Amelioration of Hypertension by Oryeongsan through Improvements of Body Fluid and Sodium Balance: Roles of the Renin-Angiotensin System and Atrial Natriuretic Peptide System

Oryeongsan (Wulingsan in China and Goreisan in Japan), a formula composed of five herbal medicines, has long been used for the treatment of imbalance of the body fluid homeostasis in Asian countries. However, the mechanism by which Oryeongsan (ORS) improves the impaired body fluid and salt metabolism is not clearly defined. The present study was performed to define the role of the cardiorenal humoral system in the ORS-induced changes in blood pressure and renal function in hypertension. Experiments were performed in normotensive and two-kidney, one-clip hypertensive rats. Changes in the fluid and salt balance were measured in rats individually housed in metabolic cages. Changes in the systemic and local renin-angiotensin system (RAS) and cardiac natriuretic peptide hormone system (NPS) were evaluated. ORS water extract was administered by oral gavage (100 mg/kg daily) for 3 weeks. ORS induced diuresis and natriuresis along with an increase in glomerular filtration rate and downregulation of the Na+/H+ exchanger 3 (NHE3) and aquaporin 2 expression in the renal cortex and medulla, respectively. Furthermore, treatment with ORS significantly decreased systolic blood pressure with contraction of body sodium and water accumulation in hypertensive rats. ORS-induced changes were accompanied by modulation of the RAS and NPS, downregulation of the systemic RAS and cardiorenal expression of angiotensin-converting enzyme (ACE) and angiotensin II subtype 1 (AT(1)) receptor, and upregulation of the plasma ANP concentration and cardiorenal expression of ANP, ACE2, Mas receptor, and AT(2) receptor. These findings indicate that ORS induces beneficial effects on the high blood pressure through modulation of the RAS and NPS of the cardiorenal system, suppression of the prohypertensive ACE-AT(1) receptor pathway and NHE3, accentuation of the antihypertensive ACE2-Mas axis/AT(2) receptor pathway in the kidney, suppression of the systemic RAS, and elevation of the plasma ANP levels and its synthesis in the heart. The present study provides a biological basis for the use of ORS in the treatment of impaired volume and pressure homeostasis.