Samchulkunbi-Tang Alleviates Vascular Endothelial Disorder and Renal Dysfunction in Nitric Oxide-Deficient Hypertensive Rats

Samchulkunbi-tang (SCT, Shen Zhu Jian pi tang in Chinese) is said to have been first recorded by Zheng Zhi Zhun Sheng during the Ming Dynasty in China. Records of SCT in Korea are known to have been cited in Donguibogam (Dong Yi Bao Jian in Chinese), Uibang Hwaltu (Yi Fang Huo Tao in Chinese), and Bang Yak Hapyeon (Fang Yao He Bian in China). Although SCT is widely used in treating chronic gastritis and gastric ulcers, the beneficial effect on renal vascular function is unknown. Hypertension is a risk factor for cardiovascular disease and endothelial dysfunction in humans and experimental animal models of arterial hypertension. In addition, kidney dysfunction is characterized by hypertension diseases. This study was conducted to evaluate the effect of SCT on the vascular function in vitro (human umbilical cord endothelial cells, HUVECs) and in vivo (NG‐nitro‐L‐arginine methyl ester, L-NAME-induced hypertensive rats). The phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) is closely related to nitric oxide (NO) production in HUVECs, and SCT in this study significantly increased these. For three weeks, hypertensive rat models were induced by L-NAME administration (40 mg/kg/day) with portable water. It was followed by oral administration with 100 and 200 mg/kg/day for two weeks to confirm the effectiveness of SCT. As a result, systolic blood pressure decreased in the SCT-treated groups, compared with that in the L-NAME-induced hypertensive group. SCT treatment restored vasorelaxation by stimulating acetylcholine and cGMP production in the thoracic aorta. In addition, SCT treatment decreased intima-media thickness, attenuated the reduction of eNOS expression, and increased endothelin-1 expression. It also increased p-Akt and p-eNOS expression in hypertensive rat aorta. Furthermore, regarding renal function parameters, SCT ameliorated urine osmolality, urine albumin level, serum creatinine, and blood urea nitrogen levels. These results demonstrate that the oriental medicine SCT exerts potent vascular and renal protective effects on nitric oxide-deficient hypertensive rats and HUVECs

Sympathetic Nerve Activity and Baroreflex are Strongly Altered in a Context of Severe Hypertension Using the Spontaneously Hypertensive Rat Model Associated with Chronic Reduction of Nitric Oxide

The aim of our study is to investigate the sympathetic output and baroreflex via renal sympathetic nerve activity (RSNA) recording in a model of severe hypertension which exhibits arterial, cardiac, and renal damages, the spontaneously hypertensive rat (SHR) under lowered NO bioavailability. SHR are treated from 18 to 20 weeks of age with a low dose of L-NAME, a NO synthase inhibitor, in drinking water (SHRLN) and compared to SHR and normotensive Wistar Kyoto (WKY) rats. After the two-week treatment, rats are anesthetized for RSNA, mean blood pressure (MBP), and heart rate (HR) recording. MBP is higher in SHR than in WKY and higher in SHRLN than in SHR. Compared to WKY, SHR displays an alteration in the baroreflex with a displacement of the sympathoinhibition curve to highest pressures; this displacement is greater in SHRLN rats. The bradycardic response is reduced in SHRLN compared to both SHR and WKY. In hypertensive rats, SHR and SHRLN, basal RSNA is modified, the maximal amplitude of burst is reduced, but minimal values are increased, indicating an increased basal RSNA with reduced bursting activity. The temporal correlation between RSNA and HR is preserved in SHR but altered in 10 SHRLN out of 10. The RSNA inhibition triggered by the Bezold–Jarisch reflex activation is not modified in hypertensive rats, SHR or SHRLN, in contrast to that triggered by the baroreflex. Histological analysis of the carotid bifurcation does not reveal any abnormality in SHRLN at the level of the carotid sinus. In conclusion, data indicate that the sympathetic outflow is altered in SHRLN with a strong reduction of the baroreflex sympathoinhibition and suggest that its central pathway is not involved. These additional results on SHRLN also confirm the usefulness of this model of severe hypertension with multiple target organ damages.

Combined antihypertensive effect of unripe Rubus coreanus Miq. and Dendropanax morbiferus H. Lév. Extracts in 1 kidney-1 clip hypertensive rats and spontaneously hypertensive rats

