Treatment with AT(1) receptor blocker restores diabetes-induced alterations in intracellular Ca(2+) transients and contractile function of rat myocardium

We investigated the effect of treatment with an angiotensin II receptor blocker, candesartan-cilexetil, on the mechanical and electrophysiological properties of cardiomyocytes isolated from streptozotocin-induced diabetic (STZ) rats. Contractile activity and electrophysiological properties were measured in papillary muscle and ventricular cardiomyocytes from normoglycemic and STZ-induced diabetic rats given vehicle or 5mg/kg/day candesartan-cilexetil for 4 weeks. Alterations in the kinetics of contractile activity and intracellular Ca(2+) transients were observed as well as a typical prolongation of action potential duration and significant decrease of potassium currents in diabetic rat heart preparations. Candesartan-cilexetil treatment recovered significantly prolonged action potential and depressed potassium currents in diabetic rats. It was also shown that treatment with AT(1) blocker restored altered kinetics of both the Ca(2+) transients in cardiomyocytes and the contractile activity in papillary muscle strips of diabetic rats. We also showed that incubation of cardiomyocytes from diabetic rats with a protein kinase C (PKC) inhibitor bisindolylmaleimide I (BIM) had a similar effect to candesartan treatment on the Ca(2+) transients. Thus, angiotensin II receptor blockade protects the heart from the development of cellular alterations typically related with diabetes, and this action of AT(1) receptors seems to be related with the activity of PKC.     

坎地沙坦酯与银杏注射液对慢性肺心病急性加重期患者肺动脉压的影响

目的:探究坎地沙坦酯联合银杏注射液对慢性肺心病急性加重期患者肺动脉压、血管内皮生长因子水平及临床疗效的影响。方法:收集我院诊治的慢性肺心病急性加重期患者134例,随机分为对照组和试验组,每组67例。对照组患者口服坎地沙坦酯片治疗,试验组患者在对照组基础上联合静脉滴注银杏注射液治疗。观察并比较两组患者的临床疗效、治疗前后的肺动脉压及血管内皮生长因子水平变化情况。结果:治疗后,两组肺动脉压及血管内皮生长因子水平均较治疗前显著降低(P0.05),与对照组相比,试验组患者治疗总有效率较高(P0.05),肺动脉压及血管内皮生长因子水平较低(P0.05)。结论:坎地沙坦酯联合银杏注射液对慢性肺心病急性加重期患者疗效明显,能够有效降低肺动脉压,可能与降低血管内皮生长因子水平有关。     

Determination of candesartan cilexetil, candesartan and a metabolite in human plasma and urine by liquid chromatography and fluorometric detection

Liquid chromatographic methods are described for the determination of a new effective anti-hypertensive drug candesartan (CV-11974), its prodrug candesartan cilexetil (TCV-116) and a metabolite, CV-15959 in human plasma and urine. The assays comprise liquid–liquid extraction and separation on a phenyl column with fluorometric detection. The methods give absolute recoveries of 70, 83 and 78% for candesartan cilexetil, candesartan and CV-15959, respectively, and the limit of quantification is 5, 1 and 3 nM of plasma (RSD<20%), respectively. The methods were applied to plasma and urine samples from biopharmaceutical and clinical studies in man.     

The application of solid-state NMR spectroscopy to study candesartan cilexetil (TCV-116) membrane interactions. Comparative study with the AT1R antagonist drug olmesartan

ΑΤ1 receptor (AT1R) antagonists exert their antihypertensive effects by preventing the vasoconstrictive hormone AngII to bind to the AT1 receptor. It has been proposed that these biological effects are mediated through a two-step mechanism reaction. In the first step, they are incorporated in the core of the lipid bilayers and in the second step they reach the active site of the receptor through lateral diffusion. In this model, drug/membrane interactions are key elements for the drugs achieving inhibition at the AT1 receptor. In this work, the interactions of the prodrug candesartan cilexetil (TCV-116) with lipid bilayers are studied at molecular detail. Solid-state ¹³C-CP/MAS, 2D ¹H-¹H NOESY NMR spectroscopy and in silico calculations are used. TCV-116 and olmesartan, another drug which acts as an AT1R antagonist are compared for their dynamic effects in lipid bilayers using solid-state ²H-NMR. We find a similar localization of TCV-116 compared to other AT1 antagonists in the intermediate polar region. In addition, we can identify specific local interactions. These interactions may be associated in part with the discrete pharmacological profiles observed for different antagonists.