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521.
522.
Wood JM Maibaum J Rahuel J Grütter MG Cohen NC Rasetti V Rüger H Göschke R Stutz S Fuhrer W Schilling W Rigollier P Yamaguchi Y Cumin F Baum HP Schnell CR Herold P Mah R Jensen C O'Brien E Stanton A Bedigian MP 《Biochemical and biophysical research communications》2003,308(4):698-705
Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases. 相似文献
523.
Impaired angiogenesis in SHR is associated with decreased KDR and MT1-MMP expression 总被引:4,自引:0,他引:4
Wang H Olszewski B Rosebury W Wang D Robertson A Keiser JA 《Biochemical and biophysical research communications》2004,315(2):363-368
This study examined whether retarded angiogenesis in a hypertension animal model was associated with impaired VEGF signaling. Furthermore, we sought to determine whether this impairment could be overcome by VEGF addition. Using a rat sponge implantation model, we confirmed impaired angiogenesis in spontaneous hypertensive rats (SHRs). Fourteen days after sponge implantation, the level of angiogenesis in SHRs was approximately half of those in age-matched normotensive Wistar-Kyoto or Sprague-Dawley rats. Significantly, expression of kinase-insert domain-containing receptor (KDR) and membrane type 1 matrix metalloproteinase (MT1-MMP) was reduced in SHRs compared to controls. Immunohistological analysis indicated endothelial proliferation was decreased in SHRs. Gene transfer of human VEGF(121) increased KDR and MT1-MMP expression in SHRs. VEGF(121) also up-regulated endothelial proliferation and angiogenesis. Our results indicate down-regulated KDR and MT1-MMP expression is associated with an impaired angiogenesis in SHRs. VEGF gene transfer is effective in ameliorating the impaired angiogenesis in SHRs. 相似文献
524.
Rezzani R 《Progress in histochemistry and cytochemistry》2004,39(2):85-128
525.
Functional genomics as an emerging strategy for the investigation of central mechanisms in experimental hypertension 总被引:4,自引:0,他引:4
Veerasingham SJ Sellers KW Raizada MK 《Progress in biophysics and molecular biology》2004,84(2-3):107-123
Centrally mediated increases in sympathetic nerve activity and attenuated arterial baroreflexes contribute to the pathogenesis of hypertension. Despite the characterization of cellular and physiological mechanisms that regulate blood pressure and alterations that contribute to hypertension, the genetic and molecular basis of this pathophysiology remains poorly understood. Strategies to identify genes that contribute to central pathophysiologic mechanisms in hypertension include integrative biochemistry and physiology as well as functional genomics. This article summarizes recent progress in applying functional genomics to elucidate the genetic basis of altered central blood pressure regulatory mechanisms in hypertension. We describe approaches others and we have undertaken to investigate gene expression profiles in hypertensive models in order to identify genes that contribute to the pathogenesis of hypertension. Finally, we provide the readers a roadmap for negotiating the route from experimental findings of gene expression profiling to translating their therapeutic potential. The combination of gene expression profiling and the phenotypic characterization of in vitro and in vivo loss or gain of function experiments for candidate genes have the potential to identify genes involved in the pathogenesis of hypertension and may present novel targets for therapy. 相似文献
526.
Mahabusarakam W Deachathai S Phongpaichit S Jansakul C Taylor WC 《Phytochemistry》2004,65(8):1185-1191
A benzil derivative: scandione, 2',2"-dihydroxy-4'-methoxy-4",5"-methylenedioxybenzil and two isoflavones: scandenal, 3'-formyl-4',5-dihydroxy-2",2"-dimethylchromeno-[6,7:5",6"]isoflavone and scanderone, 4',5-dihydroxy-3'-prenyl-2",2"-dimethylchromeno-[7,8:6",5"]isoflavone together with fifteen known compounds were isolated from the stem of D. scandens. Their structures were determined by spectroscopic methods. Radical scavenging, antibacterial and hypertensive activities of some of the compounds were investigated. 相似文献
527.
