Comparison of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP) and dual ACE/NEP inhibition on blood pressure and resistance arteries of deoxycorticosterone acetate-salt hypertensive rats.
OBJECTIVE
Omapatrilat, an inhibitor of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), is an effective antihypertensive agent. Here, we studied the relative roles of NEP and ACE inhibition and their effect on resistance artery structure and function of deoxycorticosterone acetate (DOCA)-salt hypertensive rats.


METHODS
Omapatrilat (40 mg/kg per day), the NEP inhibitor CGS 25462 (CGS, 100 mg/kg per day) and the ACE inhibitor enalapril (10 mg/kg per day), were given for 3 weeks to DOCA-salt hypertensive rats. Effects on small mesenteric resistance arteries were studied on a pressurized myograph. Collagen deposition was evaluated by confocal microscopy.


RESULTS
Systolic blood pressure of DOCA-salt rats was significantly reduced (P < 0.05) by omapatrilat and CGS. Omapatrilat and CGS treatment increased lumen diameter and decreased media width and media/lumen ratio of small arteries of DOCA-salt rats (P < 0.05). Small artery relaxation responses to acetylcholine improved under omapatrilat or CGS treatment. The stress-strain curve shifted leftward in mesenteric arteries from DOCA-salt rats compared to control rats. Omapatrilat or CGS treatment resulted in a rightward shift, which was significantly different from that induced by enalapril. Omapatrilat and CGS decreased collagen deposition in the vessel wall of DOCA-salt rats. Enalapril had no effect on blood pressure, vascular structure, endothelial function or collagen deposition in the vessel wall of DOCA-salt rats.


CONCLUSIONS
Dual inhibition of ACE/NEP in DOCA-salt hypertensive rats resulted in potent anti-hypertensive effects, prevented vascular remodelling and improved endothelial function of resistance arteries. NEP inhibition is involved to a large extent in the effect of omapatrilat in DOCA-salt rats. These actions of omapatrilat may confer protection against end-organ damage characteristic of severe hypertension.
Pu
Qian
Q
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Touyz
Rhian M
RM
Schiffrin
Ernesto L
EL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D003900:Desoxycorticosterone; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D063065:Organophosphonates / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D013599:Systole; D013841:Thiazepines / Q000627:therapeutic use*; D014655:Vascular Resistance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011725:Pyridines; D013841:Thiazepines; C086165:CGS 25462; C106266:omapatrilat; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D003094:Collagen; D015260:Neprilysin