Effects of long-term enalapril and losartan therapy of hypertension on cardiovascular aldosterone.

BACKGROUND: Plasma aldosterone escape is found during long-term angiotensin-converting enzyme inhibitor therapy. Evidence for aldosterone production in cardiovascular tissues raised the question of whether or not aldosterone escape occurs in these tissues. METHOD: Spontaneously hypertensive rats were treated with enalapril (20 mg/kg/day) and losartan (50 mg/kg/day) for 20 weeks; untreated spontaneously hypertensive and Wistar rats were used as positive and normal controls, respectively. Ex vivo mesenteric artery and heart perfusion, high-performance liquid chromatography, and radioimmunoassay for aldosterone were performed. RESULTS: The results showed that enalapril failed to significantly inhibit aldosterone production in mesenteric artery, myocardium and plasma. Losartan significantly inhibited aldosterone production to that of Wistar rats in the mesenteric artery, myocardium and plasma. CONCLUSION: This study provides the first evidence that long-term angiotensin-converting enzyme inhibition therapy induces aldosterone escape in hypertensive cardiovascular tissues, and angiotensin II subtype 1 receptor antagonist does not induce aldosterone escape in mesenteric artery, myocardium and plasma of spontaneously hypertensive rats.     

Effect of chronic losartan potassium treatment on fructose-induced hypertension

Carbohydrate enriched diets have been shown to elevate blood pressure in the rat. The precise mechanism by which carbohydrate feeding elevates blood pressure is not known. We evaluated the role of the renin-angiotensin system in the etiology of fructose-induced hypertension. Losartan potassium, an angiotensin II (AII) Type 1 (AT₁) receptor antagonist, was utilized to assess the blood pressure response to fructose treatment. Male Sprague-Dawley rats were divided into 3 groups. Rats in the control group were fed regular chow. The other two groups were fed 60% fructose diet for 4 weeks. One of these groups was chronically treated with losartan potassium in drinking water. Throughout the study there was no significant difference in body weight between the three groups. There was a significant increase in blood pressure of fructose-treated rats within one week of treatment which remained elevated for the remainder of the study. Chronic losartan treatment significantly attenuated the rise in blood pressure. Within two weeks both the dipsogenic response and the pressor response to AII demonstrated complete blockage of AII receptors. These results suggest that the renin-angiotensin system plays a role in the development of fructose-induced hypertension.     

Effect of meclofenamate on renal vascular resistance in early Goldblatt hypertension in conscious and anesthetized dog

Blood pressure and renal blood flow were monitored in conscious normotensive (N) and 2-kidney Goldblatt hypertensive (H) dogs. Plasma renin activity was significantly increased 4–8 days after partial renal artery occlusion. At this time intravenous administration of meclofenamate, 5 mg/kg, had no effect on blood pressure in the N or H or on renal vascular resistance in the N or in the H (contralateral kidney). The renal vasoconstrictor response to angiotensin II was increased in duration by meclofenamate in both the N and H. In contrast to the absence of an effect of meclofenamate on renal vascular resistance in the conscious dog, the synthesis inhibitor caused a consistent increase in RVR in the N and H when they were anesthetized in the terminal experiment. These results suggest the lack of an influence of prostaglandins on renal vascular resistance in the unaffected kidney in Goldblatt hypertension.     

Effect of chronic treatment with losartan on streptozotocin induced diabetic rats

Treatment of rats with streptozotocin (STZ, 45mg/kg, i.v.,single dose) produced cardinal symptoms of diabetes mellitus including hyperglycemia, hypoinsulinemia and increase in blood pressure. Treatment with losartan--an angiotensin (AT1) receptor antagonist, 2 mg/kg, po for 6 weeks decreased the blood glucose levels by 16.5%. There was 190% increase in AUCglucose and 59.4% decrease in AUCinsulin in STZ-diabetic rats as compared to control rats. Treatment with losartan caused slight decrease in AUCglucose and slight increase in AUCinsulin. There was no significant difference in insulin sensitivity (K(ITT)) index of STZ-diabetic group as compared to control. Losartan treatment failed to alter these levels significantly. Serum cholesterol and creatinine levels were found to be increased significantly in STZ-diabetic rats. Treatment with losartan significantly prevented the rise in cholesterol and creatinine levels by 20.1 and 81% respectively. The results suggest that losartan produces some beneficial effects in STZ-diabetic rats.     

