Author: Tom Bäcklund ; Markku S Nieminen ; Eeva Palojoki ; Anders Eriksson ; Antti Saraste ; Päivi Lakkisto ; Ilkka Tikkanen ; Olli Vuolteenaho ; Liisa-Maria Voipio-Pulkki ; Tina Grönholm ; Mika Laine

We have shown earlier that cardiomyocyte apoptosis continues at a high level late after myocardial infarction and contributes to adverse cardiac remodeling. Here we studied whether this process can be inhibited by the vasopeptidase inhibitor omapatrilat, a drug which causes simultaneous inhibition of both angiotensin converting enzyme and neutral endopeptidase. Our hypothesis was that omapatrilat-treated rats would have less cardiomyocyte apoptosis, and less adverse cardiac remodeling compared to rats treated with selective inhibitors of angiotensin converting enzyme, neutral endopeptidase or placebo. Myocardial infarction was produced by ligation of the left anterior descending coronary artery. Rats were randomized to receive omapatrilat, captopril, neutral endopeptidase inhibitor SQ-28603 or vehicle. Rats treated with omapatrilat and captopril had reduced cardiac BNP mRNA levels and less myocardial fibrosis by comparison with the vehicle-treated rats. However, omapatrilat was more effective than captopril in attenuating hypertrophy as measured by relative cardiac weight (3.0+/-0.2 vs. 3.8+/-0.2 mg/g, P<0.01) or by echocardiographically determined left ventricular mass (0.61+/-0.05 vs. 0.83+/-0.06 g, P<0.01). Myocardial apoptosis was elevated both in the infarction border zone (0.129+/-0.017%) and in the remote area (0.035+/-0.005%) still 4 weeks after myocardial infarction. Angiotensin converting enzyme inhibition proved to be important in the prevention of apoptosis since both omapatrilat and captopril reduced the number of apoptotic myocytes whereas selective neutral endopeptidase inhibitor SQ-28603 had no effect. In conclusion, myocardial apoptosis, remaining increased 4 weeks after myocardial infarction, was reduced by angiotensin converting enzyme inhibition. Vasopeptidase inhibition was more effective than selective angiotensin converting enzyme inhibition in preventing adverse cardiac remodeling after myocardial infarction.

01 Sep 1999·General Pharmacology: The Vascular System

Renal effects of 2-mercaptoacetyl-L-leucyl-L-phenylalanine, a novel selective inhibitor of neutral endopeptidase 24.11 (Neprilysin) Comparison with SQ 28,603

Article

Author: Ella Fudim ; Aviva Kaballa ; Konstantin Gurbanov ; Joseph Winaver ; Shmaryahu Blumberg ; Eva Shuranyi

The effects of 2-mercaptoacetyl-L-leucyl-L-phenylalanine (MA-LF) on the activity of neutral endopeptidase and on renal hemodynamics and excretory function were investigated in experiments in vitro and in vivo. In vitro studies showed that the compound effectively inhibited purified bovine kidney neutral endopeptidase (Ki = 0.012 microM), while having slight influence on the activity of angiotensin I converting enzyme (Ki = 0.14 microM). In experiments on normal anesthetized rats (thiobutabarbital sodium salt, 100 mg/kg), IV administration of MA-LF (20 and 60 mg/kg) produced a dose-dependent increase in absolute rate and fractional excretion of sodium (+324% and +299%, respectively) and urinary flow rate (+261%), but did not change renal and systemic hemodynamics. Renal excretory effects of the new compound were comparable to those of the selective neutral endopeptidase inhibitor SQ 28,603. These results demonstrate that MA-LF is a potent neutral endopeptidase inhibitor with prominent natriuretic and diuretic properties.

03 Dec 1997·Inflammation ResearchQ3 · MEDICINE

Neutral endopeptidase degrades endothelins in guinea pig tracheal epithelial cells

Q3 · MEDICINE

Article

Author: T. Kawaguchi ; Q. Yang ; B. Battistini ; P. Sirois

Over a period of 24 h, immunoreactive endothelin (ir-ET) was constantly released from guinea pig tracheal epithelial cells in serum-free culture.After 24 h, 1938 pg ET-1/mg protein but no ET-2 or ET-3 measured by HPLC were released.Phosphoramidon decreased the release of ir-ET by 76 and 86% after 6 and 10 h, resp.Conversely, the neutral endopeptidase inhibitors thiorphan and SQ28603 increased the release by 50 and 73% and 113 and 77%, resp. after 6 and 10 h.

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Hypertension	Discovery	US	Squibb Group Ltd.	-

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