Salt-Induced Cardiac Hypertrophy and Interstitial Fibrosis Are Due to a Blood Pressure–Independent Mechanism in Wistar Rats

Abstract

High salt intake is a known cardiovascular risk factor and is associated with cardiac alterations. To better understand this effect, male Wistar rats were fed a normal (NSD: 1.3% NaCl), high 4 (HSD4: 4%), or high 8 (HSD8: 8%) salt diet from weaning until 18 wk of age. The HSD8 group was subdivided into HSD8, HSD8+HZ (15 mg . kg(-1) . d(-1) hydralazine in the drinking water), and HSD8+LOS (20 mg . kg(-1) . d(-1) losartan in the drinking water) groups. The cardiomyocyte diameter was greater in the HSD4 and HSD8 groups than in the HSD8+LOS and NSD groups. Interstitial fibrosis was greater in the HSD4 and HSD8 groups than in the HSD8+HZ and NSD groups. Hydralazine prevented high blood pressure (BP) and fibrosis, but not cardiomyocyte hypertrophy. Losartan prevented high BP and cardiomyocyte hypertrophy, but not fibrosis. Angiotensin II type 1 receptor (AT(1)) protein expression in both ventricles was greater in the HSD8 group than in the NSD group. Losartan, but not hydralazine, prevented this effect. Compared with the NSD group, the binding of an AT(1) conformation-specific antibody that recognizes the activated form of the receptor was lower in both ventricles in all other groups. Losartan further lowered the binding of the anti-AT(1) antibody in both ventricles compared with all other experimental groups. Angiotensin II was greater in both ventricles in all groups compared with the NSD group. Myocardial structural alterations in response to HSD are independent of the effect on BP. Salt-induced cardiomyocyte hypertrophy and interstitial fibrosis possibly are due to different mechanisms. Evidence from the present study suggests that salt-induced AT(1) receptor internalization is probably due to angiotensin II binding.

High-Salt Intake Induces Cardiomyocyte Hypertrophy in Rats in Response to Local Angiotensin II Type 1 Receptor Activation

“…The dose of HZ and LOS was corrected by the body weight on a weekly basis. All doses were based on previous studies (9,27).…”

“…The ingestion of large amounts of sodium chloride [NaCl (salt)] was identified as an important contributor to CH (6). Although numerous clinical and experimental studies have detected its hypertensive effect (7,8), salt can also induce CH independent of its hemodynamic effects (7,9). Therefore, many studies have attempted to elucidate the mechanisms by which salt induces CH.…”

“…A previous study in our laboratory (9) found that dietary salt overload induced blood pressure (BP)-independent CH and increased left ventricular mass and interstitial fibrosis (IF). There was a decrease in plasma renin activity and serum aldosterone in all rats that were administered dietary salt overload, suggesting that the circulating RAS may not be involved in the development of CH.…”

“…One of the pathways more closely related to CH is RAS, and it is well established that all RAS components are locally synthesized in the cardiac tissue (10)(11)(12)(13). These components are distributed in cardiomyocytes, fibroblasts, and endothelial and vascular smooth muscle cells, and, interestingly, are regulated independently of circulating RAS (9,14).…”

Sodium, Left Ventricular Mass, and Arterial Hypertension

“…9 The other component that might facilitate the effect of Na ϩ /K ϩ balance on development of LV hypertrophy is the stimulating effect of high Na ϩ intake to increase angiotensin II type 1 receptor protein expression, 10 which can also at least in part explain the antihypertrophic effect of angiotensin II type 1 receptor blockade, even in rat models on high salt diet and normal or low circulating plasma renin. 11 Because high values of LV mass can precede the appearance of high cuff BP values, 2,12 alternative to a traditional view, the study by Rodriguez et al 6 also suggests different pathways, including potential reverse causation of the association between high BP and LV mass (Figure).…”