Pycnogenol, French maritime pine bark extract, improves endothelial function of hypertensive patients 总被引:4,自引:0,他引:4
A placebo-controlled, double-blind, parallel group study was performed with 58 patients to investigate effects of French maritime pine bark extract, Pycnogenol, on patients with hypertension. Supplementation of the patients with 100 mg Pycnogenol over a period of 12 weeks helped to reduce the dose of the calcium antagonist nifedipine in a statistically significant manner. The intake of Pycnogenol decreased endothelin-1 concentrations significantly compared to placebo while concentrations of 6-keto prostaglandin F1a in plasma were significantly higher compared to placebo. Values for nitric oxide (NO) in plasma increased in both groups, but the differences were not significant. Angiotensin II concentrations in plasma were lowered in the placebo group to a larger extent than in the Pycnogenol group. Heart rate, electrolytes and blood urea nitrogen were not changed during treatment in both groups of patients. Unwanted effects observed in both groups were of mild and transient nature, such as gastrointestinal problems, vertigo, headache and nausea. Differences in rate of side effects were not statistically significant between the two groups. Study results support a supplementation with Pycnogenol for mildly hypertensive patients. 相似文献
528.
TGR(mREN2)27 (TGR) transgenic rats develop hypertension due to the mouse mRen-2 gene inserted in their genome. At 5 weeks of age, the blood pressure of TGR rats starts rising, until a maximum is reached at 10 weeks of age. Adult TGR rats show peak values of blood pressure (BP) during the light phase, while heart rate (HR) and motor activity (MA) peak at night. In the present experiment, we evaluated the evolution of circadian rhythms in motor activity, heart rate, and blood pressure of TGR and Sprague-Dawley (SD) rats under 12h light-dark cycles (LD 12:12). Results confirmed that the blood pressure of TGR rats starts to increase at 5 weeks of age, reaching a plateau by the 11th week. Parallel to the increase in blood pressure levels, there was a decrease in the period length of the blood pressure rhythm, a delay in the onset of the alpha phase of the blood pressure rhythm with respect to that of motor activity and heart rate, and a decrease in heart rate levels. In all of the variables studied, the alpha phase of SD rats always started before darkness, whereas that of TGR rats started after lights off. In general, heart rate and motor activity levels of TGR rats were higher than those of SD rats. The amplitude of the circadian rhythms studied was greater in TGR rats than in SD rats. The present results suggest that the different evolution of circadian rhythms in TGR and SD rats might be due to differences in the functioning of the entrainment pathway or the circadian clock itself, which can be detected in young rats and that are probably caused by the expression of the mouse transgene. (Chronobiology International, 18(4), 627-640, 2001) 相似文献
529.
Yoshii H Tachi N Ohba R Sakamura O Takeyama H Itani T 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2001,128(1):27-33
Oligopeptides of 1 KDa or less were obtained by hydrolysis of chicken egg yolks with a crude enzyme, and by dialysis with a semipermeable membrane filter. Since the extracted peptides had an inhibitory action on the activity of angiotensin I-converting enzyme (ACE) in vitro, they were orally administered at 20, 100 and 500 mg/kg body weight to spontaneously hypertensive rats (SHR) for 12 weeks to analyze the physiological role on cardiovascular functions. The administered oligopeptides suppressed the development of hypertension at all dosages. After 12 weeks at 500 mg/kg body weight, the values for systolic, mean, and diastolic blood pressure were approximately 10% less in SHRs administered than controls. Furthermore, serum ACE activity of the peptide-administered groups was significantly lower than that of the control group in a dose-related manner. Our results imply that oligopeptides extracted from hen's egg yolks could potentially suppress the development of hypertension in SHR, and this effect might be induced by the inhibition of ACE activity. 相似文献
530.