Cardiac hypertrophy can lead to congestive heart failure and is a leading cause of morbidity and mortality worldwide. In recent years, it has been essential to find the treatment and prevention of cardiac hypertrophy. Betulinic acid (BA), the main active ingredient in many natural products, is known to have various physiological effects. However, as the potential effect of BA on cardiac hypertrophy and consequent renal dysfunction is unknown, we investigated the effect of BA on isoprenaline (ISO)-induced cardiac hypertrophy and related signaling. ISO was known to induce left ventricular hypertrophy by stimulating the β2-adrenergic receptor (β₂AR). ISO was injected into Sprague Dawley rats (SD rats) by intraperitoneal injection once a day for 28 days to induce cardiac hypertrophy. From the 14th day onwards, the BA (10 or 30 mg/kg/day) and propranolol (10 mg/kg/day) were administered orally. The study was conducted in a total of 5 groups, as follows: C, control; Is, ISO (10 mg/kg/day); Pr, positive-control, ISO + propranolol (10 mg/kg/day); Bl, ISO + BA (10 mg/kg/day); Bh, ISO + BA (30 mg/kg/day). As a result, the total cardiac tissue and left ventricular tissue weights of the ISO group increased compared to the control group and were significantly reduced by BA treatment. In addition, as a result of echocardiography, the effect of BA on improving cardiac function, deteriorated by ISO, was confirmed. Cardiac hypertrophy biomarkers such as β-MHC, ANP, BNP, LDH, and CK-MB, which were increased by ISO, were significantly decreased by BA treatment. Also, the cardiac function improvement effect of BA was confirmed to improve cardiac function by inhibiting calcineurin/NFATc3 signaling. Renal dysfunction is a typical complication caused by cardiac hypertrophy. Therefore, the study of renal function indicators, creatinine clearance (Ccr) and osmolality (BUN) was aggravated by ISO treatment but was significantly restored by BA treatment. Therefore, it is thought that BA in cardiac hypertrophy can be used as valuable data to develop as a functional material effective in improving cardiac-renal dysfunction.

The Vitis labrusca is a grapevine that has antioxidant, neuroprotective, hepatoprotective, and anticarcinogenic activity. However, the effect of Vitis labrusca leaves on the cardiovascular system is yet to be ascertained. The present study was designed to investigate the effects of Vitis labrusca leaves extract (HP1) on cardiovascular remodeling in spontaneously hypertensive rats. Experiments were performed in rats and were randomly divided into the following groups: Wistar Kyoto rat (WKY), normal control group; spontaneously hypertensive rats (SHR), negative control group; SHR + Losa, positive control group (losartan, 10 mg/kg/daily, AT₁ receptor blocker) and SHR + HP1 (100 mg/kg/daily). HP1 was orally administered daily for 4 weeks. The HP1 treatment significantly improved blood pressure, electrocardiographic parameters, and echocardiogram parameters compared to hypertensive rats. Additionally, the left ventricular (LV) remodeling and LV dysfunction were significantly improved in HP1-treated hypertensive rats. Furthermore, an increase in fibrotic area has been observed in hypertensive rats compared with WKY. However, administration of HP1 significantly attenuated cardiac fibrosis in hypertensive rats. Moreover, HP1 suppressed the expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), receptor for advanced glycation end products (RAGE), and extracellular signal-regulated kinases (ERK1/2) induced by hypertensive rats, resulting in improved vascular remodeling. Therefore, these results suggest that HP1 can improve the cardiovascular remodeling in hypertensive rats, and the mechanisms may be related to the suppressive effect of HP1 on HMGB1-TLR4-NFκB signaling in the cardiovascular system. Thus, the protective role of the traditional herbal medicine HP1 may provide new insights into the development of therapeutic drugs on the development of hypertensive cardiovascular dysfunction.

