Antihypertensive Efficacy of Olmesartan Medoxomil, a New Angiotensin II Receptor Antagonist, as Assessed by Ambulatory Blood Pressure Measurements

Olmesartan medoxomil is a new angiotensin II receptor blocker. In this randomized, double-blind, placebo-controlled study, the efficacy and safety of olmesartan medoxomil was assessed in 334 patients with moderate to severe essential hypertension. Patients were randomized to receive placebo; 5, 20, or 80 mg olmesartan medoxomil q.d.; or 2.5, 10, or 40 mg olmesartan medoxomil b.i.d. Ambulatory and cuff blood pressure were measured prior to and after 8 weeks of treatment. Treatment with olmesartan medoxomil resulted in a significant placebo-adjusted reduction of mean 24-hour ambulatory diastolic blood pressure of 9.6 mm Hg, 12.2 mm Hg, and 10.6 mm Hg in the 5-, 20-, and 80-mg q.d. groups, respectively. Corresponding reductions in mean ambulatory systolic blood pressure were 14.5 mm Hg, 16.5 mm Hg, and 15.4 mm Hg. Similar reductions of diastolic and systolic blood pressure were seen with b.i.d. dosing. The diastolic trough-to-peak ratios of the q.d. doses of olmesartan medoxomil ranged from 57%–70%, indicating 24-hour effectiveness. The safety profile of olmesartan medoxomil was similar to that of placebo. Olmesartan medoxomil appears to be a safe and effective once-a-day treatment for hypertension.     

Angiotensin II Receptor Antagonists and Hypertension

Over recent years, a number of imidazole derivatives that specifically bind to the angiotensin II type 1 receptor, therafter called sartans, have been developed and made available to the clinician. Whether targeting antihypertensive treatment with such a high specificity within the renin cascade may carry major clinical advantage over inhibiting angiotensin converting-enzyme remains to be demonstrated. In short-term studies, the efficacy of these drugs at reducing blood pressure was similar to that of established comparators, whereas overall side effect profile was comparable to that of placebo.     

Cardioprotective Effects of Angiotensin II Type 1 Receptor Blockade with Olmesartan on Reperfusion Injury in a Rat Myocardial Ischemia‐Reperfusion Model

We determined the effects of olmesartan on infarct size and cardiac function in a rat ischemia/reperfusion model. Rats underwent 30 min of left coronary artery (CA) occlusion followed by 2 h of reperfusion. In protocol 1, the rats received (by i.v.) 1 mL of vehicle at 10 min after CA occlusion (Group 1, n = 15); olmesartan (0.3 mg/kg) at 10 min after CA occlusion (Group 2, n = 15); 1 mL of vehicle at 5 min before CA reperfusion (Group 3, n = 15); or olmesartan (0.3 mg/kg) 5 min before CA reperfusion (Group 4, n = 15). In protocol 2, the rats received (by i.v.) 1 mL of vehicle at 5 min before CA reperfusion (Group 5, n = 21); or olmesartan (3 mg/kg) at 5 min before CA reperfusion (Group 6, n = 21). Systemic hemodynamics, left ventricular (LV) function, LV ischemic risk zone, no‐reflow zone, and infarct size were determined. In protocol 1, olmesartan (0.3 mg/kg) did not affect blood pressure (BP), heart rate, LV ± dp/dt or LV fractional shortening during the experimental procedure, and did not alter no‐reflow or infarct size. In protocol 2, olmesartan (3 mg/kg) significantly reduced infarct size to 21.7 ± 4.1% from 34.3 ± 4.1% of risk zone in the vehicle group (P= 0.035), but did not alter the no‐reflow size. Prior to CA reperfusion, olmesartan (3 mg/kg) significantly reduced mean BP by 22% and LV ±dp/dt, but did not affect heart rate. At 2 h after reperfusion, olmesartan significantly decreased heart rate by 21%, mean BP by 14%, and significantly increased LV fractional shortening from 54.1 ± 1.4% to 61.3 ± 1.6% (P= 0.0018). Olmesartan significantly reduced myocardial infarct size and improved LV contractility at a dose (3 mg/kg) with systemic vasodilating effects but not at a lower dose (0.3 mg/kg) without hemodynamic effects.     

Angiotensin II Type 1 Receptor Antagonist Suppress Angiogenesis and Growth of Gastric Cancer Xenografts

Angiotensin II (Ang II) has been reported to promote tumor progression, tumor growth and angiogenesis in many cancers. We previously observed that angiotensin II type1 receptors (AT1R) were upregulated in human gastric cancer and may be involved in the progression of gastric cancer. We studied the effects of AT1R antagonist on angiogenesis and growth in gastric cancer xenografts to observe the mechanism action of AT1R in the gastric cancer. The results showed that the growth of gastric cancer cells was significantly suppressed by treatment with AT1R antagonist. In vivo, TCV-116, at doses of both 2 and 5 mg/kg/day, significantly suppressed tumor growth in mice (47.3 and 70.2%). Microvessel density was significantly decreased by TCV-116 (3.4 ± 0.9 and 2.8 ± 0.5 per field) compared with the control group (12.9 ± 1.1 per field), and VEGF expression was significantly suppressed by AT1R antagonist. These results demonstrate that AT1R plays an important role in the progression of gastric cancer. Suppression tumor angiogenesis could be one of the mechanisms by which AT1R antagonist suppresses the growth of gastric cancer. These findings also provide a theoretical basis for the future clinical application of AT1R antagonist against gastric cancer.     

