Beneficial Renal and Cardiac Effects of Vasopeptidase Inhibition With S21402 in Heart Failure

Burrell, Louise M.; Farina, Nicole K.; Balding, Leanne C.; Johnston, Colin I.

doi:10.1161/01.hyp.36.6.1105

Cited by 31 publications

(25 citation statements)

References 50 publications

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“…These results are in line with some reports that demonstrated a greater natriuretic response of VPI in experimental CHF (9,20,32) compared with other conventional agents, such as ACE inhibitors. Administration of OMP into dogs with experimental heart failure induced by ventricular pacing pro- Fig.…”

Section: Discussionsupporting

confidence: 92%

Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Abassi

Yahia²,

Zeid³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure. Am J Physiol Heart Circ Physiol 288: H722-H728, 2005. First published October 21, 2004 doi:10.1152/ ajpheart.00737.2004 is a novel mixed inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), the enzyme that metabolizes natriuretic peptides. Congestive heart failure (CHF) is characterized by excessive sodium retention, attributed to both an excessive effect of angiotensin II and diminished responsiveness to natriuretic peptides. In this study, we examined the acute and chronic renal and cardiac effects of OMP in rats with compensated [urinary sodium excretion (U NaV) Ͼ 1,200 eq/day] and decompensated (U NaV Ͻ 100 eq/day) CHF, induced by a surgical aortocaval fistula (ACF). Bolus injection of OMP (10 mg/kg) to sham controls produced significant diuretic and natriuretic responses [U NaV increased from 0.67 Ϯ 0.19 to 3.27 Ϯ 1.35 eq/min, P Ͻ 0.05; fractional sodium excretion (FE Na) increased from 0.23 Ϯ 0.06 to 0.95 Ϯ 0.34%, P Ͻ 0.01] despite a significant decline in blood pressure (BP). Rats with compensated CHF displayed blunted diuresis and natriuresis to this dose of OMP but a significant decrease in BP. However, in rats with decompensated CHF, OMP induced significant natriuresis (FE Na increased from 0.18 Ϯ 0.15 to 0.82 Ϯ 0.26%, P Ͻ 0.05) despite a further decrease in BP (from 90 Ϯ 9 to 71 Ϯ 6 mmHg, P Ͻ 0.01). Two weeks after ACF, the heart/body weight ratio was significantly greater in rats with CHF than controls (0.51 Ϯ 0.026 vs. 0.30 Ϯ 0.004%, P Ͻ 0.0001), and U NaV was significantly lower. Immediate or late (1 or 6 days after ACF) OMP treatment in the drinking water (140 mg/l) reduced cardiac hypertrophy to 0.41-0.43% (P Ͻ 0.01) and induced natriuresis. These results suggest that OMP improves both sodium balance and cardiac remodeling and might be advantageous to ACE inhibitors for the treatment of decompensated CHF. cardiac hypertrophy; renal function; rat; angiotensin-converting enzyme inhibitor; neutral endopeptide inhibitor

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Section: Discussionsupporting

confidence: 92%

Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Abassi

Yahia²,

Zeid³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…23 Our results are consistent with the previous findings 33 reporting that ACE inhibitors did not improve fractional LV shortening but attenuated myocardial hypertrophy and remodeling in this experimental model. 34,35 A new pharmacological mechanism of action for ACE inhibitors has recently been proposed, based on the observations that ACE also degradates Ang- (1-7). 36, 37 Ferrario's group found a significant increase in ACE2 mRNA levels after AT1-blockade for 4 weeks in rats after myocardial infarction.…”

