Abstract:
:Although the most direct way to interfere with the renin-angiotensin system (RAS) is at the level of the angiotensin II (AII) receptor, the currently available AII receptor antagonists are peptides still retaining significant agonistic properties with the obvious drawbacks of limited stability and lack of oral activity. We have characterized simple N-benzylimidazoles as weak, but selective AII receptor antagonists with a competitive mode of action. Chemical modification of these early leads led to EXP6155 and EXP6803, which show approximately 10- and 100-fold higher affinity. Oral activity was obtained for EXP7711, and in particular for EXP9654. This class of compounds displaces 3H-AII from its specific binding sites in various tissues. They competitively antagonize AII-induced responses in various in vitro and in vivo preparations, but do not influence AII-induced responses to KCl, norepinephrine, and vasopressin, nor do they affect converting enzyme or renin. In high renin models of elevated blood pressure, such as the renal hypertensive rat and sodium-depleted dog, these substances produce a sustained decrease in arterial pressure without changing heart rate after intravenous and oral (EXP7711 and EXP9654) administration. None of these compounds showed agonistic activity in any of the above test systems. In conclusion, the nonpeptide structures described herein are selective and competitive AII receptor antagonists and add another dimension to the arsenal of drugs manipulating the RAS.
journal_name
Am J Hypertensjournal_title
American journal of hypertensionauthors
Timmermans PB,Carini DJ,Chiu AT,Duncia JV,Price WA Jr,Wells GJ,Wong PC,Wexler RR,Johnson ALdoi
10.1093/ajh/3.8.599subject
Has Abstractpub_date
1990-08-01 00:00:00pages
599-604issue
8 Pt 1eissn
0895-7061issn
1941-7225journal_volume
3pub_type
杂志文章,评审abstract::The effect of fish oil on potassium efflux and basal tension in aortas from stroke prone spontaneously hypertensive rats (SHRSP) was evaluated. Four-week-old male Wistar-Kyoto rats (WKY) and SHRSP were divided into two groups: one received a 5% corn oil diet; the other a 5% menhaden oil diet. After 15 weeks, mean syst...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1093/ajh/5.7.473
更新日期:1992-07-01 00:00:00
abstract:BACKGROUND:The association of adiposity during childhood with future risk of elevated blood pressure (BP) in South Asian children is not known. We aimed to investigate the relationship between waist circumference (WC) and body mass index (BMI) with BP over a 2-year period, independent of the baseline BP. METHODS:We an...
journal_title:American journal of hypertension
pub_type: 杂志文章,随机对照试验
doi:10.1038/ajh.2011.67
更新日期:2011-08-01 00:00:00
abstract::Angiotension converting enzyme (ACE) inhibitors and beta-blockers have been reported to possess disparate effects on insulin sensitivity. The aim of this study was to study the effects of the selective beta-1 blocker bisoprolol and of the ACE inhibitor captopril on cellular insulin action in hypertensive individuals. ...
journal_title:American journal of hypertension
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0895-7061(97)00320-8
更新日期:1997-12-01 00:00:00
abstract:BACKGROUND:This study investigates the effects of chronic administration of omapatrilat (OMA) on blood pressure (BP), renal injury, and other variables in N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension and in the low-renin model produced by the simultaneous administration of L-NAME and deoxycorticosterone...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1016/s0895-7061(02)03144-8
更新日期:2003-01-01 00:00:00
abstract::The objective of this study was to test the relationship between neurologic and microvascular complications of type 1 diabetes mellitus. It was hypothesized that the mechanisms operative in autonomic dysfunction seen in diabetic patients with microangiopathy play a role in the rapidity of progression to renal failure....
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1016/s0895-7061(97)00472-x
更新日期:1998-03-01 00:00:00
abstract::After a brief historic survey, sympathetic-neurogenic contributions to the multifactorial, polygenetically linked etiology of primary (essential) hypertension are outlined towards the background of experimental findings both in various rat models and in human subjects. It is emphasized how at least some variants of bo...
