scholarly journals Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: response to angiotensin II AT1 receptor blockade

2009 ◽  
Vol 297 (6) ◽  
pp. F1678-F1688 ◽  
Author(s):  
Sophie C. Lütken ◽  
Soo Wan Kim ◽  
Thomas Jonassen ◽  
David Marples ◽  
Mark A. Knepper ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Diastolic Pressure ◽  
Collecting Duct ◽  
Left Ventricular ◽  
Outer Medulla ◽  
Outer Stripe ◽  
Medullary Collecting Duct ◽  
Type 3

Heart failure (HF) was induced by ligation of the left anterior descending artery (LAD). Left ventricular end-diastolic pressure (LVEDP) >25 mmHg (at day 23 after LAD ligation) was the inclusion criterion. The rats were divided into three groups: sham-operated (Sham, n = 23, LVEDP: 5.6 ± 0.6 mmHg), HF ( n = 14, LVEDP: 29.4 ± 1.4 mmHg), and candesartan (1 mg·kg−1·day−1 sc)-treated HF (HF + Can, n = 9, LVEDP: 29.2 ± 1.2 mmHg). After 7 days (i.e., 29 days after LAD ligation) semiquantitative immunoblotting revealed increased abundance of inner medulla aquaporin-2 (AQP2) and AQP2 phosphorylated at Ser256 (p-AQP2) in HF. There was also markedly enhanced apical targeting of AQP2 and p-AQP2 in inner medullary collecting duct (IMCD) in HF compared with Sham rats, shown by immunocytochemistry. Candesartan treatment significantly reversed the increases in both AQP2 and p-AQP2 expression and targeting. In contrast, there were only modest changes in other collecting duct segments. Semiquantitative immunoblots revealed increased expression of type 3 Na+/H+ exchanger (NHE3) and Na+-K+-2Cl− cotransporter (NKCC2) in kidneys from HF compared with Sham rats: both effects were reversed or prevented by candesartan treatment. The protein abundance of α-epithelial sodium channel (α-ENaC) was increased while β-ENaC and γ-ENaC expression was decreased in the cortex and outer stripe of the outer medulla in HF compared with Sham rats, which was partially reversed by candesartan treatment. These findings strongly support an important role of angiotensin II in the pathophysiology of renal water and sodium retention associated with HF.

Adrenomedullin in experimental congestive heart failure: cardiorenal activation

1997 ◽  
Vol 273 (4) ◽  
pp. R1392-R1399 ◽  
Author(s):  
Michihisa Jougasaki ◽  
Tracy L. Stevens ◽  
Daniel D. Borgeson ◽  
Andreas Luchner ◽  
Margaret M. Redfield ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Diastolic Pressure ◽  
Collecting Duct ◽  
Renal Tissue ◽  
Left Ventricular ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
Rapid Ventricular Pacing ◽  
And Function

Adrenomedullin (ADM) is a new member of a family of vasodilating and natriuretic peptides that plays an important role in cardiorenal regulation. This study was designed to establish the plasma, urinary, cardiac, and renal tissue concentrations and immunohistochemical localizations of ADM in normal dogs and dogs with experimental congestive heart failure (CHF) produced by rapid ventricular pacing. Plasma ADM concentration was 5.6 ± 0.4 pg/ml in normal dogs and significantly increased to 14.5 ± 2.5 pg/ml in CHF dogs ( P < 0.05). Ventricular and renal tissue ADM were significantly increased in CHF dogs compared with normals. Immunohistochemical examination revealed positive ADM immunostaining within the myocytes, and ventricular ADM immunoreactivity was significantly more intense in CHF dogs than in normals. ADM immunoreactivity was also observed in the glomerulus, distal tubules, and medullary collecting duct cells in the kidney, and the intensities of ADM immunoreactivity in these sites were increased in CHF dogs compared with normals. In addition, ventricular ADM was a powerful marker for left ventricular mass, and circulating ADM correlated positively with left ventricular end-diastolic pressure and inversely with cardiac output and ejection fraction. Despite an increase in renal tissue ADM, urinary ADM did not increase in CHF dogs. The current study demonstrates that plasma concentration of ADM is increased in experimental CHF and that ventricular and renal ADM is activated in the progression of CHF. Tissue and circulating ADM also are markers for the alterations in myocardial structure and function. This study supports a potential role for ADM in the neurohumoral activation in experimental CHF.

