본태성 고혈압쥐의 성장에 따른 뇌신경 세포막 Na, K-ATPase변동에 관한 연구

류석천,허강민,석정호,이재흔 충남대학교 의과대학 지역사회의학연구소 1992 충남의대잡지 Vol.19 No.1

To investigate the development change of synaptosomal Na, K-ATPase of hypertensive rat, Na, K-ATPase activity and ouabain binding sites were measured in the synaptosomal membrane prepared from 3 days-, 2 weeks-, 20 weeks- old Sprague-Dawley rats and spontaneously hypertensive rats Resulrs are as follows; 1. in the synaptosomal Na, K-ATPase of the normotensive and hypertensive rats, there were 2 kinds of isozymes, high affinity site(IC_(50):80-260 nM) and low affinity site(IC_(50):30-60 μM) 2. Synaptosomal Na, K-ATPase activity was increased in 2 and 20 weeks(high affinity site) or 2 weeks(low affinity site) old compared to that in 3 days old rat, and showed a tendency of decrease in 33 weeks old compared to that in 20 weeks old rats(high affinity site) in both groups. 3. Synaptosomal Na, K-ATPase activities of hypertensive rats were low in 3 days and 2 weeks old(high affinity site) or 3 days old (low affinity site) compared to that age groups of normotensive rats. 4. In the ouabain binding experiments, Kd value(0.1-0.2 μM) for ouabain was slightly increased with increase of age, but no difference between normotensive and hypertensive rats was detected. 5. The numbers of ouabain binding sites were increased in 2 weeks and 20 weeks old compared to those in 3 days old rats, and showed a tendency of decrease in 33 weeks old compared to that in 20 weeks old rats. 6. In the hypertensive rats, the number of ouabain binding sites was low in 3 days, compared to that of the correponding age group of normotensive rats. From the above results, it is suggested that in the spontaneously hypertensive rat, 1) synaptosomal Na, K-ATPase of high affinity site or low affinity site is increased significantly after birth as well as in the normotensive rat, 2) but significantly less than that of normotensive rats in early periods after birth and this may due to the low concentration in both high and low affinity Na, K-ATPase isozymes for ouabain.

Pharmacokinetic changes of DA-8159, a new erectogenic, and one of its metabolites, DA-8164 after intravenous and oral administration of DA-8159 to spontaneously hypertensive rats and DOCA–salt-induced hypertensive rats

Kim, Yu C.,Shim, Hyun J.,Lee, Joo H.,Kim, Dong S.,Kwon, Jong W.,Kim, Won B.,Lee, Inchul,Lee, Myung G. John Wiley Sons, Ltd. 2005 Biopharmaceutics & drug disposition Vol.26 No.7

<P>The pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, were compared after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg to spontaneously hypertensive rats (SHRs) at 16 and 6 weeks old and their respective age-matched control normotensive Kyoto–Wistar rats (KW rats), and deoxycorticosterone acetate–salt-induced hypertensive rats (DOCA–salt rats) at 16 weeks old and their age-matched control Sprague–Dawley rats. After oral administration of DA-8159 to 16-week-old SHRs, the AUC values of both DA-8159 (157 versus 103 µg min/ml) and DA-8164 (215 versus 141 µg min/ml) were significantly greater, but the values of DA-8159 were reversed in 16-week-old DOCA–salt rats (125 versus 200 µg min/ml). However, the AUC values of both DA-8159 and DA-8164 were not significantly different between the 6-week-old SHRs and their control rats. The above AUC differences in 16-week-old SHRs may be due to neither hereditary characteristics of SHRs nor the hypertensive state itself. Copyright © 2005 John Wiley & Sons, Ltd.</P>

전침자극이 자연 발증 고혈압 흰쥐의 혈압 조절 중추에서 iNOS의 발현에 미치는 영향

황혜숙(Hwang Hyesuk),김유성(Kim Yusung),이지은(Lee Jieun),한경주(Han Kyungju),최선미(Choi Sunmi),구성태(Koo Sungtae) 한국한의학연구원 2006 한국한의학연구원논문집 Vol.12 No.3

