Blood pressure-independent renoprotection in diabetic rats treated with AT1 receptor–neprilysin inhibition compared with AT1 receptor blockade alone

2016 ◽  
Vol 130 (14) ◽  
pp. 1209-1220 ◽  
Author(s):  
Lodi C.W. Roksnoer ◽  
Richard van Veghel ◽  
Marian C. Clahsen- van Groningen ◽  
René de Vries ◽  
Ingrid M. Garrelds ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Diabetic Rats ◽  
At1 Receptor ◽  
Heart Weight ◽  
Receptor Blockade ◽  
Beneficial Effects ◽  
Neprilysin Inhibition ◽  
Pressure Independent

ARNI [dual AT1 (angiotensin II type 1) receptor–neprilysin inhibition] exerts beneficial effects on blood pressure and kidney function in heart failure, compared with ARB (AT1 receptor blockade) alone. We hypothesized that ARNI improves cardiac and kidney parameters in diabetic TGR(mREN2)27 rats, an angiotensin II-dependent hypertension model. Rats were made diabetic with streptozotocin for 5 or 12 weeks. In the final 3 weeks, rats were treated with vehicle, irbesartan (ARB) or irbesartan+thiorphan (ARNI). Blood pressure, measured by telemetry in the 5-week group, was lowered identically by ARB and ARNI. The heart weight/tibia length ratio in 12-week diabetic animals was lower after ARNI compared with after ARB. Proteinuria and albuminuria were observed from 8 weeks of diabetes onwards. ARNI reduced proteinuria more strongly than ARB, and a similar trend was seen for albuminuria. Kidneys of ARNI-treated animals showed less severe segmental glomerulosclerosis than those of ARB-treated animals. After 12 weeks, no differences between ARNI- and ARB-treated animals were found regarding diuresis, natriuresis, plasma endothelin-1, vascular reactivity (acetylcholine response) or kidney sodium transporters. Only ARNI-treated rats displayed endothelin type B receptor-mediated vasodilation. In conclusion, ARNI reduces proteinuria, glomerulosclerosis and heart weight in diabetic TGR(mREN2)27 rats more strongly than does ARB, and this occurs independently of blood pressure.

Abstract 507: Dual AT1 Receptor/Neprilysin (NEP) Inhibition (ARNI) vs. AT1 Receptor Blockade in TGR(mRen2)27 Rats: The More NEP Inhibition The Better?

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Lodi C Roksnoer ◽  
Joep H van Esch ◽  
Richard van Veghel ◽  
Ingrid M Garrelds ◽  
Usha M Bhaggoe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Reactivity ◽  
Weight Ratio ◽  
At1 Receptor ◽  
Mesenteric Arteries ◽  
Heart Weight ◽  
Sodium Reabsorption ◽  
High Dose ◽  
Arterial Blood ◽  
Nep Inhibition

Objective: Neprilysin inhibitors (NEPi) prevent the breakdown of natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin and endothelin-1 (ET1). This study compared the combination of an AT1 receptor antagonist (irbesartan, IRB) ± a low or a high dose of the NEPi thiorphan in renin-overexpressing, hypertensive TGR(mREN2)27 rats. Methods: TGR(mREN2)27 rats were treated for three weeks with vehicle, IRB (15 mg/kg.day) or IRB + thiorphan (0.1 or 1.0 mg/kg.day; TH0.1 and TH1.0). Hemodynamics were evaluated by telemetry, and vascular reactivity was determined in isolated mesenteric arteries (Mulvany myograph). Results: Baseline mean arterial blood pressure (MAP) was 168±3 mmHg. All treatments lowered MAP by ≈50 mmHg around day 4. After 7 days, MAP started to increase during treatment with IRB or IRB+TH1.0 (to 141±10 mmHg and 133±10 mmHg, respectively, on day 21), while MAP in rats treated with IRB+TH0.1 remained low at 104±5 mmHg on day 21. Heart weight/body weight ratio, cardiac ANP expression and myocyte size decreased only in the IRB+TH0.1 group. Plasma ET1 was increased only by TH1.0 versus IRB alone, and this increase was accompanied by an increase in renal sodium-hydrogen exchanger 3 (NHE3) protein expression: ET1-induced constriction was reduced by IRB+TH0.1 only. Vascular ET B R expression levels and studies with the ET1 type B receptor (ET B R) antagonist BQ788 revealed that this reduction was most likely due to ET B R upregulation. Conclusion: TH0.1 enhanced the blood pressure-lowering effects of irbesartan and diminished cardiac hypertrophy. Higher doses of thiorphan resulted in significant ET1 rises and renal NHE3 upregulation, thereby increasing blood pressure and sodium reabsorption. The simultaneously occurring upregulation of vasodilatory ET B R was insufficient to overcome this effect. Clearly therefore, too much NEPi on top of AT1 receptor antagonism might be harmful.

Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure

2001 ◽  
Vol 101 (6) ◽  
pp. 559-566 ◽  
Author(s):  
J. C. VAILE ◽  
S. CHOWDHARY ◽  
F. OSMAN ◽  
H. F. ROSS ◽  
J. FLETCHER ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Heart Rate ◽  
Heart Rate Variability ◽  
Angiotensin Ii ◽  
Baroreflex Sensitivity ◽  
At1 Receptor ◽  
Receptor Blockade ◽  
Double Blind ◽  
Rr Interval

The objective of the present study was to determine the autonomic effects of angiotensin II (AT1) receptor blocker therapy in heart failure. In a randomized double-blind cross-over study, we compared the effects of candesartan and placebo on baroreflex sensitivity and on heart rate variability at rest, during stress and during 24h monitoring. Acute effects were assessed 4h after oral candesartan (8mg) and chronic effects after 4 weeks of treatment (dose titrated to 16mg daily). The study group comprised 21 patients with heart failure [mean (S.E.M.) ejection fraction 33% (1%)], in the absence of angiotensin-converting enzyme (ACE) inhibitor therapy. We found that acute candesartan was not different from placebo in its effects on blood pressure or mean RR interval. Chronic candesartan significantly reduced blood pressure [placebo, 137 (3)/82 (3)mmHg; candesartan, 121 (4)/75 (2)mmHg; P<0.001; values are mean (S.E.M.)], but had no effect on mean RR interval [placebo, 857 (25)ms; candesartan, 857 (21)ms]. Compared with placebo there were no significant effects of acute or chronic candesartan on heart rate variability in the time domain and no consistent effects in the frequency domain. Baroreflex sensitivity assessed by the phenylephrine bolus method was significantly increased after chronic candesartan [placebo, 3.5 (0.5)ms/mmHg; candesartan, 4.8 (0.7)ms/mmHg; P<0.05], although there were no changes in cross-spectral baroreflex sensitivity. Thus, in contrast with previous results with ACE inhibitors, angiotensin II receptor blockade in heart failure did not increase heart rate variability, and there was no consistent effect on baroreflex sensitivity.

Blood pressure-independent effect of angiotensin AT1 receptor blockade on renal endothelin-1 production in hypertensive uremic rats

2001 ◽  
Vol 19 (8) ◽  
pp. 1479-1487 ◽  
Author(s):  
Yannick Dumont ◽  
Martin D'Amours ◽  
Marcel Lebel ◽  
Richard Larivière
Keyword(s):  
Blood Pressure ◽  
At1 Receptor ◽  
Independent Effect ◽  
Receptor Blockade ◽  
Endothelin 1 ◽  
Pressure Independent

scholarly journals Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes.

1993 ◽  
Vol 4 (1) ◽  
pp. 40-49
Author(s):  
A Remuzzi ◽  
N Perico ◽  
C S Amuchastegui ◽  
B Malanchini ◽  
M Mazerska ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Receptor Antagonist ◽  
Diabetic Rats ◽  
Receptor Blockade ◽  
Fractional Clearance ◽  
Short And Long Term ◽  
Normal Controls

The short- and long-term effects of specific angiotensin II (AII) receptor blockade on the evaluation of glomerular injury in moderately hyperglycemic diabetic rats were studied. Three groups of animals were used, a control group, a group of diabetic rats treated with insulin, and a group of insulin-treated diabetic rats receiving the AII receptor antagonist losartan in drinking water. After 4 to 6 wk of observation, diabetic rats showed higher systolic blood pressure and GFR than normal controls. Losartan treatment prevented both systolic blood pressure and GFR rise. Three other groups of rats, similarly treated for a 1-yr period, were used for renal functional and morphologic evaluation. Diabetic animals had higher urinary protein excretion and glomerulosclerosis incidence than did normal controls. Losartan significantly prevented proteinuria and glomerulosclerosis. Evaluation of the sieving properties of the glomerular membrane by Ficoll fractional clearance showed an important increase in the filtration of this marker in diabetic animals, as compared with that in controls, and almost complete prevention of this change in losartan-treated animals. Theoretical analysis of fractional clearance data with a heteroporous model of glomerular size-selectivity showed that in diabetic animals the size of membrane pores was increased uniformly, as compared with that in controls. These changes were completely prevented by the AII receptor antagonist. The results presented here strongly indicate that reduction of AII activity plays a crucial role in the preservation of glomerular structure and function and suggest that the favorable effects previously observed with angiotensin-converting enzyme inhibition in this model depend directly on the reduction of AII activity.

