Effects of Renal Denervation on the Enhanced Renal Vascular Responsiveness to Angiotensin II in High-Output Heart Failure: Angiotensin II Receptor Binding Assessment and Functional Studies in Ren-2 Transgenic Hypertensive Rats

Detailed mechanism(s) of the beneficial effects of renal denervation (RDN) on the course of heart failure (HF) remain unclear. The study aimed to evaluate renal vascular responsiveness to angiotensin II (ANG II) and to characterize ANG II type 1 (AT1) and type 2 (AT2) receptors in the kidney of Ren-2 transgenic rats (TGR), a model of ANG II-dependent hypertension. HF was induced by volume overload using aorto-caval fistula (ACF). The studies were performed two weeks after RDN (three weeks after the creation of ACF), i.e., when non-denervated ACF TGR enter the decompensation phase of HF whereas those after RDN are still in the compensation phase. We found that ACF TGR showed lower renal blood flow (RBF) and its exaggerated response to intrarenal ANG II (8 ng); RDN further augmented this responsiveness. We found that all ANG II receptors in the kidney cortex were of the AT1 subtype. ANG II receptor binding characteristics in the renal cortex did not significantly differ between experimental groups, hence AT1 alterations are not responsible for renal vascular hyperresponsiveness to ANG II in ACF TGR, denervated or not. In conclusion, maintained renal AT1 receptor binding combined with elevated ANG II levels and renal vascular hyperresponsiveness to ANG II in ACF TGR influence renal hemodynamics and tubular reabsorption and lead to renal dysfunction in the high-output HF model. Since RDN did not attenuate the RBF decrease and enhanced renal vascular responsiveness to ANG II, the beneficial actions of RDN on HF-related mortality are probably not dominantly mediated by renal mechanism(s).

Download Full-text

Enhanced Renal Vascular Responsiveness to Angiotensin II and Norepinephrine: A Unique Feature of Female Rats with Congestive Heart Failure

Kidney & Blood Pressure Research ◽

10.1159/000502379 ◽

2019 ◽

Vol 44 (5) ◽

pp. 1128-1141 ◽

Cited By ~ 1

Author(s):

Vojtěch Krátký ◽

Soňa Kikerlová ◽

Zuzana Husková ◽

Janusz Sadowski ◽

František Kolář ◽

...

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Renal Dysfunction ◽

Unique Feature ◽

Female Rats ◽

Male Rats ◽

Published Data ◽

Ang Ii ◽

Vascular Responsiveness ◽

Renal Vascular

Background/Aims: We found recently that the aortocaval fistula (ACF)-induced heart failure (HF) results in higher mortality in female than in male rats. Possibly, the development of renal dysfunction in the females, unlike in males, is associated with altered renal vascular responsiveness to angiotensin II (ANG II). Methods: Five or 20 weeks after ACF creation (compensated and decompensated HF, respectively), we assessed renal blood flow (RBF) responses to intrarenal administration of ANG II, norepinephrine (NE), and acetylcholine (Ach) in female ACF and sham-operated rats. Results: In ACF females, ANG II decreased RBF more than in healthy animals, unlike with earlier published data in male ACF rats that responded similarly. Also, NE decreased RBF more in female ACF rats, whereas Ach increased RBF to the same extent in female ACF and sham-operated rats. RBF responses to intravenous administration of NE and Ach were almost identical in female and male ACF rats. Conclusion: Female ACF rats studied at the onset of HF decompensation reveal, in contrast to male rats, enhanced renal vascular responsiveness to both NE and ANG II. When associated with the demonstrated increased intrarenal ANG II and NE concentrations, such hyperresponsiveness might promote the development of renal dysfunction and accelerate HF decompensation.

Download Full-text

Altered Renal Vascular Responsiveness to Vasoactive Agents in Rats with Angiotensin II-Dependent Hypertension and Congestive Heart Failure

Kidney & Blood Pressure Research ◽

10.1159/000501688 ◽

2019 ◽

Vol 44 (4) ◽

pp. 792-809 ◽

Cited By ~ 1

Author(s):

Šárka Vacková ◽

Soňa Kikerlová ◽

Vojtěch Melenovsky ◽

František Kolář ◽

John D. Imig ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Angiotensin Ii ◽

Renal Dysfunction ◽

Volume Overload ◽

Epoxyeicosatrienoic Acids ◽

Ang Ii ◽

Vasoactive Agents ◽

Vascular Responsiveness ◽

Renal Vascular

Objective: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs). Methods: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation). Results: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR. Conclusion: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF.

Download Full-text

Renal Sympathetic Denervation Attenuates Congestive Heart Failure in Angiotensin II-Dependent Hypertension: Studies with Ren-2 Transgenic Hypertensive Rats with Aortocaval Fistula

Kidney & Blood Pressure Research ◽

10.1159/000513071 ◽

2021 ◽

pp. 1-19

Author(s):

Zuzana Honetschlagerová ◽

Olga Gawrys ◽

Šárka Jíchová ◽

Petra Škaroupková ◽

Soňa Kikerlová ◽

...

