Translational Success Stories: Angiotensin Receptor 1 Antagonists in Heart Failure

Dell’Italia, Louis J.

doi:10.1161/circresaha.110.238550

Cited by 55 publications

(73 citation statements)

References 202 publications

(155 reference statements)

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“…The increased sensitivity to NE was still observed in the neurons, and there was no ANG II-induced potentiation of adrenergic or muscarinic responses in the MI animals treated with captopril for 6 wk. Although captopril inhibits ACE1, it does not affect the activity of other proteases, such as chymase, which have been shown to increase in cardiac tissues with MI (6,22). Thus, although the normal pathways for ANG II production are inhibited by captopril, the alternative pathways for generating ANG II are unaffected by drug treatment, and may be of greater importance in elevating local ANG II levels within the cardiac interstitium (6,22).…”

Section: Discussionmentioning

confidence: 98%

“…Increased sympathetic activity evokes elevated levels of norepinephrine (NE) release within the heart (7). An increase in the synthesis of ANG II from both enhanced renin release and increased protease activity within the heart interstitial tissues contributes to the hyperdynamic sympathetic response (6,21,24). Inhibition of adrenergic receptors (e.g., ␤-blockade) or treatment with drugs that target ANG II synthesis (ACE inhibitors) or receptor activation (AT 1 inhibitors) has been demonstrated to alter adverse remodeling of the cardiac muscle (30).…”

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confidence: 99%

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Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus

Hardwick

Ryan

Powers

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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), or AT2 receptor agonist (CGP42112A, 0.14 mg·kg Ϫ1 ·day Ϫ1 ) on remodeling of the guinea pig intrinsic cardiac plexus following chronic myocardial infarction (MI). MI was surgically induced and animals recovered for 6 or 7 wk, with or without drug treatment. Intracellular voltage recordings from whole mounts of the cardiac plexus were used to monitor changes in neuronal responses to norepinephrine (NE), muscarinic agonists (bethanechol), or ANG II. MI produced an increase in neuronal excitability with NE and a loss of sensitivity to ANG II. MI animals treated with captopril exhibited increased neuronal excitability with NE application, while MI animals treated with CGP42112A did not. Losartan treatment of MI animals did not alter excitability with NE compared with untreated MIs, but these animals did show an enhanced synaptic efficacy. This effect on synaptic function was likely due to presynaptic AT1 receptors, since ANG II was able to reduce output to nerve fiber stimulation in control animals, and this effect was prevented by inclusion of losartan in the bath solution. Analysis of AT receptor expression by Western blot showed a decrease in both AT 1 and AT2 receptors with MI that was reversed by all three drug treatments. These data indicate that neuronal remodeling of the guinea pig cardiac plexus following MI is mediated, in part, by activation of both AT 1 and AT2 receptors.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus

Hardwick

Ryan

Powers

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…10,12 These peptides therefore block the negative cardiac effects of angiotensin II (Ang II) and aldosterone in HF patients, including sodium retention, vasoconstriction, and endothelial dysfunction. 13,14 Whereas ANP and BNP predominantly serve as circulating hormones, CNP is derived from endothelial cells and synthesized in cardiac fibroblasts and may have important antiremodeling effects in the myocardium by means of local regulation of collagen synthesis and cellular hypertrophy inhibition. 15,16 These actions are all mediated by means of NP receptors via the cyclic guanosine monophosphate (cGMP) second messenger system.…”

Section: Natriuretic Peptidesmentioning

confidence: 99%

“…63 The effects on RAAS-mediated neurohormonal levels were similar to those seen previously with valsartan 66 and likely mediated through loss of the normal feedback inhibition via the Ang II type 1 receptor. 13 These early data with LCZ696 in the context of previously demonstrated beneficial effects of neprilysin inhibition by means of other agents provided the rationale to proceed with larger phase III studies of LCZ696 without additional phase II work.…”

Section: Lcz696mentioning

confidence: 99%

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

Buggey

Mentz

DeVore

et al. 2015

Journal of Cardiac Failure

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Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future. (J Cardiac Fail 2015;21:741e750)

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“…[Drummond et al 2007]. Their well-known protective effects on the heart, blood vessels, kidney, and central nervous system, among others, could be considered additional benefits [Dell'Italia, 2011;Schrader et al 2005].…”

Section: Renin-dependence Versus Volumedependencementioning

confidence: 99%

Direct renin inhibition: extricating facts from façades

Juncos¹

2013

Therapeutic Advances in Cardiovascular Disease

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Abstract:The renin-angiotensin system (RAS) affects vascular tone, cardiac output and kidney function. By these means the RAS plays a key role in the pathogenesis of arterial hypertension. As a result, RAS inhibition is highly effective not only in lowering blood pressure but also in reducing kidney disease progression (particularly when associated with proteinuria) and cardiovascular events.Among RAS blocking agents, direct renin inhibitors have shown not only excellent efficacy in hypertension control but also pharmacologic tolerance that is comparable with other reninangiotensin suppressors. Indeed, aliskiren, the only direct renin inhibitor available is effective in controlling blood pressure as monotherapy or in combination with other antihypertensive drugs, irrespective of patient's age, ethnicity or sex. It is also effective in patients with metabolic syndrome, obesity and diabetes. Long-term studies comparing 'hard endpoints' of aliskiren therapy versus treatment with other RAS inhibitors, including cardiac and kidney protection, are currently ongoing. Combined with other antihypertensive agents, aliskiren not only improves their hypotensive response but may also lessen the adverse effects of other drugs. In high-risk patients, however, precautions should be taken when combining two or more renin-angiotensin inhibiting agents, as tissue perfusion may be highly renin-dependent in these patients and serious adverse side effects could take place.

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Translational Success Stories: Angiotensin Receptor 1 Antagonists in Heart Failure

Cited by 55 publications

References 202 publications

Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus

Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

Direct renin inhibition: extricating facts from façades

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