Section: Discussionmentioning

confidence: 99%

Enalapril Attenuates Downregulation of Angiotensin-Converting Enzyme 2 in the Late Phase of Ventricular Dysfunction in Myocardial Infarcted Rat

et al. 2006

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Abstract-The early and long-term effects of coronary artery ligation on the plasma and left ventricular angiotensinconverting enzyme (ACE and ACE2) activities, ACE and ACE2 mRNA levels, circulating angiotensin (Ang) levels [Ang I, Ang-(1-7), Ang-(1-9), and Ang II], and cardiac function were evaluated 1 and 8 weeks after experimental myocardial infarction in adult Sprague Dawley rats. Sham-operated rats were used as controls. Coronary artery ligation caused myocardial infarction, hypertrophy, and dysfunction 8 weeks after surgery. At week 1, circulating Ang II and Ang-(1-9) levels as well as left ventricular and plasma ACE and ACE2 activities increased in myocardial-infarcted rats as compared with controls. At 8 weeks post-myocardial infarction, circulating ACE activity, ACE mRNA levels, and Ang II levels remained higher, but plasma and left ventricular ACE2 activities and mRNA levels and circulating levels of Ang-(1-9) were lower than in controls. No changes in plasma Ang-(1-7) levels were observed at any time. Enalapril prevented cardiac hypertrophy and dysfunction as well as the changes in left ventricular ACE, left ventricular and plasmatic ACE2, and circulating levels of Ang II and Ang-(1-9) after 8 weeks postinfarction. Thus, the decrease in ACE2 expression and activity and circulating Ang-(1-9) levels in late ventricular dysfunction post-myocardial infarction were prevented with enalapril. These findings suggest that in this second arm of the renin-angiotensin system, ACE2 may act through Ang-(1-9), rather than Ang-(1-7), as a counterregulator of the first arm, where ACE catalyzes the formation of Ang II. Key Words: angiotensin-converting enzyme Ⅲ myocardial infarction Ⅲ renin-angiotensin system Ⅲ remodeling Ⅲ cardiac function T he renin-angiotensin system (RAS) is a more complex system than originally thought. A new angiotensin-converting enzyme (ACE), ACE2, has been recently identified as a homologue of ACE. 1 ACE2 is also a metalloprotease consisting of 805 amino acids with a considerable degree of homology to ACE (40% identity and 61% similarity). 2,3 ACE2 contains a single zinc-binding domain and is a carboxypeptidase, unlike somatic ACE, which contains 2 zinc-binding domains and is a dipeptidyl carboxypeptidase. 2 Both ACE2 and ACE are bound to the plasma membrane and must be cleaved to release the soluble enzyme. 2 Their cellular and tissue distributions are also different, in that ACE is expressed in the endothelium throughout the vasculature, whereas ACE2 is distributed to most tissues, including to the heart and kidney. 3 Analyses in vitro have shown that ACE2 cleaves angiotensin (Ang) I to Ang-(1-9), which is then cleaved by ACE to Ang-(1-7). However, ACE2 also cleaves Ang II to form Ang-(1-7). Because Ang-(1-7) is a potent vasodepressor peptide, its actions could counterbalance the vasopressor effect of Ang II. 4,5 ACE2 does not act on bradykinins and its activity is not inhibited by ACE inhibitors. 2 Although a significant activation of the RAS system occurs after myocardial infarction, 6 -10 ...

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“…Although the lung weight of the treated rats was not reversed to the normal level, chronic NEP inhibition appears to have a beneficial effect on pulmonary congestion caused by CHF. Burrell et al (2000) reported that S21402, a vasopeptidase inhibitor, may offer several advantages, such as enhanced sodium and water excretion and relief of pulmonary congestion in rats with CHF. Considering these observations, we suggest that sampatrilat prevented worsening of the symptoms of CHF, at least in part, due to chronic inhibition of NEP activity.…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Sampatrilat, a Novel Vasopeptidase Inhibitor, on Cardiac Remodeling and Function of Rats with Chronic Heart Failure following Left Coronary Artery Ligation

Maki¹,

Nasa²,

Tanonaka³

et al. 2002

J Pharmacol Exp Ther

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Beneficial Renal and Cardiac Effects of Vasopeptidase Inhibition With S21402 in Heart Failure

Cited by 31 publications

References 50 publications

Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Enalapril Attenuates Downregulation of Angiotensin-Converting Enzyme 2 in the Late Phase of Ventricular Dysfunction in Myocardial Infarcted Rat

Beneficial Effects of Sampatrilat, a Novel Vasopeptidase Inhibitor, on Cardiac Remodeling and Function of Rats with Chronic Heart Failure following Left Coronary Artery Ligation

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