Aims: Acupuncture has been used for the treatment of essential hypertension, but the efficacy and the mechanism of acupuncture in prevention of hypertension are still unclear. We tested the hypothesis that electroacupuncture (EA) applied to Baekhoe (GV20) changes NO/NOS system during development of hypertension in spontaneously hypertensive rats (SHR) , and thereby causes the delay of development of hypertension in SHR. Methods: The male SHR rats in the developmental stages of hypertension (7-8 weeks) were randomly divided into three groups (control group, GV20 acupuncture group, and tail acupuncture group). And the age matched Wistar Koyto Rats (WKY) were randomly divided into two groups (negative control, GV20 acupuncture group). EA treatments (10Hz, 1mA, 0.1ms) were carried out for 25 mini day for five consecutive days. The systolic blood pressure (SBP) was determined in conscious rats by the tail-cuff method using automatic BP mornitoring system. We investigated the activations of inducible NO synthase (iNOS) in nuclei of solitary tract (NTS) and rostral ventrolateral medulla (RVLM) of SHR by the western blotting method. Results: The SBP after the termination of EA stimulation applied to the GV20 was stabilized at 169.14±3.67 ㎜Hg which is lower value than that of the control group. The SBP of control group was elevated to 178.14±3.49 ㎜Hg. In addition, we evaluated NOS activity as well as iNOS protein expression of NTS and RVLM in both of SHR and WKY. The iNOS activity in NTS was significantly higher in SHR than in WKY. Furthermore, the iNOS activity of NTS showed significant decreases in EA groups compare to that of non treated SHR group. Although iNCS expression of RVLM showed non significant changes between SHR and WKY, EA significantly enhanced the iNCS expression in SHR. Our data support the hypothesis that delayed development of hypertension and altered iNOS expression of NTS and RVLM by EA stimulations in SHR rats. Conclusions: The findings demonstrate that acupuncture can change NO/NCS system in NTS and RVLM, and exert beneficial role on development of hypertension.

Expression of Class I and Class II a/b Histone Deacetylase is Dysregulated in Hypertensive Animal Models

기해진,김귀란,Ming Quan Lin,최신영,류유희,Li Jin,Zhe Hao Piao,정명호 대한심장학회 2017 Korean Circulation Journal Vol.47 No.3

Background and Objectives: Dysregulation of histone deacetylase expression and enzymatic activity is associated with a number of diseases. It has been reported that protein levels of histone deacetylase (HDAC)1 and HDAC5 increase during human pulmonary hypertension, and that the enzymatic activity of HDAC6 is induced in a chronic hypertensive animal model. This study investigated the protein expression profiles of class I and II a/b HDACs in three systemic hypertension models. Materials and Methods: We used three different hypertensive animal models: (i) Wistar-Kyoto rats (n=8) and spontaneously hypertensive rats (SHR; n=8), (ii) mice infused with saline or angiotensin II to induce hypertension, via osmotic mini-pump for 2 weeks, and (iii) mice that were allowed to drink L-NG-nitro-L-arginine methyl ester (L-NAME) to induce hypertension. Results: SHR showed high systolic, diastolic, and mean blood pressures. Similar increases in systolic blood pressure were observed in angiotensin II or L-NAME-induced hypertensive mice. In SHR, class IIa HDAC (HDAC4, 5, and 7) and class IIb HDAC (HDAC6 and 10) protein expression were significantly increased. In addition, a HDAC3 protein expression was induced in SHR. However, in L-NAME mice, class IIa HDAC protein levels (HDAC4, 5, 7, and 9) were significantly reduced. HDAC8 protein levels were significantly reduced both in angiotensin II mice and in SHR. Conclusion: These results indicate that dysregulation of class I and class II HDAC protein is closely associated with chronic hypertension.

고콜레스테롤 식이가 Spontaneously Hypertensive Rat의 체내지질과 항산화성 영양소 상태에 미치는 영향

유언호 ( Yu Eon Ho ),류왕성 ( Lyu Wang Seong ),김현대 ( Kim Hyeon Dae ),유재격 ( Yu Jae Gyeog ),최영선 ( Choe Yeong Seon ),이희숙 ( Lee Hui Sug ),조성희 ( Jo Seong Hui ) 대한내과학회 1993 대한내과학회지 Vol.44 No.5