Role of endogenous atrial natriuretic peptide on systemic and renal hemodynamics in heart failure rats

1994 ◽  
Vol 267 (1) ◽  
pp. H182-H186 ◽  
Author(s):  
T. Nishikimi ◽  
K. Miura ◽  
N. Minamino ◽  
K. Takeuchi ◽  
T. Takeda
Keyword(s):  
Heart Failure ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Diastolic Pressure ◽  
Urinary Sodium Excretion ◽  
Left Ventricular ◽  
Renal Hemodynamics ◽  
Renal Tubular ◽  
Atrial Natriuretic

To investigate the role of endogenous atrial natriuretic peptide (ANP) in rats with heart failure (HF), we administered HS-142-1 (HS; 3 mg/kg body wt iv), a novel nonpeptide ANP-receptor antagonist, to rats with surgically induced myocardial infarction and sham-operated rats. HF was characterized by a higher left ventricular end-diastolic pressure and higher plasma ANP concentration vs. controls. HS administration significantly reduced the plasma and urinary levels of guanosine 3',5'-cyclic monophosphate in rats with HF [plasma concentration 10.6 +/- 2.6 vs. 2.7 +/- 0.4 nM (P < 0.05); urinary excretion 48 +/- 8 vs. 12 +/- 2 pmol/min (P < 0.05)]. Systemic and renal hemodynamics were unaffected by HS administration. Urine flow (-35%) and urinary sodium excretion (-50%) were significantly decreased after HS only in those rats with HF that had no changes in systemic and renal hemodynamics. These results suggest that the elevated ANP levels in HF do not contribute directly to the maintenance of systemic hemodynamics but rather compensate for the HF mainly via diuresis and natriuresis, achieved by the inhibition of renal tubular reabsorption rather than by renal vasodilatation.

Progressive myocardial dysfunction associated with increased vascular resistance

1980 ◽  
Vol 239 (4) ◽  
pp. H477-H477 ◽  
Author(s):  
Joseph A. Franciosa ◽  
Richard Heckel ◽  
Catherine Limas ◽  
Jay N. Cohn
Keyword(s):  
Heart Failure ◽  
Systemic Vascular Resistance ◽  
Vascular Resistance ◽  
Diastolic Pressure ◽  
Myocardial Dysfunction ◽  
Peripheral Circulation ◽  
Left Ventricular ◽  
Stroke Work ◽  
Low Cardiac Output

To study heart failure from a myocardial lesion, we injected glass beads into the circumflex coronary artery of 11 conscious dogs and followed hemodynamics for 10 mo. Heart rate remained unchanged. Control mean arterial pressure of 112.3 ± 3.0 (SE) mmHg was unchanged at 1 and 3 mo, but rose to 127.2 ± 8.5 to 84.0 ± 7.6 ml . kg-1 . min-1 at 10 mo (P < 0.02), but was unchanged at 1 and 3 mo. Left ventricular end-diastolic pressure (LVEDP) averaged 4.6 ± 0.8 mmHg at control and rose to 11.8 ± 1.4 mmHg at 1 mo and 14.9 ± 2.5 mmHg at 10 mo (both P < 0.01). Systemic vascular resistance rose significantly by 10 mo. The ratio of stroke work to LVEDP fell from 13.1 ± 0.1 at control to 3.8 ± 0.5 by 10 mo (P < 0.01). In this dog model, left ventricular dysfunction is manifest early by increased LVEDP and later by high systemic vascular resistance with low cardiac output, thus suggesting a role of the peripheral circulation in the progression of heart failure.

Immunolocalization of electroneutral Na-HCO3 − cotransporter in rat kidney

2000 ◽  
Vol 279 (5) ◽  
pp. F901-F909 ◽  
Author(s):  
Henrik Vorum ◽  
Tae-Hwan Kwon ◽  
Christiaan Fulton ◽  
Brian Simonsen ◽  
Inyeong Choi ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Electron Microscopic Level ◽  
Thick Ascending Limb ◽  
Intercalated Cells ◽  
Electron Microscopic ◽  
Outer Medulla ◽  
Outer Stripe ◽  
Medullary Collecting Duct

