(s):  
T. Stevens ◽  
P. L. Janssen ◽  
A. Tucker
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Reactivity ◽  
Acute Hypoxia ◽  
Tnf Alpha ◽  
Ang Ii ◽  
Necrosis Factor Alpha ◽  
Arterial Hypoxemia ◽  
Pressor Responses

Tumor necrosis factor-alpha (TNF-alpha) causes pulmonary hypertension and arterial hypoxemia, but the mechanisms are unknown. We conducted two experiments to test the hypothesis that TNF-alpha alters pulmonary vascular reactivity, which in turn could cause either pulmonary hypertension or arterial hypoxemia. In experiment 1, rats were given acute or long-term injections of TNF-alpha (recombinant human) in vivo. Rats treated acutely received either saline or TNF-alpha (40 micrograms/kg iv in saline) 3 min (TNF-3 min; n = 8), 20 min (TNF-20 min; n = 8), or 24 h (TNF-24 h; n = 5) before the lungs were isolated. Rats treated chronically received injections of either saline or TNF-alpha (250 micrograms/kg ip in saline) two times per day for 7 days (TNF-7 days; n = 9). Lungs were isolated and perfused with Earle's salt solution (+2 g/l NaHCO3 + 4 g/100 ml Ficoll), and vascular reactivity was tested with acute hypoxia (3 min; 3% O2) and angiotensin II (ANG II; 0.025–0.40 micrograms). Pulmonary pressor responses to hypoxia were greater (P less than 0.05) in TNF-20 min and TNF-7 day groups. ANG II responses were increased (P less than 0.05) in TNF-7 day rats. In experiment 2, lungs were isolated and perfused and received direct pulmonary arterial injections of TNF-alpha (0.2, 2.0, and 20 micrograms) or saline, after stable responses to hypoxia and ANG II (0.10 microgram) were attained. Reactivity was not different between control and TNF-alpha rats before the injections, but TNF-alpha increased (P less than 0.05) responses to hypoxia and ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daniel J Fehrenbach ◽  
Meena S Madhur
Keyword(s):  
Blood Pressure ◽  
T Cell ◽  
Angiotensin Ii ◽  
Repeated Measures ◽  
Flow Cytometric Analysis ◽  
Coiled Coil ◽  
Ang Ii ◽  
Induced Hypertension

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

Abstract 603: Effective And Sustained ACE2 Delivery Using Minicircles Technology

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Jan Wysocki ◽  
Philipp K Haber ◽  
Minghao Ye ◽  
Christoph Maier ◽  
Mark J Osborn ◽  
...  
Keyword(s):  
Viral Vectors ◽  
Gene Replacement ◽  
Ang Ii ◽  
Hydrodynamic Approach ◽  
New Gene ◽  
Cloned Cdna ◽  
Dose Dependent ◽  
Delivery Technology

Chronic and sustained amplification of ACE2 activity in vivo has required the development of transgenic mice or the use of viral vectors. Minicircle is a new gene delivery technology which is resistant to gene silencing, and therefore represents an attractive platform for gene replacement strategies in vivo . Here we cloned cDNA of soluble mouse ACE2 into a circular expression cassette and the resulting ACE2 minicircle (MC) was injected to female FVB mice using iv. hydrodynamic approach (10ug or 30ug/mouse). At 3-7d after MC administration, serum ACE2 activity in mice that received 10ug ACE2MC (n=9) was over 100-fold higher than in controls (n=9) (138±48 vs 0.7±0.2 RFU/uL/hr) and in ACE2MC mice (30ug) (n=8) was almost 1000-fold higher than in controls (n=14) (480 ±153 vs 0.5±0.1 RFU/uL/hr, respectively). Mice that received 10 ug ACE2MC were followed for consecutive serum ACE2 activity monitoring, BP measurements and plasma Ang levels. The increase in serum ACE2 activity was sustained until the end of the study (up to 82 days) (Figure). Despite such a marked increase in serum ACE2 activity in ACE2MC mice, conscious SBP was not different from controls (137±8 vs 138±7 mmHg, respectively). At the end of the study, when Ang II was infused acutely (0.2 ug/kg BW i.p.), the increase in plasma Ang II in ACE2MC mice was significantly reduced compared to control mice (915±154 vs 1420±131 fmoL/mL, p<0.05). Mini-circle delivery of ACE2 results in a dose-dependent and sustained long-term increase in serum ACE2 that efficiently degrades plasma Ang II. Extremely high increases in serum ACE2 activity do not reduce BP probably due to activation of non-ACE2 dependent compensatory Ang-hydrolyzing pathways.