연구배경 : 고혈압과 고콜레스테롤혈증은 동맥경화와 심혈관계 질환의 대표적인 위험인자로 알려져있다. 순환기 질환과 관련된 영양은 주로 지질영양에 편중되어 왔으며 항산화기능을 영양소에 관하여 조사된 바가 적다. 동맥경화 과정에서 저밀도지단백의 산화는 지질과 산화물의 형성에 의하여 개시되고 촉진되므로 이 과정에서 과산화물 생성을 억제하는 항산화영양소들의 역할이 주목된다. 방법 : 성장기 Wistar쥐 및 자연발생고혈압쥐(SHR)를 대상으로 하여 고콜레스테롤식이를 6개월간 섭취케 함으로써 고콜레스테롤증을 유발시켰으며 고혈압과 고콜레스테롤혈증이 중복된 상황에서 체내 지질상태의 변화와 고혈압 대상의 지질대사 특이성을 조사하고 과산화지질의 형성과 항산화성 영양소들의 유지수준을 평가하였다. 결과 : Wistar쥐의 수축기혈압이 전체 실험기간 동안 102∼120㎜Hg에 머무르는데 비하여 SHR의 수축기혈압은 생후 5주째 평균 118㎜Hg에서 점차 혈압이 상승하여 식이 2개월에는 175±13㎜Hg로 고혈압이 뚜렷하여 졌으며 Wistar쥐와 SHR 모두에서 고콜레스테롤식이에 따른 혈압의 변화는 없었다. 혈청과 간의 콜레스테롤은 식이콜레스텔롤에 의하여 각각 약 2배, 10배 증가하였다. 혈청중성지방과 인지질은 SHR에서 다소 낮았고 간의 중성지방은 고콜레스테롤식이로 유의하게 증가하였다. 혈청지질 과산화물은 SHR에서 높았으나 식이콜레스테롤에 의한 영향은 적었고 간에서는 고혈아과 식이콜레스테롤 모두에 의하여 증가되었다. 혈청, 간의 비타민 E수준은 SHR에서 낮았고 고콜레스테롤식이에 의하여 혈청수준은 더 감소하였다. 비타민 A 수준도 식이콜레스테롤에 의하여 현저히 낮아졌다. 결론 : 고혈압과 고콜레스테롤혈증은 체내 지질과산화물을 증가시키고 비타민 E와 A의 소모를 가져올수 있다. Backgrounds: Hypertension and hypercholesterolemia are two of the most important risk factors for atherosclerosis and cardiovascular morbidity. The mechanism by which hypertension and hypercholesterolemia accelerates atherosclerosis is still uncertain. Methods: To investigate the effect of high cholesterol diet on lipid and antioxidant nutritent status in spontaneously hypertensive rat (SHR), SHRs and Wistar rats were fed diets with or without 2% cholesterol and 0.3% Na-taurocholate for 6 months. Results: SHRs became apparently hypertensive after 2 months of feedings, when their systolic pressure was over 180 mmHg. Heart weight-to-body weight ratios of SHRs were significantly higher than those of Wistar rats. Levels of serum total cholesterol were increased about two-folds and those of liver, ten-folds in both SHRs and Wistar rats by dietary cholesterol. Serum HDL-cholesterol of SHRs were significantly lower than those of Wistar rats and HDL·/total cholesterol. Serum TG levels were not changed, but liver levels increased by dietary cholesterol and lower in SHRs. Serum TBARS levels were higher in SHRs, but little changed by dietary cholesterol. Liver levels appeared to be higher in SHRs and cholesterol groups. Serum and liver vitamin E levels were lower in SHR. Serum vitamin A levels were little changed, but liver contents were somewhat decreased in SHRs and remarkably reduced by dietary cholesterol. Conclusions: It is concluded that hypertension and hypercholesterolemia, individually, result in accumulation of lipid peroxide as well as consumption of body tocopherol and retinol, which can be further augmented by coexistence of two abnormal conditions.