A Review on Telmisartan: A Novel,Long‐Acting Angiotensin II‐Receptor Antagonist

Telmisartan is a potent, long‐lasting, nonpeptide antagonist of the angiotensin II type‐1 (AT₁) receptor that is indicated for the treatment of essential hypertension. It selectively and insurmountably inhibits stimulation of the AT₁ receptor by angiotensin II without affecting other receptor systems involved in cardiovascular regulation. Very high lipophilicity, a unique feature of telmisartan, coupled with a high volume of distribution, indicate that the compound offers the clinically important advantage of good tissue penetration. Telmisartan is not a prodrug and has a longer terminal elimination half‐life than other commercially available sartans (～24 h), making it suitable for once‐daily dosing. The compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for P450‐based drug interactions. In animal models, telmisartan exhibits pronounced cardio‐and renoprotective effects in animals with severe, essential hypertension. In clinical studies, telmisartan shows comparable antihypertensive activity to members of other major antihypertensive classes, such as ACE inhibitors, beta blockers and calcium antagonists. These trials have confirmed the placebo‐like safety and tolerability of telmisartan in hypertensive patients. Based on these data, telmisartan offers advantages over other sartans and represents an important new treatment option for hypertension.     

奥美沙坦酯治疗轻度及中度原发性高血压疗效和安全性的评价

目的:评价奥美沙坦酯治疗轻度及中度原发性高血压的疗效和安全性。方法:80例轻度及中度原发性高血压患者随机接受奥美沙坦酯20 mg或缬沙坦80 mg治疗,每日1次,总疗程8周。结果:奥美沙坦酯组治疗前的收缩压(SBP)/舒张压(DBP)为(155.2±11.4)/(96.1±5.2)mmHg(1 mmHg=0.133 kPa),治疗后的血压为(138.8±10.2)/(86.5±4.8)mmHg,血压下降幅度为(16.4±8.1/9.6±5.1)mmHg。缬沙坦组治疗前的SBP/DBP为(156.1±12.2)/(97.2±5.1)mmHg,治疗后的血压为(139.5±10.4)/(88.0±5.5)mmHg,血压下降幅度为(15.6±7.8/9.1±4.9)mmHg。2组治疗前后血压下降幅度差异均有统计学意义(P<0.01),2组间差异无统计学意义(P>0.05)。奥美沙坦酯组和缬沙坦组降压显效率分别为59.0%和60.5%,总有效率分别为87.2%和86.8%,2组间差异无统计学意义。本实验中奥美沙坦酯组出现不良反应者少。结论:奥美沙坦酯治疗轻度及中度原发性高血压疗效确切,且安全可靠。     

In Vivo Pharmacology of L-159,913, A New Highly Potent and Selective Nonpeptide Angiotensin II Receptor Antagonist

The present study was designed to characterize the in vivo pharmacology of L-159,913 (4-[[2′-(N-benzoylsulfamoyl)biphenyl-4-yl]-5butyl-2,4-dihydro-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazcl-3-one); a potent All receptor antagonist. In normotensive rats, dogs, rhesus monkeys, and chimpanzees, L-159,913 inhibited All-induced elevations in blood pressure. In conscious rats, the relative potencies (ED₅₀) were 0.51 mg/kg i.v. and 0.72 mg/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. L-159,913 was 3 times less potent than losartan in rats and equipotent to losartan in monkeys. All induced elevation of plasma aldosterone in rats was also inhibited by L-159,913. L-159,913 was antihypertensive in high renin hypertensive rats (aortic coarctation). The maximum hypotensive response to an acute dose of L-159,913 (10 mg/kg, PO) was equal to that of enalaprilat (0.3 mg/kg, iv) in this renin dependent animal model. In conscious normotensive dogs, L-l59,913 had a moderate diuretic, natriuretic and kaliuretic response with no effect on glomerular filtration rate, effective renal plasma flow or filtration fraction, suggesting a tubular site of action. L-159,913 is a selective and potent All receptor antagonist with good oral activity, long duration of action and antihypertensive efficacy.     

Cardioprotective Effect of Enalapril in Renovascular and Angiotensin II Hypertension

The influence of chronic treatment with enalapril or losartan (10 or 30mg/kg/24h, respectively) on cardiac mass was evaluated in one-kidney, one clip (1K-1C) hypertensive rats submitted to sodium restriction 3 weeks after clipping and in rats infused for 10 days with angiotensin II (ANGII: 200ng/kg/min). In 1K-1C hypertension, cardiac mass and arterial pressure were reduced to a similar extent by enalapril and losartan. In ANGII hypertension, enalapril and losartan blunted the increase in cardiac mass whereas losartan but not enalapril prevented the development of hypertension. The cardioprotective effect of enalapril was attenuated by concomitant blockade of bradykinin receptors (Hoe 140: 300pg/kg/24h) in both models. The beneficial influence of enalapril on cardiac mass appears to be independent of its effect on blood pressure and ANGII generation and seems partly mediated by endogenous bradykinin in these high ANGII models of hypertension.     

