Effect of dual angiotensin converting enzyme/neutral endopeptidase inhibition, angiotensin converting enzyme inhibition, or AT1 antagonism on coronary microvasculature in spontaneously hypertensive rats

Abstract

Microvascular remodeling contributes to increased cardiovascular risk in hypertension. The dual angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitor omapatrilat improves small artery remodeling in hypertension. The aim of the present study was to compare effects of omapatrilat to the ACE inhibitor fosinopril and the AT(1) antagonist irbesartan on the coronary microvasculature in spontaneously hypertensive rats (SHR). Ten-week-old SHR were treated for 10 weeks with omapatrilat (20 or 40 mg/kg/d), irbesartan (50 mg/kg/d), or fosinopril (20 mg/kg/d). Arterioles and capillaries were identified in the myocardium by immunolabeling. After 10 weeks, systolic blood pressure (BP) was significantly reduced in treated versus untreated SHR (P <.01). Myocardial arteriolar density/mm(2) was higher (P <.05) in untreated SHR versus Wistar-Kyoto (WKY), and was reduced by omapatrilat (at both high and low doses) and by fosinopril (P <.01). Irbesartan decreased only subepicardial arteriolar density (P <.05). Myocardial capillary density/mm(2) was decreased in untreated SHR versus WKY (P <.01), associated with increase in cardiomyocyte cross-sectional area and cardiomyocyte-to-capillary ratio, and a decrease in myocyte density. Omapatrilat (at both high and low doses) resulted in increased capillary density, decreased myocyte hypertrophy and cardiomyocyte to capillary ratio, and increased myocyte density (P <.01). Fosinopril and irbesartan reduced myocyte hypertrophy of SHR, but had no effect on capillary density. Dual ACE/NEP inhibition was more effective than ACE inhibition or AT(1) antagonism in improving microvascular and cardiomyocyte remodeling in the hypertensive heart. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.

The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease

“…Spontaneously hypertensive rats have been used as a model of genetic hypertension (Okamoto et al, 1966). Although generally considered to be characterized by low activity of the circulating RAS (Vincent et al, 1976;Kuriyama et al, 1982), several studies indicated that treatment with ACEIs and/or ARBs reduces cardiac and/or renal dysfunction in spontaneously hypertensive rats (Nakamura et al, 2001;Teng et al, 2002;Pu et al, 2003), suggesting that the intrarenal RAS may be inappropriately activated and in turn contribute to the development of hypertension and hypertension-induced renal damage in this animal model.…”

Hypertension

“…30 Experimental data concerning the myocardial microcirculation deserve a separate mention because of the concomitant myocardial hypertrophy. A reduced myocardial capillary density (ie, a smaller number of vessels per square millimeter of tissue cross-sectional area) has been largely documented in adult hypertensive animals, [37][38][39][40][41][42] possibly reflecting an inability of microcirculatory growth (through angiogenesis) to keep up with the progressive increase in myocardial mass and myocyte dimensions. In support of such interpretation, young spontaneously hypertensive rats (2.5 months, an age of fast growth in body dimensions with presumably more active angiogenesis than later in life) had a normal capillary density in their already hypertrophic left ventricle, whereas rarefaction was detected in older animals (7 months).…”

Erythropoietin Enhances Neovascularization of Ischemic Myocardium and Improves Left Ventricular Dysfunction After Myocardial Infarction in Dogs

“…The peroxidase was visualized by incubation with 3,3'-diaminobenzidine, followed by incubation with a DAB-enhancing solution (Dako). We counted the numbers of capillaries and cardiomyocytes in 20 random high-power fields (ϫ400 power), and then calculated the average capillary density and capillary-to-myocyte ratio (18). Measurements of regional MBF.…”