Beneficial effects of losartan on vascular injury induced by advanced glycosylation end products and their receptors in spontaneous hypertension rats

The purpose of this study was to examine the effects of ENA Actimineral Resource A (ENA-A), seaweed origin alkaline water, on postmenopausal osteoporosis in ovariectomized (OVX) rats. The 12-week old Wistar rats were divided randomly into 4 groups: ovariectomized (OVX), OVX plus 0.5% ENA-A, OVX plus 5% ENA-A and OVX plus 10% ENA-A. A histopathological analysis indicated that ENA-A could prevent OVX-induced bone loss by increasing femur trabecular bone area in a dose-dependent manner. ENA-A significantly (p < 0.05) increased serum estradiol levels, decreased serum osteocalcin activity and suppressed serum pyridinoline (PYD) levels. The in vitro effects of ENA-A were also studied using MC3T3-E1 cells. ENA-A significantly stimulated cell proliferation and increased both ALP activity and calcium deposition in a dose-dependent manner. These results suggest that the treatment of ovariectomized rats with ENA-A not only prevents bone resorption but also appears to maintain the cancellous bone structure of postmeopausal osteoporosis.     

Arterial hypertension caused by low renin: comparison of the calcium antagonist nifedipine and the ACE-inhibitor enalapril as to antihypertensive efficacy

The aim of this study was to compare the clinical effects of calcium-entry blocker Nifedipine and ACE-inhibitor Enalapril in hypertensive patients with glucose intolerance that have lower plasma renin activity. A blood sample for basal PRA was obtained from 21 subjects; then, 11 patients received Nifedipine (20 mg. b.i.d.) and 10 Enalapril (20 mg. q.d.). The extent of blood pressure fall after 12 weeks of treatment was inversely related to basal PRA levels in Nifedipine treated group only; however, the hypotensive effect of both drugs was comparable.     

Modification of myosin protein and gene expression in failing hearts due to myocardial infarction by enalapril or losartan

The effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, and losartan, an angiotensin II receptor type I antagonist, were investigated on alterations in myofibrillar ATPase activity as well as myosin heavy chain (MHC) content and gene expression in failing hearts following myocardial infarction (MI). Three weeks after ligation of the left coronary artery, rats were treated with or without enalapril (10 mg/kg/day), and/or losartan (20 mg/kg/day) for 5 weeks. The infarcted animals exhibited an increase in left ventricle (LV) end diastolic pressure and depressed rates of LV pressure development as well as pressure decay. LV myofibrillar Ca2+ -stimulated ATPase activity was decreased in the infarcted hearts compared with controls, MHC alpha-isoform content was significantly decreased whereas that of MHC beta-isoform was markedly increased. The level of MHC alpha-isoform mRNA was decreased whereas that of MHC beta-isoform was increased in the viable infarcted LV. Treatment of animal with enalapril, losartan, or combination of enalapril and losartan partially prevented the MI induced changes in LV function, myofibrillar Ca2+ -stimulated ATPase activity, MHC protein expression and MHC gene expression. The results suggest that the beneficial effects of the renin-angiotensin system blockade in heart failure are associated with partial prevention of myofibrillar remodeling.     

Effect of celecoxib on the antihypertensive effect of losartan in a rat model of renovascular hypertension

Certain nonsteroidal anti-inflammatory drugs have been reported to elevate blood pressure in some hypertensive patients, who are either untreated or treated with antihypertensive agents. This study was undertaken to determine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the antihypertensive effects of the angiotensin II type 1 receptor (AT1) antagonist, losartan potassium. We studied the effect of oral treatment with losartan (30?mg/kg), celecoxib (3?mg/kg), and their combination on the mean arterial blood pressure (MAP), plasma renin activity (PRA), and plasma prostaglandin E2 (PGE2) in male Sprague-Dawley rats with renovascular hypertension (RVH) induced by partial subdiaphragmatic aortic constriction. Treatment was continued for 7 days after aortic coarctation. Aortic coarctation led to significant increases in the MAP, PRA, and plasma PGE2. In RVH rats, losartan treatment caused a significant decrease of MAP with a significant increase in both plasma PGE2 and PRA. Celecoxib caused a nonsignificant change in MAP with a significant decrease in the raised levels of plasma PGE2 and PRA. Concomitant administration of celecoxib and losartan did not significantly affect the lowering effect of losartan on MAP with a subsequent significant decrease in the plasma PGE2 and PRA in RVH rats. Therefore, celecoxib could be used in renin-dependent hypertensive patients who receive losartan, without fear of a rise in their blood pressure.     

Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation

It is known that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) can be used to mitigate radiation-induced renal injury. However, for a variety of reasons, these previous results are not directly applicable to the development of agents for the mitigation of injuries caused by terrorism-related radiation exposure. As part of an effort to develop an animal model that would fit the requirements of the U.S. Food and Drug Administration (FDA) "Animal Efficacy Rule", we designed new studies which used an FDA-approved ACEI (captopril) or an FDA-approved ARB (losartan, Cozaar?) started 10 days after a single total-body irradiation (TBI) at drug doses that are equivalent (on a g/m(2)/day basis) to the doses prescribed to humans. Captopril and losartan were equally effective as mitigators, with DMFs of 1.23 and 1.21, respectively, for delaying renal failure. These studies show that radiation nephropathy in a realistic rodent model can be mitigated with relevant doses of FDA-approved agents. This lays the necessary groundwork for pivotal rodent studies under the FDA Animal Efficacy Rule and provides an outline of how the FDA-required large-animal studies could be designed.     

Effect of ginsenoside Re on depression- and anxiety-like behaviors and cognition memory deficit induced by repeated immobilization in rats

In this study, we assessed the effects of ginsenoside Re (GRe) administration on repeated immobilization stressinduced behavioral alterations using the forced swimming test (FST), the elevated plus maze (EPM), and the active avoidance conditioning test (AAT). Additionally, we examined the effect of GRe on the central adrenergic system by observing changes in neuronal tyrosine hydroxylase (TH) immunoreactivity and brain-derived neurotrophic factor (BDNF) mRNA expression in the rat brain. Male rats received 10, 20, or 50 mg/kg GRe (i.p.) 30 min before daily exposures to repeated immobilization stress (2 h/day) for 10 days. Activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to repeated immobilization was confirmed by measuring serum levels of corticosterone (CORT) and the expression of corticotrophin-releasing factor (CRF) in the hypothalamus. Repeated immobilization stress increased immobility in the FST and reduced openarm exploration in the EPM test. It also increased the probability of escape failures in the AAT test, indicating a reduced avoidance response. Daily administration of GRe during the repeated immobilization stress period significantly inhibited the stress-induced behavioral deficits in these behavioral tests. Administration of GRe also significantly blocked the increase in TH expression in the locus coeruleus (LC) and the decrease in BDNF mRNA expression in the hippocampus. Taken together, these findings indicate that administration of GRe prior to immobilization stress significantly improved helpless behaviors and cognitive impairment, possibly through modulating the central noradrenergic system in rats. These findings suggest that GRe may be a useful agent for treating complex symptoms of depression, anxiety, and cognitive impairment.     

氯沙坦对肾血管性高血压大鼠血清中血管紧张素Ⅱ-1受体自身抗体产生的影响

目的和方法：采用两肾一夹型肾血管性高血压（RVH）模型,以合成的大鼠血管紧张素Ⅱ－1受体（AT1R）细胞外第二环165－191位氨基酸序列作为特异性抗原,用ELISA法检测大鼠血清中血管紧张素Ⅱ－1受体自身抗体,动态观察（13周）氯沙坦（术后第2周开始,5mg/kg dig,连续12周）治疗对模型大鼠AT1R自身抗体产生的影响。结果：RVH组大鼠血清中AT1R自身抗体从术后1周起阳性率、滴度逐渐升高;给予氯沙坦治疗不仅可抑制模型大鼠心脏功能和结构的改变,而且使血清AT1R自身抗体的阳性率和滴度明显低于肾血管性高血压组。结论：氯沙坦有抑制AT1R自身抗体产生而达到降压的作用。     

