Cardiorenal protective effects of vasopeptidase inhibition with omapatrilat in hypertensive transgenic (mREN-2)27 rats.
Vasopeptidase inhibitors simultaneously inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of this study was to determine the cardiorenal effects of the vasopeptidase inhibitor omapatrilat in the transgenic m(Ren-2)27 rat which exhibits fulminant hypertension and severe organ pathology. At 6 weeks of age, male Ren-2 rats were randomized to receive no treatment (N = 10), the ACE inhibitor fosinopril 10 mg/kg/day (N = 10), or omapatrilat 10 mg/kg/day (N = 10) or 40 mg/kg/day (N = 10) by daily gavage for 24 weeks. Various cardiorenal functional and structural parameters were assessed. Compared to controls, all treatment groups reduced hypertension in control Ren-2 rats, with both doses of omapatrilat reducing systolic blood pressure significantly more than fosinopril (control, 178 +/- 3 mmHg; fosinopril 10 mg/kg/day, 130 +/- 4 mmHg; omapatrilat 10 mg/kg/day, 110 +/- 3 mmHg; omapatrilat 40 mg/kg/day, 91 +/- 3 mmHg). Omapatrilat dose-dependently reduced cardiac hypertrophy, caused a greater inhibition of renal ACE than fosinopril, and was the only treatment to inhibit renal NEP. Attenuation of albuminuria, glomerulosclerosis and cardiorenal fibrosis occurred to a similar degree with omapatrilat and fosinopril. Omapatrilat confers cardiorenal protection in the hypertensive Ren-2 rat. Although inhibition of tissue NEP may contribute to the superior blood pressure reduction by omapatrilat, overall, the results are consistent with the central role that angiotensin II plays in renal and cardiac fibrosis in this model of hypertension.
Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia.
Sally A
SA
Mifsud
Louise M
LM
Burrell
Eiji
E
Kubota
Kassie
K
Jaworski
Mark E
ME
Cooper
Jennifer L
JL
Wilkinson-Berka
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017328:Fosinopril / Q000008:administration & dosage / Q000009:adverse effects; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology* / Q000401:mortality; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008955:Models, Cardiovascular; D015260:Neprilysin / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats / Q000235:genetics; D012083:Renin / Q000097:blood / Q000187:drug effects; D013223:Statistics as Topic; D016019:Survival Analysis; D013599:Systole / Q000187:drug effects; D013841:Thiazepines / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D015415:Biomarkers; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D012083:Renin; D015260:Neprilysin; D017328:Fosinopril