An electroneutral Na-HCO3 − cotransporter (NBCN1) was recently cloned, and Northern blot analyses indicated its expression in rat kidney. In this study, we determined the cellular and subcellular localization of NBCN1 in the rat kidney at the light and electron microscopic level. A peptide-derived antibody was raised against the COOH-terminal amino acids of NBCN1. The affinity-purified antibody specifically recognized one band, ∼180 kDa, in rat kidney membranes. Peptide- N-glycosidase F deglycosylation reduced the band to ∼140 kDa. Immunoblotting of membrane fractions from different kidney regions demonstrated strong signals in the inner stripe of the outer medulla (ISOM), weaker signals in the outer stripe of the outer medulla and inner medulla, and no labeling in cortex. Immunocytochemistry demonstrated that NBCN1 immunolabeling was exclusively observed in the basolateral domains of thick ascending limb (TAL) cells in the outer medulla (strongest in ISOM) but not in the cortex. In addition, collecting duct intercalated cells in the ISOM and in the inner medulla also exhibited NBCN1 immunolabeling. Immunoelectron microscopy demonstrated that NBCN1 labeling was confined to the basolateral plasma membranes of TAL and collecting duct type A intercalated cells. Immunolabeling controls were negative. By using 2,7-bis-carboxyethyl-5,6-caboxyfluorescein, intracellular pH transients were measured in kidney slices from ISOM and from mid-inner medulla. The results revealed DIDS-sensitive, Na- and HCO3 −-dependent net acid extrusion only in the ISOM but not in mid-inner medulla, which is consistent with the immunolocalization of NBCN1. The localization of NBCN1 in medullary TAL cells and medullary collecting duct intercalated cells suggests that NBCN1 may be important for electroneutral basolateral HCO3 − transport in these cells.

Abstract 13438: The Role and Mechanism of Chronic Beta3-Adrenergic Receptor Blockade on the Progression of Heart Failure in a Rat Model

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Xiaoqiang Sun ◽  
Che Cheng ◽  
Jing Cao ◽  
Zhi Zhang ◽  
Tiankai Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Left Ventricular ◽  
Plasma Norepinephrine ◽  
Functional Responses ◽  
Generating Capacity ◽  
Precise Role ◽  
Mini Pump

Background: The negative inotrope and up-regulation of β 3 -adrenergic receptors (AR) in human and animal failing hearts suggest a direct and contributing role of cardiac β 3 -AR activation on the progression of congestive heart failure (CHF). However, its precise role is still being debated. We hypothesize that up-regulation of cardiac β 3 -AR is detrimental and chronic β 3 -AR blockade may prevent CHF-caused intrinsic defects of left ventricular (LV) myocyte force-generating capacity and relaxation and improve β-AR regulation, thereby limiting the progression of CHF. Methods: We compared the alterations of LV and myocyte functional responses and [Ca 2+ ] i transient ([Ca 2+ ] iT ) in SD rats divided into 3 groups (8/group): 1) CHF 3 months after isoproterenol (ISO) (170 mg/kg, sq, for 2 days); 2) ISO/β 3 -ANT , 2 months after receiving ISO, a selective β 3 -AR antagonist (ANT), L-748,337, was initiated (10 -7 M/kg/day, sq. by mini-pump) and was given for 1 month; and 3) Sham controls . Results: Compared with controls, the animals that received ISO treatment had CHF onset at 1 month and progressed to severe HF at 3 months after ISO. Plasma norepinephrine (NE) (1295 vs 259 pg/ml) increased 5-fold; whereas, stroke volume (SV) (39 vs 91 μl) and ejection fraction (EF) (39 vs 62%) significantly decreased, and LV end-diastolic pressure (P ED ) (13.9 vs 6.0 mmHg) was doubled. These changes were paralleled with about 50% reductions in cell contraction (dL/dt max , 93 vs 186 μm/s) and relaxation (dR/dt max , 96 vs 159 μm/s) associated with a significant decrease in the peak systolic [Ca 2+ ] iT , (0.17 vs 0.26). In addition, superfusion of ISO (10 -8 M) caused much less increases in dL/dt max (39 vs 68%), dR/dt max (23 vs 54%), and [Ca 2+ ] IT (14 vs 28%). Treatment with β 3 -ANT increased SV (89 μl) and EF (60%), decreased P ED more than 90% from ISO-treated values, and corrected the elevation of plasma NE (301 pg/ml), dL/dt max (184 μm/s), dR/dt max (152 μm/s), and [Ca 2+ ] iT (0.24). ISO-induced increase in dL/dt max and [Ca 2+ ] iT also returned close to control levels. Conclusion: Chronic β 3 -ANT treatment after CHF significantly improves LV and myocyte contractile function and [Ca 2+ ] i regulation and limits the development of CHF. Thus, β 3 -AR blocker may provide a new therapeutic strategy for the treatment of CHF.