scholarly journals Beneficial Effects of Combined AT1 Receptor/Neprilysin Inhibition (ARNI) Versus AT1 Receptor Blockade Alone in the Diabetic Eye

2016 ◽  
Vol 57 (15) ◽  
pp. 6722 ◽  
Author(s):  
Tuhina Prasad ◽  
Lodi C. W. Roksnoer ◽  
Ping Zhu ◽  
Amrisha Verma ◽  
Yiming Li ◽  
...  
Keyword(s):  
At1 Receptor ◽  
Receptor Blockade ◽  
Beneficial Effects ◽  
Neprilysin Inhibition

scholarly journals Angiotensin II receptor blockade and insulin sensitivity in overweight and obese adults with elevated blood pressure

2013 ◽  
Vol 7 (1) ◽  
pp. 11-20 ◽  
Author(s):  
Elaina L. Marinik ◽  
Madlyn I. Frisard ◽  
Matthew W. Hulver ◽  
Brenda M. Davy ◽  
Jose M. Rivero ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Angiotensin Ii ◽  
Elevated Blood Pressure ◽  
Receptor Blockade ◽  
Elevated Blood ◽  
Angiotensin Ii Receptor ◽  
Obese Adults ◽  
Angiotensin Ii Receptor Blockade

Dissociation of Direct and Indirect Effects of Angiotensin II on the Heart

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 683-684
Author(s):  
Jorge P van Kats ◽  
David W Silversides ◽  
Timothy L Reudelhuber
Keyword(s):  
Heart Rate ◽  
Angiotensin Ii ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Renin Angiotensin System ◽  
Cardiac Cells ◽  
Heart Weight ◽  
Ang Ii ◽  
Direct Stimulation ◽  
Beneficial Effects

33 Cardiac angiotensin II (Ang II), either derived from the circulation or locally synthesized, is often suggested to be involved in the structural adaptations occurring in the heart in hypertension and following myocardial infarction. However, it is debated whether the proven beneficial effects of renin-angiotensin system blockade in these pathologies are related to an inhibition of the direct cardiac actions of the peptide. The objective of the present study was to investigate which of the effects of cardiac Ang II are due to direct stimulation of cardiac cells by Ang II. To test for cardiac specific functions of Ang II, transgenic mice were developed that express an Ang II-releasing fusion protein (J Biol Chem 1997;272:12994-99) exclusively in cardiomyocytes. Blood pressure, heart rate, cardiac and plasma Ang II content, Ang II receptor binding and organ morphology were monitored in transgenic (TG) and non-transgenic littermate mice (control). Cardiac Ang II levels in TG mice were 20-40 fold higher than in hearts of control mice (15±3 pg/100 mg ww). In 3 independent founder lines of TG mice, plasma Ang II concentration was not altered as compared to control (119±20 vs. 127±20 pg/mL). The heart weight to body weight ratio in TG mice (4.0±0.1 mg/g) was not different from controls (3.8±0.1 mg/g), neither was systolic pressure (137±4 and 138±7 mm Hg respectively) or heart rate (618±13 and 662±15 bpm respectively). Microscopic inspection of TG hearts did not reveal any differences with control regarding size and number of cardiomyocytes and organization of extracellular matrix proteins. TG mice had not become less sensitive for Ang II signaling since Ang II receptor number was not altered in TG mice (Bmax = 23±3 fmol/mg protein) as compared to control (22±2 fmol/mg protein). Our data show that very high Ang II levels in hearts of TG mice do not lead to myocardial enlargement or affect cardiovascular physiology. We conclude that elevated Ang II in the heart has no direct effects on cardiac cells and we hypothesize that effects of cardiac Ang II become apparent upon altered hemodynamic loading.

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