Effects of combined AT1 receptor antagonist/NEP inhibitor on vascular remodeling and cardiac fibrosis in SHRSP

J Hypertens. 2008 Feb;26(2):322-33. doi: 10.1097/HJH.0b013e3282f16aaf.

Abstract

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).

Methods and 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Animals
  • Antihypertensive Agents / pharmacology*
  • Blood Pressure / drug effects*
  • Drug Therapy, Combination
  • Endomyocardial Fibrosis / drug therapy
  • Endothelium, Vascular / drug effects
  • Hydralazine / pharmacology
  • Hypertension / drug therapy*
  • Male
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / pathology
  • Neprilysin / antagonists & inhibitors*
  • Rats
  • Rats, Inbred SHR
  • Rats, Wistar
  • Stroke / etiology
  • Tetrazoles / pharmacology*
  • Tyrosine / analogs & derivatives*
  • Tyrosine / pharmacology
  • Valine / analogs & derivatives*
  • Valine / pharmacology
  • Valsartan

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Antihypertensive Agents
  • N-((1-((2-(acetylthio)-3-methyl-1-oxobutyl)amino)-1-cyclopentyl)carbonyl)-O-methyl-L-tyrosine ethyl ester
  • Tetrazoles
  • Hydralazine
  • Tyrosine
  • Valsartan
  • Neprilysin
  • Valine