Abstract 172: Interleukin-10-mediated Activation of AKT and Bcl2 Inhibits Chronic Angiotensin II-induced Pathological Autophagy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Suresh K Verma ◽  
Prasanna Krishnamurthy ◽  
Venkata N Girikipathi ◽  
Tatiana Abramova ◽  
Moshin Khan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Pressure Overload ◽  
Interleukin 10 ◽  
Left Ventricular ◽  
Beclin 1 ◽  
Neonatal Rat ◽  
Physical Interaction ◽  
Ang Ii

Rationale: Although, autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological (stress-induced exaggerated/defective) autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly inhibited pressure overload-induced hypertrophy and heart failure, but role of IL-10 in regulation of pathological autophagy is not known. Hypothesis: We tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and this process, in part, led to improved cardiac function. Methods and Results: Pathological autophagy was induced in wild type (WT) and IL10-knockout (IL-10 KO) mice by angiotensin II (Ang II for 28 days) infusion. Ang II-induced left ventricular (LV) dysfunction and hypertrophic remodeling were accentuated in IL-10 KO mice compared to WT mice. IL-10 KO mice showed exaggerated autophagy as observed by Electron Microscopy and Western blotting (beclin 1, LC3 II/I and CHOP) with reduced AKT phosphorylation at serine-473. In neonatal rat ventricular cardiomyocytes (NRCM), Ang II treatment enhanced beclin1, LC3 and CHOP protein levels and inhibited AKT and 4EBP1 phosphorylation and Bcl2 levels. Interestingly, IL-10 inhibited Ang II-induced autophagic marker proteins. Additionally, IL-10 restored Ang II-induced suppression of AKT and 4EBP1 phosphrylation and restoration of Bcl2 protein level. Pharmacological inhibition of AKT via PI3K inhibitor (LY290002), reversed IL-10 responses on the Ang II-induced pathological autophagy, confirming that IL-10 mediated inhibition of autophagy is AKT dependent. Finally, as physical interaction of Bcl2 with beclin 1 is important to inhibit autophagy, we performed immunoprecipitation pull-down experiments, which showed Ang II disrupts the physical interaction of beclin 1 with Bcl2 and IL-10 reestablished this physical interaction to reduce autophagy. Conclusion: Our data provides a novel role of IL-10 in regulation of pathological autophagy and thus can act as a potential therapeutic molecule in treatment of chronic heart disease.

scholarly journals New perspective of ClC-Kb/2 Cl− channel physiology in the distal renal tubule

2016 ◽  
Vol 310 (10) ◽  
pp. F923-F930 ◽  
Author(s):  
Oleg Zaika ◽  
Viktor Tomilin ◽  
Mykola Mamenko ◽  
Vivek Bhalla ◽  
Oleh Pochynyuk
Keyword(s):  
Collecting Duct ◽  
Electrolyte Balance ◽  
Thick Ascending Limb ◽  
Medullary Collecting Duct ◽  
New Perspective ◽  
Renal Tubular ◽  
And Function ◽  
Type 3

Since its identification as the underlying molecular cause of Bartter's syndrome type 3, ClC-Kb (ClC-K2 in rodents, henceforth it will be referred as ClC-Kb/2) is proposed to play an important role in systemic electrolyte balance and blood pressure regulation by controlling basolateral Cl− exit in the distal renal tubular segments from the cortical thick ascending limb to the outer medullary collecting duct. Considerable experimental and clinical effort has been devoted to the identification and characterization of disease-causing mutations as well as control of the channel by its cofactor, barttin. However, we have only begun to unravel the role of ClC-Kb/2 in different tubular segments and to reveal the regulators of its expression and function, e.g., insulin and IGF-1. In this review we discuss recent experimental evidence in this regard and highlight unexplored questions critical to understanding ClC-Kb/2 physiology in the kidney.

Congestive heart failure in rats is associated with increased collecting duct vasopressin sensitivity and vasopressin type 2 receptor reexternalization

2013 ◽  
Vol 305 (11) ◽  
pp. F1547-F1554 ◽  
Author(s):  
Lone Brønd ◽  
Katrine M. Müllertz ◽  
Malene Torp ◽  
Jonas Nielsen ◽  
Martin Græbe ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Diastolic Pressure ◽  
Collecting Duct ◽  
Water Channel ◽  
Left Ventricular ◽  
Receptor Internalization ◽  
Surface Binding ◽  
Binding Studies