Keyword(s):

Heart Failure ◽

Survival Rate ◽

Angiotensin Ii ◽

Renal Sympathetic Denervation ◽

Aortocaval Fistula ◽

Ang Ii ◽

Vascular Responsiveness ◽

Final Survival ◽

Renal Vascular ◽

Renal Sympathetic

Objective: We examined if renal denervation (RDN) attenuates the progression of aortocaval fistula (ACF)-induced heart failure or improves renal hemodynamics in Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension. Methods: Bilateral RDN was performed 1 week after creation of ACF. The animals studied were ACF TGR and sham-operated controls, and both groups were subjected to RDN or sham denervation. In separate groups, renal artery blood flow (RBF) responses were determined to intrarenal ANG II (2 and 8 ng), norepinephrine (NE) (20 and 40 ng) and acetylcholine (Ach) (10 and 40 ng) 3 weeks after ACF creation. Results: In nondenervated ACF TGR, the final survival rate was 10 versus 50% in RDN rats. RBF was significantly lower in ACF TGR than in sham-operated TGR (6.2 ± 0.3 vs. 9.7 ± 0.5 mL min−1 g−1, p < 0.05), the levels unaffected by RDN. Both doses of ANG II decreased RBF more in ACF TGR than in sham-operated TGR (−19 ± 3 vs. −9 ± 2% and −47 ± 3 vs. −22 ± 2%, p < 0.05 in both cases). RDN did not alter RBF responses to the lower dose, but increased it to the higher dose of ANG II in sham-operated as well as in ACF TGR. NE comparably decreased RBF in ACF TGR and sham-operated TGR, and RDN increased RBF responsiveness. Intrarenal Ach increased RBF significantly more in ACF TGR than in sham-operated TGR (29 ± 3 vs. 17 ± 3%, p < 0.05), the changes unaffected by RDN. ACF creation induced marked bilateral cardiac hypertrophy and lung congestion, both attenuated by RDN. In sham-operated but not in ACF TGR, RDN significantly decreased mean arterial pressure. Conclusion: The results show that RDN significantly improved survival rate in ACF TGR; however, this beneficial effect was not associated with improvement of reduced RBF or with attenuation of exaggerated renal vascular responsiveness to ANG II.

Download Full-text

Effect of angiotensin-II receptor blocker candesartan alone or in combination with aldoster-one antagonist spironolactone on diastolic function in patients with chronic heart failure and relatively no

European Journal of Heart Failure Supplements ◽

10.1016/s1567-4215(08)60438-5 ◽

2008 ◽

Vol 7 ◽

pp. 159-159

Author(s):

F AGEEV ◽

O SVIRIDA ◽

A OVCHINNIKOV

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Chronic Heart Failure ◽

Diastolic Function ◽

Receptor Blocker ◽

Angiotensin Ii Receptor Blocker ◽

Angiotensin Ii Receptor

Download Full-text

Angiotensin II Receptor Antagonist Improves the Immune Activations of Patients With Chronic Heart Failure

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(97)83860-0 ◽

1998 ◽

Vol 31 (2) ◽

pp. 33A

Author(s):

T Tsutamoto

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Chronic Heart Failure ◽

Receptor Antagonist ◽

Angiotensin Ii Receptor ◽

Angiotensin Ii Receptor Antagonist

Download Full-text

Angiotensin II regulates nephrogenesis and renal vascular development

AJP Renal Physiology ◽

10.1152/ajprenal.1995.269.1.f110 ◽

1995 ◽

Vol 269 (1) ◽

pp. F110-F115 ◽

Cited By ~ 42

Author(s):

A. Tufro-McReddie ◽

L. M. Romano ◽

J. M. Harris ◽

L. Ferder ◽

R. A. Gomez

Keyword(s):

Angiotensin Ii ◽

Kidney Development ◽

Rana Catesbeiana ◽

Angiotensin Converting Enzyme Inhibition ◽

Ang Ii ◽

Newborn Rats ◽

Sprague Dawley ◽

Renal Growth ◽

Glomerular Size ◽

Renal Vascular

To test the hypothesis that angiotensin II (ANG II) is necessary for normal embryonic and postnatal kidney development, the effect of angiotensin receptor blockade or angiotensin converting enzyme inhibition on nephrovascular development was studied in newborn Sprague-Dawley rats and in Rana catesbeiana tadpoles undergoing prometamorphosis. Blockade of ANG II type 1 receptor (AT1) in newborn rats induced an arrest in nephrovascular maturation and renal growth, resulting in altered kidney architecture, characterized by fewer, thicker, and shorter afferent arterioles, reduced glomerular size and number, and tubular dilatation. Inhibition of ANG II generation in tadpoles induced even more marked developmental renal abnormalities. Blockade of ANG II type 2 receptor (AT2) in newborn rats did not alter renal growth or morphology. Results indicate that ANG II regulates nephrovascular development, a role that is conserved across species.