Abstract P301: Renal Expression of Collectrin (TMEM27) is Downregulated During Angiotensin II-induced Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sylvia Cechova ◽  
Pei-Lun Chu ◽  
Joseph Gigliotti ◽  
Thu H Le
Keyword(s):  
Angiotensin Ii ◽  
Catalytic Domain ◽  
Collecting Duct ◽  
Amino Acid Transporters ◽  
Ang Ii ◽  
Salt Loading ◽  
Transmembrane Glycoprotein ◽  
First Time ◽  
Renal Expression

Collectrin ( Tmem27 ) is transmembrane glycoprotein with homology to ACE-2, but lacks any catalytic domain. It plays a key role as a chaperone of amino acid transporters, and is abundantly expressed in the kidney in the proximal tubules and collecting duct. Deletion of collectrin in the mouse results in hypertension (HTN) at baseline and augmented salt-sensitivity that are associated with decreased renal nitric oxide and increased superoxide levels. During high salt diet, renal expression of collectrin is upregulated, suggesting an adaptive homeostatic response to salt loading. Here, we queried whether the expression of collectrin is regulated by angiotensin II (Ang II). Wild-type 129S6 mice were made hypertensive with Ang II osmotic minipump @ 600 ng/kg/min x 2 weeks, and were compared to age-matched untreated WT 129 mice. Shown in Fig. 1 , renal mRNA expression of collectrin is significantly reduced after 2 weeks of Ang II (Panel A). Immunostaining shows collectrin protein level is also significantly diminished to near undetectable level (Panel B). We show for the first time that Ang II regulates the expression of collectrin, suggesting that the action of Ang II on blood pressure may be mediated, in part, through the downregulation of collectrin. Further studies are needed to determine the effect of AT 1 and AT 2 receptor signaling on renal expression of collectrin during Ang II-HTN in vivo.

scholarly journals Impact of angiotensin II-mediated stimulation of sodium transporters in the nephron assessed by computational modeling

2019 ◽  
Vol 317 (6) ◽  
pp. F1656-F1668 ◽  
Author(s):  
Aurélie Edwards ◽  
Alicia A. McDonough
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Ang Ii ◽  
Sodium Transporters ◽  
Short And Long Term ◽  
Physiological Impact ◽  
Pressure Natriuresis ◽  
Excretion Rates ◽  
Volume Output

Angiotensin II (ANG II) raises blood pressure partly by stimulating tubular Na+ reabsorption. The effects of ANG II on tubular Na+ transporters (i.e., channels, pumps, cotransporters, and exchangers) vary between short-term and long-term exposure. To better understand the physiological impact, we used a computational model of transport along the rat nephron to predict the effects of short- and long-term ANG II-induced transporter activation on Na+ and K+ reabsorption/secretion, and to compare measured and calculated excretion rates. Three days of ANG II infusion at 200 ng·kg−1·min−1 is nonpressor, yet stimulates transporter accumulation. The increase in abundance of Na+/H+ exchanger 3 (NHE3) or activated Na+-K+-2Cl− cotransporter-2 (NKCC2-P) predicted significant reductions in urinary Na+ excretion, yet there was no observed change in urine Na+. The lack of antinatriuresis, despite Na+ transporter accumulation, was supported by Li+ and creatinine clearance measurements, leading to the conclusion that 3-day nonpressor ANG II increases transporter abundance without proportional activation. Fourteen days of ANG II infusion at 400 ng·kg−1·min−1 raises blood pressure and increases Na+ transporter abundance along the distal nephron; proximal tubule and medullary loop transporters are decreased and urine Na+ and volume output are increased, evidence for pressure natriuresis. Simulations indicate that decreases in NHE3 and NKCC2-P contribute significantly to reducing Na+ reabsorption along the nephron and to pressure natriuresis. Our results also suggest that differential regulation of medullary (decrease) and cortical (increase) NKCC2-P is important to preserve K+ while minimizing Na+ retention during ANG II infusion. Lastly, our model indicates that accumulation of active Na+-Cl− cotransporter counteracts epithelial Na+ channel-induced urinary K+ loss.

Abolition of long-term vascular influence of renin-angiotensin system

1990 ◽  
Vol 259 (2) ◽  
pp. H543-H553
Author(s):  
R. D. Randall ◽  
B. G. Zimmerman
Keyword(s):  
Blood Pressure ◽  
Vascular Tissue ◽  
Renin Angiotensin System ◽  
Ace Inhibition ◽  
Ang Ii ◽  
Flow Measurements ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Normal Controls

Rabbits were bilaterally nephrectomized for 24 h or received an angiotensin-converting enzyme (ACE) inhibitor chronically (5 days) before an acute experiment. Conductance responses to sympathetic nerve stimulation (SNS) (0.25, 0.75, and 2.25 Hz) and norepinephrine (NE) administration (0.2, 0.6, and 1.8 micrograms ia) were determined from simultaneous blood pressure and iliac blood flow measurements. Conductance responses to SNS were significantly reduced in nephrectomized (44, 26, and 20%) and chronic ACE inhibition (39, 31, and 24%) groups compared with normal controls, whereas conductance responses to NE were unchanged. Continuous infusion of angiotensin II (ANG II) for 24 h restored the depressed responses to SNS in nephrectomized and chronic ACE inhibition groups compared with normal controls but did not change conductance responses to NE. Acute ACE inhibition did not affect the conductance responses to SNS or NE compared with controls. Vascular tissue ACE activity was inhibited to a similar degree (50%) in both acute and chronic ACE inhibition groups compared with normal rabbits. Sodium depletion increased the conductance responses to SNS (30 and 24% at 0.25 and 0.75 Hz, respectively), but responses to NE were not affected. Chronic ACE inhibition significantly attenuated the conductance responses to SNS and slightly decreased responses to NE in sodium-depleted rabbits. Thus, in the anesthetized rabbit, the renin-angiotensin system potentiates the effect of SNS, presumably by ANG II acting at a prejunctional site, and this effect of ANG II appears to be long term in nature. Therefore, the renin-angiotensin system exerts a physiological role in the control of blood pressure in addition to the ability of this system to support arterial pressure in pathophysiological states.