journal_title:American journal of hypertension
pub_type: 杂志文章,评审
doi:10.1093/ajh/2.3.103s
更新日期:1989-03-01 00:00:00
abstract:BACKGROUND:Many studies have examined differences in hypertension across race/ethnic groups but few have evaluated differences within groups. METHODS:We investigated within-group geographic variations in hypertension prevalence among 3,322 black and white participants of the Multi-Ethnic Study of Atherosclerosis (MESA...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1038/ajh.2009.211
更新日期:2010-01-01 00:00:00
abstract::Plasma renin activity (PRA) declines with age in normal individuals, but the effect of age on plasma angiotensin II (ANG II) is less clear. A decline in plasma ANG II with age could result in altered platelet ANG II receptor density since plasma hormone levels influence their target organ receptors. To investigate thi...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1093/ajh/5.10.687
更新日期:1992-10-01 00:00:00
abstract::Mesangial cells in the glomerulus have several important physiological functions, as has been demonstrated by past research. Platelet derived growth factor, thrombin, endothelin, and angiotensin II have all been shown to affect mesangial cell growth and protein synthesis. First generation Ca channel blockers also have...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:
更新日期:1992-12-01 00:00:00
abstract:BACKGROUND:It is unclear whether serum uric acid (SUA) is associated with development of new-onset diabetes (NOD) in patients with hypertension and left ventricular hypertrophy (LVH). The aim of the present investigation was to test the hypothesis that SUA predicts development of NOD in these patients. METHODS:In the ...
journal_title:American journal of hypertension
pub_type: 杂志文章,随机对照试验
doi:10.1038/ajh.2010.89
更新日期:2010-08-01 00:00:00
abstract:BACKGROUND:Large artery stiffness is increased in diabetes mellitus and causes an excessive pulsatile load to the heart and to the microvasculature. The identification of pathways related to arterial stiffness may provide novel therapeutic targets to ameliorate arterial stiffness in diabetes. Matrix Gla-Protein (MGP) i...
journal_title:American journal of hypertension
pub_type: 杂志文章,多中心研究
doi:10.1093/ajh/hpw146
更新日期:2017-02-01 00:00:00
abstract:BACKGROUND:Liddle's syndrome (LS) is a monogenic form of hypertension simulating a mineralocorticoid excess, and is currently suspected in young hypokalemic hypertensives. The aims of the study were: (i) to evaluate the clinical phenotype of LS in a newly identified Italian family of Sicilian origin carrying a gain-of-...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1038/ajh.2011.76
更新日期:2011-08-01 00:00:00
abstract::Insulin resistance, the most important factor in metabolic syndrome X, has been considered to raise blood pressure. Recently it was reported that insulin resistance was related to an elevated plasma level of leptin, which is an adipocyte-specific ob gene product and which plays a role in food intake suppression, therm...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1016/s0895-7061(97)00310-5
更新日期:1997-10-01 00:00:00
abstract:BACKGROUND:Little is known about hypertension in the HIV-infected population. This study aimed to assess the prevalence of hypertension and related factors in HIV-infected patients. METHODS:In this prospective cross-sectional study, 710 HIV-infected patients (626 on combination antiretroviral therapy and 84 naive) man...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1016/j.amjhyper.2005.05.016
更新日期:2005-11-01 00:00:00
abstract::The purpose of this double-blind, forced titration study was to compare the antihypertensive effect duration of candesartan cilexetil, which has a longlasting binding to the human AT1-receptor, to that of losartan on ambulatory BP (ABP) not only during the 24-h dosing interval but also during the day of a missed dose ...
journal_title:American journal of hypertension
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1016/s0895-7061(99)00142-9
更新日期:1999-12-01 00:00:00
abstract::The treatment of diseases has been based on the concept of homeostasis and has not incorporated an understanding of biologic rhythms and their underlying mechanisms. Biologic rhythms are implicated in cardiovascular events. Failure to recognize the circadian decline in blood pressure may result in iatrogenic chronopat...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1016/s0895-7061(01)02173-2
更新日期:2001-09-01 00:00:00
abstract:BACKGROUND:Hypertensive disorders of pregnancy, including preeclampsia (PE), affect approximately 7-10% of pregnancies in the US. Clinical and experimental studies strongly suggest that the maternal immune system plays a role in the development of these disorders; however, few therapeutic options exist aside from deliv...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1038/ajh.2009.125
更新日期:2009-10-01 00:00:00
abstract::The purpose of this study was to investigate whether acute hyperinsulinemia induces selective hemodynamic effects in the mesenteric, renal, and iliac vascular beds, and to determine whether nitric oxide (NO) plays a role in the regulation of blood flow and mean arterial pressure (MAP) during acute hyperinsulinism. In ...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1016/s0895-7061(98)00133-2
更新日期:1998-10-01 00:00:00
abstract::The effects of dietary Na+ on 5 alpha- and 5 beta-reductase pathways of aldosterone metabolism in the liver were studied in male rats maintained on low, control, and high Na+ diets. A high Na+ diet caused significant increases in the synthesis of 5 beta-reduced metabolites, primarily 3 alpha, 5 beta-tetrahydroaldoster...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1093/ajh/1.3.272
更新日期:1988-07-01 00:00:00
abstract::Increased dietary K+ increases plasma [K+] and is linked to or associated with reduced mortality from stroke and reduced blood pressure in humans and animals. We hypothesized that physiologic increases in extracellular [K+] ([K]o) directly inhibit cultured vascular smooth muscle cell (VSMC) proliferation. Studies were...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1093/ajh/7.4.346
更新日期:1994-04-01 00:00:00
abstract::Managing hypertension is a complex undertaking, where even the definition of the disorder is subject to discussion. Recently, there has been controversy concerning the most appropriate measure to determine health risks associated with hypertension. In the past, diastolic blood pressure (DBP) was the prime measure for ...