Anti-hypertensive Effects of Electroacupuncture at ST36 in Spontaneously Hypertensive Rat

박현정,김성옥,함대현,이혜정,김희영,심인섭 한의병리학회 2009 동의생리병리학회지 Vol.23 No.3

The present study investigated whether electroacupuncture (EA) can alleviate hypertension and concomitant disorders such as decreased kidney weight and elevation of serum creatinine in spontaneous hypertensive rats. EA (2 Hz, 3 mA, 10 min) was applied to Joksamni (ST36) once daily for 7 days. Body weight, blood pressure and heart rate were measured on Day 0, 2, 6, 8, 10 and 12, and kidney weight and serum creatinine levels were examined after sacrifice (on Day 12 after last examination). In the ST36 group, the blood pressure were significantly decreased from 6thdays and its effects lasted up to Day12 (up to 5days after cessation of acupuncture), compared to control. And, significant decreases of the heart rates after EA at ST36 were also observed on Day 2, 6, and 8. However, there were no significant differences in daily body weight, kidney weight and serum creatinine between acupuncture and control group. These results showed that EA at ST36 caused anti-hypertension by decreasing blood pressure and heart rates in spontaneous hypertenstive rats, although it failed to alleviate concomitant disorders such as the decreased kidney weight and elevation of serum creatinine shown in hypertensive rats.

자연발증 고혈압쥐에서 Atenolol이 대동맥 미세구조변화에 미치는 영향

김용태,이승일,장경식 朝鮮大學校 附設 醫學硏究所 1992 The Medical Journal of Chosun University Vol.17 No.1

Hypertension has been known as a major risk factor for atherosclerosis, left ventricular hypertrophy, sudden death and other cardiovascular diseases. Hypertension-induced vascular changes are thought to be adaptive to the increased stress. Adaptation in the media includes incresed synthesis of the major connective tissue components, elastin and collagen, hypertrophy and hyperplasia of smooth muscle cells (SMC), which are due to wall thickening and increase in arterial cell mass. The present electronmicroscopic study was performed in normal Wistar-Kyoto rats(WKR), nontreated spontaneously hypertensive rats(SHR) and atenolol-treated SHR (2.5 ㎎/Kg/day) to define and compare the morphologic changes of aorta induced by hypertension as well as the restoration on its wall in normal WKR, SHR & atenolol treated SHR. Pretreatment with atenolol for 22 weeks thickness of media of the SHR aorta caused by hypertension was decreased and space between prominent elastic laminae was narrowed as compared to the control SHR. Irregularly arranged collagenous fibers among the abundant SMC in control SHR aorta are regularly distributed as shown in control WKR or atenolo-pretreated SHR. Cross bands of collagen fibrils are partly apparrent in atenolol-treated SHR. While were not clear and some fragemented in the media of the control SHR aorta. Ultrastructural study also revealed that nucleus with double membrane was well-developed, heterochromatin along with normally distributed, enchromatin and that various-sized vacuoles disappeared follow ing improvement of hypertension by chronic pretreatment with atenolol. According to the from these experimental results, it is thought that atenolol a beta-adrenergic antagonist may improve vascular changes inducde by hypertension. Euchromatin are normally distributed and various-sized vacuoles disappeared following reversal of hypertension. From these experimental results, it is thought that atenolol, one of the beta-adrenergic blockades may improve vascular changes induced by hypertension.

트레드밀 운동이 고혈압 흰쥐의 골대사에 미치는 영향

김창선(Chang-Sun Kim) 한국생활환경학회 2012 한국생활환경학회지 Vol.19 No.5

There have been many researches that studied the influence of exercise on secondary bone loss by hypertension. However, the researches still have a little question. For a better understanding between exercise and bone mineral density (BMD), the purpose of this study was to examine the effects of treadmill exercise on bone metabolic turnover in Spontaneously Hypertension Rats(SHR). Six-week-old male, fourteen SHR, and seven Wister-Kyoto (WKY) rats were investigated on bone status including BMD and biomechanical markers from serum. After a week of stabilization, the rats were randomly divided into three groups: WKY control group (n=7, WKY), SHR control group (n=7, SC) and SHR treadmill exercise group (n=7, SE). Treadmill exercise training was performed at 20m/min, 60min/day, 5days/week for 16 weeks. All that rats were fed an commercial standard lab chow and allowed free access to tap water. At the end of the experimental period, the rats were sacrificed with blood drawn and femur were removed for analysis of BMD by dual energy x-ray absorptionmetry (DEXA). In SC group, blood pressure showed significant higher (p〈.001) than that of WKY group with a lower BMD(p〈.05), BMC(p〈.01), bone mass(p〈.01), serum Ca(p〈.01) and adjusted Ca(p〈.01). In SE group, blood pressure was significantly decreased (p〈.001), there was no change in BMD, BMC and bone mass as well as serum bone metabolic markers compared with SC group. Blood pressure was negatively correlated with all femur bone indexes and serum Ca concentration(p〈.01), and there was a positive correlation between femur bone indexes and serum Ca concentration(p〈.01). Results indicated that although SHR showed characteristics of osteoporosis, and treadmill exercise training improves blood pressure but does not prevent bone loss.