Vascular smooth muscle function of renal glomerular and interlobar arteries predicts renal damage in rats

2012 ◽  
Vol 303 (8) ◽  
pp. F1187-F1195 ◽  
Author(s):  
Peter Vavrinec ◽  
Robert H. Henning ◽  
Maaike Goris ◽  
Diana Vavrincova-Yaghi ◽  
Hendrik Buikema ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Intravital Microscopy ◽  
Renal Damage ◽  
Renal Arteries ◽  
Ang Ii ◽  
Vascular Integrity ◽  
Relative Expression ◽  
Glomerular Arterioles

Previously, it was shown that individuals with good baseline (a priori) endothelial function in isolated (in vitro) renal arteries developed less renal damage after ⅚ nephrectomy (5/6Nx; Gschwend S, Buikema H, Navis G, Henning RH, de Zeeuw D, van Dokkum RP. J Am Soc Nephrol 13: 2909–2915, 2002). In this study, we investigated whether preexisting glomerular vascular integrity predicts subsequent renal damage after 5/6Nx, using in vivo intravital microscopy and in vitro myogenic constriction of small renal arteries. Moreover, we aimed to elucidate the role of renal ANG II type 1 receptor (AT1R) expression in this model. Anesthetized rats underwent intravital microscopy to visualize constriction to ANG II of glomerular afferent and efferent arterioles, with continuous measurement of blood pressure, heart rate, and renal blood flow. Thereafter, 5/6Nx was performed, interlobar arteries were isolated from the extirpated kidney, and myogenic constriction was assessed in a perfused vessel setup. Blood pressure and proteinuria were assessed weekly for 12 wk, and focal glomerulosclerosis (FGS) was determined at the end of study. Relative expression AT1R in the kidney cortex obtained at 5/6Nx was determined by PCR. Infusion of ANG II induced significant constriction of both afferent and efferent glomerular arterioles, which strongly positively correlated with proteinuria and FGS at 12 wk after 5/6Nx. Furthermore, in vitro measured myogenic constriction of small renal arteries negatively correlated with proteinuria 12 wk after 5/6Nx. Moreover, in vivo vascular reactivity negatively correlated with in vitro reactivity. Additionally, relative expression of AT1R positively correlated with responses of glomerular arterioles and with markers of renal damage. Both in vivo afferent and efferent responses to ANG II and in vitro myogenic constriction of small renal arteries in the healthy rat predict the severity of renal damage induced by 5/6Nx. This vascular responsiveness is highly dependent on AT1R expression. Intraorgan vascular integrity may provide a useful tool to guide the prevention and treatment of renal end-organ damage.

scholarly journals Autophagy inhibition by chloroquine prevents increase in blood pressure and preserves endothelial functions

2020 ◽  
Vol 19 (4) ◽  
pp. 789-796
Author(s):  
Moon Jain ◽  
Hina Iqbal ◽  
Pankaj Yadav ◽  
Himalaya Singh ◽  
Debabrata Chanda ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Angiotensin Ii ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Autophagy Flux ◽  
Endothelial Functions

Purpose: To determine the effects of lysosomal inhibition of autophagy by chloroquine (CHQ) onhypertension-associated changes in the endothelial functions. Method: Angiotensin II (Ang II)-treated human endothelial cell line EA.hy926 and renovascularhypertensive rats were subjected to CHQ treatment (in vitro: 0.5, 1, and 2.5 μM; in vivo: 50 mg/kg/dayfor three weeks). Changes in the protein expressions of LC3b II (autophagosome formation marker) andp62 (autophagy flux marker) were assessed using immunoblotting. Cell migration assay, tubuleformation assay (in vitro), and organ bath studies (in vivo) were performed to evaluate the endothelialfunctions. Hemodynamic parameters were measured as well. Results: A higher expression of LC3b II and a reduced expression of p62 observed in the Ang II-treatedendothelial cells, as well as in the aorta of the hypertensive rats, indicated enhanced autophagy.Treatment with CHQ resulted in reduced autophagy flux (in vitro as well as in vivo) and suppressed AngII-induced endothelial cell migration and angiogenesis (in vitro). The treatment with CHQ was alsoobserved to prevent increase in blood pressure in hypertensive rats and preserved acetylcholineinducedrelaxation in phenylephrine-contracted aorta from the hypertensive rats. In addition, chloroquineattenuated Ang II-induced contractions in the aorta of normotensive as well as hypertensive rats. Conclusion: These observations indicated that CHQ lowers the blood pressure and preserves thevascular endothelial function during hypertension. Keywords: Angiotensin II, Autophagy, Chloroquine, Endothelial function, Hypertension, Vasculardysfunction

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