journal_title:American journal of hypertension
pub_type: 杂志文章,评审
doi:10.1016/s0895-7061(01)02131-8
更新日期:2001-07-01 00:00:00
abstract:BACKGROUND:Obese and overweight patients are at increased risk of arterial stiffness, and visceral, epicardial and hepatic fat accumulation is associated with cardiovascular disease risk. In general, muscular lipids are stored either in interstitial adipose tissue (extramyocellular lipid (EMCL)) or in lipid droplets wi...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1093/ajh/hpv041
更新日期:2015-12-01 00:00:00
abstract::We have previously reported that young, primigravid, African-American women who developed preeclampsia exhibited insulin resistance (elevated fasting insulin:glucose ratios) and abnormal intracellular free calcium ([Ca2+]i) metabolism as early as the second trimester of pregnancy. To determine if these abnormalities p...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1093/ajh/6.4.302
更新日期:1993-04-01 00:00:00
abstract::We assessed the efficacy of monotherapy with trandolapril, an angiotensin converting enzyme (ACE) inhibitor, and of verapamil slow-release (SR), a calcium antagonist, each in a range of three doses as monotherapy, and in the nine possible combinations of therapy in patients with stage I to III diastolic hypertension. ...
journal_title:American journal of hypertension
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0895-7061(97)00102-7
更新日期:1997-07-01 00:00:00
abstract::The purpose of the present study was to determine whether the physiological dopamine prodrug, L-dopa, could suppress streptozotocin-induced diabetic glomerular hyperfiltration, and thus prevent further evolution of the diabetic nephropathy. Male Wistar rats treated with streptozotocin (60 mg/kg, intravenously) rapidly...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1093/ajh/3.6.72s
更新日期:1990-06-01 00:00:00
abstract::To clarify the function of polymorphonuclear leukocytes (PMN) in spontaneously hypertensive rats (SHR) and the effect of beraprost sodium (BS) on these functions, we examined superoxide anion (O2-) production and adherent activity by PMN, as well as modification of these functions by BS ex vivo and in vitro. In study ...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1016/s0895-7061(01)01309-7
更新日期:2001-07-01 00:00:00
abstract::The Captopril Prevention Project (CAPPP) is an ongoing prospective intervention study in 10,800 hypertensive patients in Sweden and Finland. Patients are randomized to treatment with either conventional antihypertensive therapy, ie, diuretics or beta-blockers, or the angiotensin-converting enzyme inhibitor captopril. ...
journal_title:American journal of hypertension
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1994-09-01 00:00:00
abstract::This study was undertaken to characterize blood pressure (by continuous blood pressure recording), renal hemodynamics, and excretory function in high-fructose-fed insulin-resistant dogs. We fed 10 mongrel dogs for 28 days with a normal sodium diet containing 60% of the calories either as fructose (n = 6) or dextrose (...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1016/0895-7061(95)00118-9
更新日期:1995-07-01 00:00:00
abstract::The syndrome of apparent mineralocorticoid excess (AME) is characterized by persistent hypertension and hypokalemia, which is caused by impaired inactivation of cortisol (F) to cortisone (E). The thyroid hormone has been known to influence the F to E conversion leading to efficacious inactivation of F into E. However,...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1016/j.amjhyper.2006.06.012
更新日期:2007-01-01 00:00:00
abstract:BACKGROUND:Obesity is a risk factor for the development of cardiovascular diseases that are associated with impaired angiogenesis. Nifedipine, a calcium-channel blocker, has a number of blood pressure (BP)-independent effects as well, such as improving endothelial function and decreasing oxidative stress. Here, we inve...
journal_title:American journal of hypertension
pub_type: 杂志文章
doi:10.1038/ajh.2011.239
更新日期:2012-04-01 00:00:00