Investigating cognitive genetics and its implications for the treatment of cognitive deficit

Cognitive impairment in the elderly, caused by either normal ageing process or dementia, is an increasing problem in developed countries that has enormous social and economic considerations. Research investigating the genetic basis of cognition is a new and rapidly developing field that may aid in the development of new treatments for age-related cognitive deficit. Over the past 6 years, a number of quantitative trait loci (QTLs) have been associated with cognitive functioning in humans including loci within the genes catechol- o -methyltransferase, brain-derived neurotrophic factor, muscle segment homeobox 1, serotonin transporter 2A (HTR2A), cholinergic muscarinic receptor 2, cathepsin D, metabotrophic glutamate receptor and most recently the class II human leukocyte antigens. Unfortunately, inconsistency within the literature, which is a hallmark of almost all association studies investigating complex diseases and traits, is casting doubt as to which genes are truly associated with cognition and which are a result of Type 2 error. This review will highlight implicated intelligence QTLs, examine the probable reasons for the current discrepancies between reports and discuss the potential advantages that may be procured from the study of cognitive genetics.     

Effect of experimentally induced hypertension on cerebellum of postmenopausal rat

Cerebellum seems to be a specific target for both the decrease of estrogen and hypertension in menopause. The aim of this study was to investigate the hypertension and menopause-induced changes in rat’s cerebellar cortex and the possible mechanisms of these changes. Rats were divided into four groups: the sham-operated control (SC-group), the ovariectomized (OVX-group), the hypertensive (H-group), and the ovariectomized-hypertensive (OVX-H-group) group. The mean arterial pressure (MAP), serum nitric oxide (NO), lipid peroxides and antioxidant catalase enzyme levels were assayed. Cerebellar tissue homogenization for analysis of lipid peroxides, antioxidant catalase enzyme, tumor necrosis factor-α (TNF-α), and estradiol was done. Quantification of adrenomedullin (AM) and interleukin-10 (IL-10) mRNA was also done. Cerebella were processed for histological, immunohistochemical and transmission electron microscopic examination. In the OVX-group, insignificant structural and biochemical changes were observed compared with the SC-group apart from the significantly increased lipid peroxides and decreased NO and catalase levels in serum. The H-group showed an elevated lipid peroxides and TNF-α levels, reduced catalase level, numerous degenerated Purkinje cells, vacuolations of the neuropil, some axonal degeneration, and few ghosts in the granular cell layer (GL). However, in OVX-H-group, oxidative stress, inflammation, and cerebellar damage were exacerbated and cerebellar estrogen was reduced associated with reduction in GL thickness and decreased Purkinje cells number. Most axoplasms had degenerated neurofilaments with abnormal myelination. The immunoexpression of glial fibrillary acidic protein were significantly increased in both OVX-group and H-group and significantly decreased in OVX-H group. Gene expression of AM and IL-10 were increased in cerebellar tissues of H-group compared with the SC-group but it was significantly decreased in OVX-H-group compared with H-group. Taken together, postmenopausal rats with hypertension suffered from structural cerebellar changes than rats with only hypertension or estrogen deficiency separately due to augmentation of the increased oxidative stress markers and the proinflammatory cytokines (TNF-α) with down regulation of the anti-inflammatory cytokine (IL-10) and the blood pressure regulator, AM. These suggested that high blood pressure is a critical factor for postmenopausal cerebellum.     

Caveolin-3与高血压性心肌肥大

Caveolae是富含胆固醇、鞘磷脂和鞘糖脂的胞膜内陷结构,在信号转导过程中起到“信使中心”的作用。Caveolin-3是整合在Caveolae上的肌细胞特异性蛋白,其异常可能与一些心血管疾病、肌营养不良症等有密切的关系,对Caveolin-3的调控也是维持心脏正常功能及内环境稳定的必要因素。目前研究已将注意力集中到Caveolin-3在心肌细胞信号转导中的作用,本文将以Caveolin-3为切入点,探讨Caveolin-3与高血压性心肌肥大的关系,从分子水平进一步阐明高血压性心肌肥大的发病机制。