Effects of combined AT1 receptor antagonist/NEP inhibitor on vascular remodeling and cardiac fibrosis in SHRSP.
BACKGROUND
The association of an angiotensin-converting enzyme inhibitor (ACEI) with a neutral endopeptidase inhibitor (NEPI) has potent blood pressure (BP) lowering action, but is associated with side-effects. We evaluated the effects of combining an angiotensin II type 1 (AT1) receptor blocker (ARB, valsartan) and a NEPI (CGS 25354) in comparison with a dual ACEI/NEPI (CGS 30440) in stroke-prone spontaneously hypertensive rats (SHRSP).


RESULTS
Ten-week-old SHRSP were treated with valsartan (10 mg/kg per day), valsartan + CGS 25354 (100 mg/kg per day), CGS 25354, CGS 30440 (10 mg/kg per day) or hydralazine (25 mg/kg per day) for 10 weeks. Mesenteric resistance arteries were studied on a pressurized myograph, whereas cardiac effects were assessed by histology and immunohistochemistry. BP of SHRSP was lowered by combined valsartan/NEPI and ACEI/NEPI slightly more than valsartan, whereas NEPI was ineffective. Valsartan, valsartan/NEPI and ACEI/NEPI normalized resistance artery relaxation responses to acetylcholine, and significantly decreased media/lumen ratio and collagen deposition. All treatments decreased vascular NAD(P)H oxidase-mediated superoxide production. Valsartan/NEPI and ACEI/NEPI decreased media/lumen ratio of intramyocardial coronary arteries, while valsartan alone had no effect. Valsartan/NEPI and ACEI/NEPI increased vascular matrix metalloproteinase-2 activity, and decreased tissue inhibitors of metalloproteinase-2 activity and macrophage infiltration.


CONCLUSIONS
Combined valsartan/NEPI was almost as effective as a dual ACEI/NEPI in lowering BP and improving vascular remodeling in SHRSP. These findings suggest the potential therapeutic value of combining ARB and NEPI in the treatment of hypertension.
Pu
Qian
Q
Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Brassard
Pascal
P
Javeshghani
Danesh M
DM
Iglarz
Marc
M
Webb
Randy L
RL
Amiri
Farhad
F
Schiffrin
Ernesto L
EL
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004359:Drug Therapy, Combination; D004719:Endomyocardial Fibrosis / Q000188:drug therapy; D004730:Endothelium, Vascular / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D020521:Stroke / Q000209:etiology; D013777:Tetrazoles / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; C100918:N-((1-((2-(acetylthio)-3-methyl-1-oxobutyl)amino)-1-cyclopentyl)carbonyl)-O-methyl-L-tyrosine ethyl ester; D013777:Tetrazoles; D006830:Hydralazine; D014443:Tyrosine; D000068756:Valsartan; D015260:Neprilysin; D014633:Valine