A number of studies have shown that rats with congestive heart failure (CHF) have increased protein levels of the vasopressin (AVP)-regulated water channel aquaporin-2 (AQP2) even during conditions with unchanged circulating levels of AVP, suggesting an increase in the sensitivity of the AVP type 2 (V2) receptor in experimental CHF. The present study was aimed at investigating AVP signaling in rats with moderate CHF (left ventricular end diastolic pressure >10 mmHg; normal plasma AVP levels) induced by ligation of the left anterior descending coronary artery. Sham-operated rats were used as controls. Western blotting analyses revealed an increased abundance of AQP2 in renal cortex (+33 ± 9% of sham; P < 0.05) and in inner medulla (IM) (+54 ± 15% of sham; P < 0.05) in CHF rats compared with sham-operated controls. Dose-response studies on isolated collecting ducts (CDs) showed an increased accumulation of cAMP in response to AVP in CHF rats compared with controls. V2 receptor surface-binding studies in isolated IMCDs showed a marked and comparable AVP-induced V2 receptor internalization in response to AVP in both CHF and control rats. As expected V2 receptor surface binding remained low after AVP challenge in control rats. In contrast to this, V2 receptor surface binding returned to pre-AVP levels within 30 min in the CHF rats, indicating an obtained recycling ability of the V2 receptor in CHF. Together the results indicate the presence of an increased AVP sensitivity in the CDs from CHF rats, associated with an acquired recycling ability of the V2 receptor.

scholarly journals Estrogen restores role of basal nitric oxide in control of vascular tone in rats with chronic heart failure

1998 ◽  
Vol 274 (6) ◽  
pp. H2094-H2099 ◽  
Author(s):  
Ali Akbar Nekooeian ◽  
Catherine C. Y. Pang
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Diastolic Pressure ◽  
Peripheral Resistance ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Ovariectomized Rats ◽  
17Β Estradiol

This study examined the cardiovascular effects of 17β-estradiol in ovariectomized rats with heart failure. Two groups (50–60 days old) were implanted with 60-day-release pellets containing 17β-estradiol (25 μg/day) or vehicle at 7 days before ligation of the left coronary artery. Another group was sham operated and given vehicle pellets. After 7 wk, they were studied under pentobarbital anesthesia. Relative to sham-operated rats, ligated rats had reduced mean arterial pressure (MAP, −24 ± 6 mmHg), cardiac output (−27 ± 4 ml/min), left ventricular (LV) end-systolic pressure (−29 ± 8 mmHg), depressor responses to ACh (−6 ± 4 mmHg at 7.2 μg/kg) and sodium nitroprusside (SNP, −22 ± 6 mmHg at 9 μg/kg), and pressor responses to N G-nitro-l-arginine methyl ester (l-NAME, −14 ± 6 mmHg at 8 mg/kg) and increased LV end-diastolic pressure (LVEDP, 10.3 ± 0.8 mmHg) but no change in total peripheral resistance (TPR). Treatment of ligated rats with 17β-estradiol reduced TPR (−0.19 ± 0.06 mmHg ⋅ min ⋅ ml−1), LVEDP (−3.6 ± 1 mmHg), and responses to ACh (−16 ± 4 mmHg) and augmented responses tol-NAME (14 ± 3 mmHg) but did not alter other variables. Therefore, 17β-estradiol reduces preload and afterload and restores the vasodilator role of basal nitric oxide in ovariectomized rats with chronic heart failure.

Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice

2003 ◽  
Vol 285 (5) ◽  
pp. H2179-H2187 ◽  
Author(s):  
Xinhua Yan ◽  
Robert L. Price ◽  
Masaharu Nakayama ◽  
Kenta Ito ◽  
Adam J. T. Schuldt ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Dilated Cardiomyopathy ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Specific Expression ◽  
Protein Levels

The angiotensin II type 2 (AT2) receptor is upregulated in the left ventricle in heart failure, but its pathophysiological roles in vivo are not understood. In the present study, AT2 receptors were expressed in transgenic (TG) mice using the ventricular-specific myosin light-chain (MLC-2v) promoter. In TG compared with nontransgenic (NTG) mice, in vivo left ventricular (LV) systolic pressure and peak +dP/d t were depressed while LV diastolic pressure was elevated ( P < 0.05). Echocardiography showed severely depressed LV fractional shortening, increased systolic and diastolic dimensions, and wall thinning ( P < 0.05). Confocal and electron microscopy studies revealed an increase in the size of myocytes and interstitial spaces as well as an increase in interstitial collagen, disruption of the Z-band, and changes in cytochrome c localization. The changes were most prominent in the highest-expressing TG line, which implies a dose-response relationship. AT2 overexpression was also directly associated with the increase of phosphorylated protein levels of PKC-α, PKC-β, and p70S6 kinase. These data demonstrate that ventricular myocyte-specific expression of AT2 receptors promotes the development of dilated cardiomyopathy and heart failure in vivo.

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