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

Abstract

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 (AT1) receptor, and upregulation of the plasma ANP concentration and cardiorenal expression of ANP, ACE2, Mas receptor, and AT2 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-AT1 receptor pathway and NHE3, accentuation of the antihypertensive ACE2-Mas axis/AT2 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.

Herbal medicine (Oryeongsan) for fluid and sodium balance in renal cortex of spontaneously hypertensive rats

“… 9 , 10 , 11 The present study showing an antihypertensive effect of ORS through modulation of the RAS-NHE3 signaling in the renal cortex supports the previous observations in the Goldblatt hypertensive rats. 6 Activation of ACE-AT 1 receptor-NHE3 signaling pathway induces anti-natriuresis, Na + accumulation, and hypertension. In contrast, activation of the Ang III-AT 2 receptor pathway is antagonistic to the ACE-AT 1 receptor activation in general and AT 2 receptor-NHE3 signaling induces natriuresis and lowering of SBP.…”

“…Although the etiology of the rise of hypertension is different between Goldblatt hypertensive rats, an animal model of human secondary hypertension, and SHR hypertensive rats, an animal model of human essential hypertension, the effects of ORS are similar in both experimental models. We studied the effects of ORS on the body fluid and Na + metabolism in association with the RAS and NPS in the Goldblatt hypertensive rats 6 and SHR (present study). The reason of the similar effects of ORS in both models of hypertension may be that the animal models are renin-dependent hypertensive models 6 , 34 , 35 and major mechanism of action of ORS are modulation of the renin-angiotensin system.…”

“…RT PCR analysis was performed as previously reported. 6 , 22 Total RNA of the cortex of the right kidney was extracted using TRIzol reagent (Ambion, Carlsbad, CA, USA) according to the manufacturer's instructions. cDNA was synthesized using the High Capacity RNA-to-cDNA kit (Applied Biosystems, Waltham, MA, USA).…”

“…Data normalization of the gene expression was conducted by StepOne™ software version 2.3 (Applied Biosystems, Waltham, MA, USA). The specific sense and antisense primers used were as follows: 6 , 22 AT 1 receptor: S(5′-CTC AAG CCT GTC TAC GAA AAT GAG-3′), A(5′-TAG ATC CTG AGG CAG GGT GAA T-3′); AT 2 receptor: S(5′-GAA TCC CTG GCA AGC ATC TTA T-3′), A(5′-ATG TTG GCA ATG AGG ATA GAC AAG-3′); Mas receptor: S(5′-GGA TGC CAG AAT TGA ACA CAG A-3′), A(5′-CAC TGG CCC TCC TGA A-3′); ACE: S(5′-GGG CAT TGA CCT AGA GAC TGA TG-3′), A(5′-CTT GGG CTG TCC GGT CAT AC-3′); ACE2: S(5′-ACC AAA GCA TTA AAG TGA GGA TAA G-3′), A(5′- GTT GGT CCA TTC ATA TGC ATT-3′); NHE3: S(5′-CTG AGG AAC CGA GCA-3′), A(5′-AGG CCC AGA ACG ATG AGT AG-3′); ANP: S(5′- GAG AAG ATG CCG GTA G-3′), A(5′-CTA GAG AGG GAG CTA AGT G-3′); NPR-C: S(5′-TTC TGG CTT TGC ATG AAG TG-3′), A(5′-ATT TTG AAC CGG CCT TCT TT-3′); GAPDH: S(5′-GTC GGT GTG AAC GGA TTT G-3′), A(5′-CTT GCC GTG GGT AGA GTC AT-3′).…”

“…The beneficial effects of the treatment with ORS in the Goldblatt model of renovascular (Goldblatt) hypertensive rats, promotion of the renal function including natriuresis, diuresis, and decrease in systolic blood pressure (SBP), were accompanied by modulation of the RAS and NPS. 6 Chronic treatment with ORS decreased abundance of Na + /H + exchanger 3 (NHE3) gene expression along with a suppression of ACE-AT 1 receptor and concurrent accentuation of AT 2 receptor/ACE2-Mas receptor pathway in the cortex of the kidney from Goldblatt hypertensive rats. It was also shown that chronic treatment with ORS powder decreased SBP in Goldblatt hypertensive rats and SHR 7 , 8 with a decrease in plasma levels of renin activity (PRA), Ang II, aldosterone, and a decrease in AT 1 receptor gene expression and an increase in ACE2 expression in the ventricular myocardium.…”