血管紧张素转化酶基因I／D多态性与奥美沙坦酯降压疗效的临床研究

目的：探讨血管紧张素转化酶（ACE）基因I／D多态性与奥美沙坦酯降压疗效的关系。方法：高血压患者服用奥美沙坦酯8周,在观察降压疗效的同时,用PCR—RFLP方法对患者血白细胞基因组DNA多态性位点ACEI／D基因型进行检测;按不同ACE基因型进行分组,比较不同基因型患者的血压下降值、降压总有效率的差异。结果：ACE基因ID＋DD基因型和II基因型患者使用奥美沙坦酯8周后收缩压下降幅度分别为16．23±6．51mmHg（2．164±0．868kPa,1kPa=7．5mmHg）、5．10±8．66mmHg,降压总有效率分别为81．25％、33．34％,组间比较有统计学差异（P〈0．05）;舒张压下降幅度分别为13．34±7．25mmHg、6．21±5．29mmHg,组间比较无统计学差异（P〉0．05）。结论：ACE基因ID＋DD基因型高血压患者对奥美沙坦酯降压治疗较敏感。     

Efficacy of Irbesartan, a Receptor Selective Antagonist of Angiotensin II, in Reducing Portal Hypertension

The use of angiotensin II antagonists in the treatment of portal hypertension remains controversial. Our aims were to assess the effect of Irbesartan on portal pressure and to evaluate its safety in cirrhotic patients with portal hypertension. Twenty-five cirrhotic patients were treated in a pilot study with Irbesartan 300 mg orally once daily for 60 days. Hemodynamic evaluations and biochemical tests were performed before therapy and after two months of treatment. Three patients (12%) discontinued treatment for symptomatic arterial hypotension (mean arterial pressure –26.% ± 3.1 versus basal). In the 18 responders, the hepatic venous pressure gradient diminished by a mean of 18.1% ± 10.5 from baseline (p = 0.02); the gradient decreased by 20% or more in only 5 patients (23%). The mean arterial pressure decreased significantly during therapy (92 ± 7 vs 109 ± 25 mm Hg, P < 0.001). In conclusions, Irbesartan induced a marginal reduction in portal pressure and its safety was limited by the pronounced effects on arterial pressure.     

血管紧张素 II 受体阻滞剂治疗肥厚型心肌病的Meta 分析

目的 使用Meta分析的方法,评价血管紧张素Ⅱ受体拮抗剂（ARBs）类药物对肥厚型心肌病（HCM）的疗效。方法 检索Web of Science, PubMed, EMBASE,Cochrane Central Register of Controlled Trials,中国知网（CNKI）,中国生物医学文献光盘数据库（CBMdisk）的文献。纳入与安慰剂或常规治疗相比较的临床随机对照试验,分析ARB类药物治疗HCM的效果。结果 包括228例患者的6个随机对照试验纳入Meta分析,研究显示ARB类药物对于左室射血分数、二尖瓣舒张早期最大血流速度（E）与舒张晚期最大血流速度（A）及左室质量的影响未见统计学差异。结论 ARB类药物对于HCM患者的心脏功能可能没有影响。     

Effects of Olmesartan, an Angiotensin II Receptor Blocker, on Mechanically-Modulated Genes in Cardiac Myocytes

Background: Angiotensin II plays an important role in cardiac hypertrophy or remodeling. Angiotensin II receptor blockers (ARB) are clinically useful for the treatment of hypertension and heart failure. However, the molecular effects of ARB in the mechanically-stressed myocardium have not been completely defined. We investigated the effects of ARB on mechanically-modulated genes in cardiac myocytes. Methods: We used powerful DNA microarray technology to study the effects of the ARB, CS-886 (olmesartan), on genes modulated in neonatal rat cardiac myocytes using mechanical stimuli. Mechanical deformation was applied to a thin and transparent membrane on which neonatal rat cardiac myocytes were cultured in the presence or absence of RNH-6270, an active metabolite of CS-886. Expression profiles of 8000 rat genes using the Affymetrix GeneChip (Rat Genome U34A) were investigated with mRNA obtained from the samples above. Results: Nine genes induced under 4% mechanical strain were significantly suppressed by RNH-6270 in rat cardiac myocytes: monoamine oxidase B, neuromedine B receptor, olfactory receptor, synaptotagmin XI, retinol-binding protein, and 4 expressed sequence tags (ESTs). In contrast, 21 genes suppressed under mechanical strain were significantly restored by RNH-6270: major acute phase alpha 1-protein, Sp-1, Bcl-Xalpha, JAK2, 2 genes encoding detoxification, few genes for receptor, structure, metabolism or ion channel, and 10 ESTs. Conclusions: As some of these genes may be involved in promoting or modulating cardiac remodeling, these findings suggest that ARB may affect cardiovascular morbidity and mortality partially via these molecular alterations.