Gallic acid attenuates calcium calmodulin‐dependent kinase II‐induced apoptosis in spontaneously hypertensive rats

Jin, Li,Piao, Zhe Hao,Liu, Chun Ping,Sun, Simei,Liu, Bin,Kim, Gwi Ran,Choi, Sin Young,Ryu, Yuhee,Kee, Hae Jin,Jeong, Myung Ho John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.3

<P><B>Abstract</B></P><P>Hypertension causes cardiac hypertrophy and leads to heart failure. Apoptotic cells are common in hypertensive hearts. Ca<SUP>2+</SUP>/calmodulin‐dependent protein kinase II (CaMKII) is associated with apoptosis. We recently demonstrated that gallic acid reduces nitric oxide synthase inhibition‐induced hypertension. Gallic acid is a trihydroxybenzoic acid and has been shown to have beneficial effects, such as anti‐cancer, anti‐calcification and anti‐oxidant activity. The purpose of this study was to determine whether gallic acid regulates cardiac hypertrophy and apoptosis in essential hypertension. Gallic acid significantly lowered systolic and diastolic blood pressure in spontaneously hypertensive rats (SHRs). Wheat germ agglutinin (WGA) and H&E staining revealed that gallic acid reduced cardiac enlargement in SHRs. Gallic acid treatment decreased cardiac hypertrophy marker genes, including atrial natriuretic peptide (<I>ANP</I>) and brain natriuretic peptide (<I>BNP</I>), in SHRs. The four isoforms, α, β, δ and γ, of <I>CaMKII</I> were increased in SHRs and were significantly reduced by gallic acid administration. Gallic acid reduced cleaved caspase‐3 protein as well as <I>bax</I>,<I> p53</I> and <I>p300 </I>mRNA levels in SHRs. <I>CaMKII</I> δ overexpression induced <I>bax</I> and <I>p53</I> expression, which was attenuated by gallic acid treatment in H9c2 cells. Gallic acid treatment reduced DNA fragmentation and the TUNEL positive cells induced by angiotensin II. Taken together, gallic acid could be a novel therapeutic for the treatment of hypertension through suppression of CaMKII δ‐induced apoptosis.</P>

오령산(五苓散)의 본태성 고혈압 동물모델에서 혈압강하 및 혈관 이완 효과

장윤재,김혜윰,홍미현,윤정주,이호섭,강대길 대한한의학방제학회 2022 大韓韓醫學方劑學會誌 Vol.30 No.3

Oryeongsan (ORS), a formula composed of five herbal medicines, has long been used to treat impairments of the regulation of body fluid homeostasis. The purpose of this study was to determine the antihypertensive and renal protective effects of ORS in rats with hypertension. Spontaneously hypertensive rats (SHR) were divided into two groups with similar mean baseline systolic blood pressure (SBP). Then, 1 mL/kg of vehicle (distilled water) or 1.5, 3 g/kg of ORS extract were administered orally once a day for 4 weeks. SBP and diastolic blood pressure (DBP) were measured at weeks 1, 2, 3 and 4. At the end of the experiment, blood was collected, and heart were removed for histology. By the 2 weeks after initiation of treatment, the ORS treated group had significantly lower SBP than SHR rats. The ORS treatment significantly improved blood pressure and echocardiogram parameters compared to hypertensive rats. Additionally, the left ventricular (LV) remodeling and LV dysfunction were significantly improved in ORS treated group hypertensive rats. Furthermore, an increase in fibrotic area has been observed in SHR rats compared with Wistar-Kyoto rats (WKY). Furthermore, administration of ORS significantly attenuated cardiac fibrosis in hypertensive rats. Therefore, these findings suggest that ORS has a protective effect on heart failure by alleviating hypertensive heart disease and cardiovascular dysfunction in SHR.