Download Full-text

Angiotensin II Receptor Type 1 mRNA is Upregulated in Atria of Patients with End-stage Heart Failure

Journal of Molecular and Cellular Cardiology ◽

10.1006/jmcc.1997.0458 ◽

1997 ◽

Vol 29 (8) ◽

pp. 2299-2304 ◽

Cited By ~ 13

Author(s):

Raffi R Kaprielian ◽

Emmanuel Dupont ◽

Sassan Hafizi ◽

Philip A Poole-Wilson ◽

Asghar Khaghani ◽

...

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Receptor Type ◽

Angiotensin Ii Receptor ◽

End Stage Heart Failure ◽

End Stage

Download Full-text

Prevention of new-onset atrial fibrillation and its predictors with angiotensin II-receptor blockers in the treatment of hypertension and heart failure

Journal of Hypertension ◽

10.1097/01.hjh.0000254378.26607.1f ◽

2007 ◽

Vol 25 (1) ◽

pp. 15-23 ◽

Cited By ~ 34

Author(s):

Tonje A Aksnes ◽

Arnljot Flaa ◽

Arne Strand ◽

Sverre E Kjeldsen

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Angiotensin Ii ◽

Angiotensin Ii Receptor Blockers ◽

Angiotensin Ii Receptor ◽

Treatment Of Hypertension ◽

Receptor Blockers ◽

Onset Atrial Fibrillation ◽

New Onset

Download Full-text

Abstract 180: Synergistic Salutary Effects of HMG-CoA Reductase Inhibitor and Angiotensin II Receptor Blocker on Load-induced Heart Failure

Circulation Research ◽

10.1161/res.115.suppl_1.180 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Yasuhiro Maejima ◽

Mitsuaki Isobe

Keyword(s):

Heart Failure ◽

Angiotensin Ii ◽

Reductase Inhibitor ◽

Neonatal Rat ◽

Receptor Blocker ◽

Angiotensin Ii Receptor Blocker ◽

Angiotensin Ii Receptor ◽

Hmg Coa Reductase ◽

Hmg Coa Reductase Inhibitor ◽

Coa Reductase

We have shown previously that combined HMG-CoA reductase inhibitor (statin) and angiotensin II receptor blocker (ARB) therapy significantly improves both symptoms and left ventricular (LV) function over time in patients with heart failure (HF) by a clinical study [ HF-COSTAR Trial]. We elucidated the mechanisms of combination therapy with the ARB (losartan, LOS) and long-acting and statin (simvastatin, SIM) for the treatment of load-induced heart failure. Salt-loaded Dahl salt-sensitive (DS) rats were treated with vehicle, LOS (5mg/kg/day), SIM (2mg/kg/day) and LOS + SIM for 16 weeks. LOS and SIM in combination improved LV dysfunction (ΔLV fractional shortening; LOS = 60%, SIM = 42%, LOS + SIM = 24%, p <0.05), limited LV hypertrophy (ΔLV septal thickness; LOS = −21%, SIM = −18%, LOS + SIM = −13%, p <0.05) and reduced cardiac fibrosis (ΔLV collagen density; LOS = −26%, SIM = −16%, LOS + SIM = −28%, p <0.05) more than LOS or SIM alone. Both Rho and matrix metalloprotease-9 (MMP-9) activity in LV tissue were increased in untreated DS rats, and LOS and SIM in combination decreased these changes more than did LOS and SIM monotherapies. We confirmed that the plasma level of Exp-3174 (E3174), a LOS metabolite and a potent inverse agonist of angiotensin II receptor type 1, was higher in rats treated with LOS and SIM in combination than in those treated with LOS alone (E3174/LOS ratio; LOS = 2.6 ± 0.3 vs. LOS + SIM = 3.2 ± 0.2, p <0.05). Next, to mimic the response of volume-overload heart failure in vitro , cultured neonatal rat cardiomyocytes (CMs) were cyclically stretched. Stretch-induced increased CM hypertrophy was suppressed by pretreatment with both SIM and E3174 more than by pretreatment with LOS, E3174, SIM, or LOS and SIM in combination. Mechanical stretch also induced activation of extracellular signal regulated kinase (ERK) and the stretch-induced ERK activation of CMs was also significantly suppressed by SIM + E3174. In conclusion, LOS and SIM had beneficial myocardial effects in rats with salt-sensitive hypertension, partly through promoting the accumulation of plasma E3174. SIM enhanced the myocardial protective effects of LOS through suppression of Rho and MMP-9 activity. Thus, a combination of ARB with statin has a promising potential as a therapeutic strategy for HF.

Download Full-text