Oryeongsan (ORS), a herbal medicine formula, has long been used for the treatment of impaired body water balance in Asian countries. Recently, it was shown that ORS administration modulates the renin-angiotensin system (RAS). Purpose of the present study was to determine characteristics of atrial ANP secretion and effects of ORS on the secretion in the atria from spontaneously hypertensive rats (SHR). Normotensive WKY groups (WKY-V, WKY-ORS, WKY-LOS) and hypertensive SHR groups (SHR-V, SHR-ORS, SHR-LOS) treated with vehicle, ORS, and losartan as a positive control group, respectively, were used. Experiments were performed in perfused beating atria (1.3 Hz) allowing atrial distension, acetylcholine (ACh) stimulation, and serial collection of atrial perfusates. The secreted ANP concentration was measured using radioimmunoassay. Interstitial fluid (ISF) translocation was measured using [³H]inulin clearance. Stepwise increase in atrial distension by 1.1, 2.0, and 2.7 cmH₂O above basal distension further increased ANP secretion proportionally in the atria from WKY-V, but the response was significantly suppressed in the atria from SHR-V. Cardiomyocyte ANP release, the first step of atrial ANP secretion, was suppressed in the atria from SHR-V compared to those from WKY-V (-8.02 ± 2.86, -15.86 ± 2.27, and -20.09 ± 3.62%; n = 8, for SHR-V vs. 8.59 ± 2.81, 15.65 ± 7.14, and 38.12 ± 8.28%; n = 8, for WKY-V; p < 0.001 for all stepwise distension, respectively). Chronic treatment with ORS reversed the suppressed ANP release in atria from SHR-ORS group (6.76 ± 3.92, 9.12 ± 2.85, and 28.79 ± 1.79% for SHR-ORS; n = 5 vs. SHR-V; n = 8; p = 0.01, p < 0.001, p < 0.001, respectively). The effects of ORS were comparable to those of losartan. Trans-endocardial translocation of ISF, the second step of atrial ANP secretion was similar in the atria from the hypertensive SHR-V and normotensive WKY-V. ACh-induced ANP secretion and cardiomyocyte ANP release were also suppressed in the atria from SHR-V compared to WKY-V and ORS reversed the suppression. These findings were accompanied with accentuation of the AT₁ receptor expression and suppression of the AT₂/Mas receptor, M₂ mACh receptor and GIRK4, a molecular component of K_ACh channel, expression in the atria from SHR-V. Further, treatment with ORS or losartan reversed the expressions in the groups of SHR-ORS and SHR-LOS. These results show that ANP secretion is suppressed in the atria from SHR in association with accentuation of AT₁ receptor and suppression of AT₂/Mas receptor and K_ACh channel expression. Treatment with ORS ameliorates impaired ANP secretion through improving cardiomyocyte ANP release with modulation of the cardiac RAS and muscarinic signaling. These findings provide experimental evidence which supports the effect of ORS on the regulation of atrial ANP secretion in the atria from SHR.

Myocardial infarction (MI) is a leading cause of heart failure, characterized by adverse cardiac remodeling. This study evaluated the cardioprotective potential of Dohongsamul-tang (DHT), a traditional Korean herbal formula, in a rat model of MI-induced heart failure. Rats underwent left anterior descending (LAD) artery ligation and were treated with either 100 mg/kg or 200 mg/kg of DHT daily for 8 weeks. DHT treatment significantly improved cardiac function, as evidenced by increased ejection fraction (EF) from 62.1% to 70.1% (100 mg/kg) and fractional shortening (FS) from 32.3% to 39.4% (200 mg/kg) compared to the MI control group. Additionally, DHT reduced infarct size by approximately 63.3% (from 60.0% to 22.0%) and heart weight by approximately 16.7% (from 3.6 mg/g to 3.0 mg/g), and significantly decreased levels of heart failure biomarkers: LDH was reduced by 37.6% (from 1409.1 U/L to 879.1 U/L) and CK-MB by 47.6% (from 367.3 U/L to 192.5 U/L). Histological analysis revealed a reduction in left ventricle (LV) fibrosis by approximately 50% (from 24.0% to 12.0%). At the molecular level, DHT inhibited the expression of phospho-JAK by 75% (from 2-fold to 0.5-fold), phospho-STAT3 by 30.8% (from 1.3-fold to 0.9-fold), Bax/Bcl-2 by 56.3% (from 3.2-fold to 1.4-fold), and caspase-3 by 46.3% (from 1.23-fold to 0.66-fold). These results suggest that DHT exerts cardioprotective effects by modulating the JAK/STAT3 signaling pathway, highlighting its potential as a therapeutic option for heart failure.

In this study, we evaluated the effect of a traditional herbal formula, Ma Huang Tang (MHT), on blood pressure and vasodilation in a rat model of N^GnitroLarginine methylester- (L-NAME-) induced hypertension. We found that MHT-induced vascular relaxation in a dose-dependent manner in rat aortas pretreated with phenylephrine. However, pretreatment of endothelium-intact aortic rings with LNAME, an inhibitor of nitric oxide synthesis (NOS), or 1H[1, 2, 4]oxadiazole[4, 3α]quinoxalin1one (ODQ), an inhibitor of soluble guanylyl cyclase, significantly abolished vascular relaxation induced by MHT. MHT also increased the production of guanosine 3,5-cyclic monophosphate (cGMP) in the aortic rings pretreated with L-NAME or ODQ. To examine the in vivo effects of MHT, Sprague Dawley rats were treated with 40mg/kg/day L-NAME for 3 weeks, followed by administration of 50 or 100mg/kg/day MHT for 2 weeks. MHT was found to significantly normalize systolic blood pressure and decreased intima-media thickness in aortic sections of rats treated with L-NAME compared to that of rats treated with L-NAME alone. MHT also restored the L-NAME-induced decrease in vasorelaxation response to acetylcholine and endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) expression. Furthermore, MHT promoted the recovery of renal function, as indicated by osmolality, blood urea nitrogen (BUN) levels, and creatinine clearance. These results suggest that MHT-induced relaxation in the thoracic aorta is associated with activation of the nitric oxide/cGMP pathway. Furthermore, it provides new therapeutic insights into the regulation of blood pressure and renal function in hypertensive patients.