Background We previously showed that enzymatically hydrolyzed Dendropanax morbiferus H. Lév. leaf (Hy-DP) and unripe Rubus coreanus Miq. (5-uRCK) extracts exhibit potent vasodilator effects on isolated aortic rings from rats partly through endothelium-dependent and endothelium-independent mechanisms. These two extracts have different mechanisms of action; however, their combined effect on antihypertensive activity has not been explored. Methods The present study aims to investigate the effect of a chronic optimized mixture (HDR-2, composed of Hy-DP and 5-uRCK in a 2:1 mass ratio) on vascular tension and blood pressure in two different hypertensive rat models. Results The results showed that HDR-2 concentration-dependently relaxed endothelium-intact and endothelium-denuded aortic rings precontracted with phenylephrine. Antihypertensive effects were assessed in vivo on a 1 kidney-1 clip (1 K-1C) rat model of hypertension and spontaneously hypertensive rats (SHRs). Acute HDR-2 treatment significantly decreased systolic blood pressure (SBP) 3 h posttreatment in both models. Chronic HDR-2 administration also significantly decreased SBP in the hypertensive rat models. Moreover, HDR-2 increased eNOS protein expression and phosphorylation levels in the aorta. Conclusion Chronic HDR-2 administration may effectively improve vascular function by decreasing plasma angiotensin-converting enzyme (ACE) activity and AngII levels. HDR-2 significantly improved acetylcholine (ACh)-induced aortic endothelium-dependent relaxation and affected sodium nitroprusside (SNP)-induced endothelium-independent relaxation in SHRs.

Renin-Angiotensin System Induced Secondary Hypertension: The Alteration of Kidney Function and Structure

Long-term hypertension is known as a major risk factor for cardiovascular and chronic kidney disease (CKD). The Renin-angiotensin system (RAS) plays a key role in hypertension pathogenesis. Angiotensin II (Ang II) enhancement in Ang II-dependent hypertension leads to progressive CKD and kidney fibrosis. In the two-kidney one-clip model (2K1C), more renin is synthesized in the principal cells of the collecting duct than juxtaglomerular cells (JGCs). An increase of renal Ang I and Ang II levels and a decrease of renal cortical and medullary Ang 1–7 occur in both kidneys of the 2K1C hypertensive rat model. In addition, the activity of the angiotensin-converting enzyme (ACE) increases, while ACE2’s activity decreases in the medullary region of both kidneys in the 2K1C hypertensive model. Also, the renal prolyl carboxypeptidase (PrCP) expression and its activity reduce in the clipped kidneys. The imbalance in the production of renal ACE, ACE2, and PrCP expression causes the progression of renal injury. Intrarenal angiotensinogen (AGT) expression and urine AGT (uAGT) excretion rates in the unclipped kidney are greater than the clipped kidney in the 2K1C hypertensive rat model. The enhancement of Ang II in the clipped kidney is related to renin secretion, while the elevation of intrarenal Ang II in the unclipped kidney is related to stimulation of AGT mRNA and protein in proximal tubule cells by a direct effect of systemic Ang II level. Ang II-dependent hypertension enhances macrophages and T-cell infiltration into the kidney which increases cytokines, and AGT synthesis in proximal tubules is stimulated via cytokines. Accumulation of inflammatory cells in the kidney aggravates hypertension and renal damage. Moreover, Ang II-dependent hypertension alters renal Ang II type 1 & 2 receptors (AT1R & AT2R) and Mas receptor (MasR) expression, and the renal interstitial fluid bradykinin, nitric oxide, and cGMP response to AT1R, AT2R, or BK B2-receptor antagonists. Based on a variety of sources including PubMed, Google Scholar, Scopus, and Science-Direct, in the current review, we will discuss the role of RAS-induced secondary hypertension on the alteration of renal function.

Speckle Tracking Echocardiography Verified the Efficacy of Qianyangyuyin Granules in Alleviating Left Ventricular Remodeling in a Hypertensive Rat Model

Background. Global longitudinal strain (GLS) can be assessed by speckle tracking echocardiography (STE) to express the degree of cardiac fibrosis. Qianyangyuyin (QYYY) granules can effectively improve GLS in hypertensive patients. Using a hypertensive rat model, we carried out speckle tracking echocardiography to validate the effect of QYYY in diminishing LV remodeling. Methods. We randomly divided 16 spontaneously hypertensive rats (SHRs) into SHR, SHR + valsartan (SHR + V), SHR + low-dose QYYY (SHR + QL), and SHR + high-dose QYYY (SHR + QH) groups, with four rats in each group. Another group of 4 Wistar-Kyoto (WKY) rats were selected into a normal control (WKY) group. At the 8th week, conventional echocardiographic parameters were measured by GE Vivid E95 ultrasound (12S probe, 10–12 MHz) and GLS by speckle tracking echocardiography with EchoPAC (version 203) software. HE and Masson’s trichrome staining were performed to detect the cardiomyocyte width and collagen volume fraction after rat sacrifice. Collagen I, α-SMA, S100A4, TGF-β, Smad 3, MYH6, and MYH7 were further analyzed by Western blot. Results. The absolute values of GLS significantly increased in the SHR + QH group compared to the SHR group, while the CVF and CW values significantly decreased. In addition, Collagen I, α-SMA, S100A4, TGF-β, Smad3, MYH7, and MYH7/MYH6 ratio remarkably reduced in the SHR + QH group. The value of GLS could be repetitively measured and positively correlated with the collagen volume fraction of the myocardium and the cardiomyocyte width of the left ventricular free wall. Conclusions. GLS is a reliable indicator to evaluate the therapeutic effect on left ventricular remodeling in hypertension. QYYY granules can inhibit the development of cardiac fibrosis in the hypertensive rat model.