Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense?

Both angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) interfere with the activity of the renin-angiotensin system (RAS) in a different way. Theoretically, one might expect beneficial effects when they are used in combination, as a more complete suppression of the RAS can be achieved. But can this additional effect still be seen in patients on full-dose ACE-inhibition? Several controlled trials demonstrated that combination therapy can have additional benefits in hypertensive patients, in chronic heart failure patients, and in both diabetic and non-diabetic nephropathy patients. However, the clinical benefit was not always as pronounced as expected and not every patient will benefit from dual blockade of the RAS. There is some evidence of a less pronounced effect of combination therapy when a full dose of the ACE-inhibitor is given. However, it is well known that ACE-inhibitors cannot completely suppress the formation of angiotensin II, in particular, when the RAS is activated. Indeed, clinical trials indicated that add-on therapy with an ARB was especially of use when the RAS remained activated despite full-dose ACE-inhibitor treatment. In summary, combination of a full-dose ACE-inhibitor and an ARB can be a rational choice in selected patients.     

Angiotensin II type 2 receptor gene polymorphisms and cardioprotective role in essential hypertension

Angiotensin II type 2 receptor (AT2R) has been proved to be involved in a cardioprotective role, but only a few studies have addressed the association of AT2R-genotype with this role. Whether the AT2R genotype is associated with hypertension is controversial. The aim of the study was to explore the information of single-nucleotide polymorphisms (SNPs) of the AT2R gene in Cantonese, an essential subpopulation of Chinese, and study the association of SNPs in the AT2R gene with hypertension, and to detect the genotypes that indicate a cardioprotective role. Two hundred and sixty-two patients with essential hypertension and 75 normotensive subjects were enrolled for a case-control study. All of the subjects were Cantonese. Sixteen individuals were chosen to sequence the AT2R gene and 16 SNPs were acquired. G/T rs5193 and G/A rs5194 were two SNPs in the 3′ untranslated region which were focused on the association of the AT2R-genotype and phonotype. Polymerase chain reaction was performed to amplify the fragment spanning the two SNPs. Genotype and haplotype were identified by dot blot hybridization. Four haplotypes in males (G-G, G-A, T-A, T-G) and eight haplotype combinations in females (G-G/G-G, G-A/G-A, G-G/G-A, G-G/T-A, G-G/T-G, T-A/T-A, T-G/T-G, and T-A/T-G) were detected. G-G and G-A haplotype were predominant, while T-A and T-G were rare in Cantonese. None of these was associated with hypertension. T-A carriers with essential hypertension indicated lower levels of left ventricular mass (LVM) and left ventricular hypertrophy index (LVHI). The levels of LVM and LVHI were still significantly lower in T-A carriers with hypertension adjusted for age or body mass index for men and women separately. No episodes of coronary heart disease and heart failure were detected in T-A carriers with hypertension. Haplotypes of G/T rs5193-G/A rs5194 are not associated with essential hypertension. Among these haplotypes, T-A may be implicated in a cardioprotective role to protect hypertense subjects from left ventricular hypertrophy.     

血管紧张素1-7：肾素-血管紧张素系统新调节因子

血管紧张素（Ang）1-7是肾素-血管紧张素系统的新调节因子，它能够拮抗AngⅡ的扩血管和促增殖等效应，并对肾脏发挥复杂的调节作用。通过药物作用干预血管紧张素酶2-Ang-（1-7）-Mas轴的功能，将会为心血管疾病、肾脏、肝脏疾病和糖尿病的治疗提供新的可能。     

P2X3受体在心血管疾病中的研究进展

P2X3受体属于嘌呤能受体P2X受体家族中的一员,主要表达于初级感觉神经元中.ATP作为P2X3受体的天然配体,在病理状态如神经损伤、心肌缺血时释放显著增加.与ATP结合后,P2X3受体将外周信号传入神经中枢,进一步引起病理生理变化.研究证实P2X3受体与各种病理性疼痛,尤其是炎症性疼痛有关.近年来发现P2X3受体在高...     

Changes in protein and gene expression of angiotensin II receptors (AT1 and AT2) in aorta of diabetic and hypertensive rats

Diabetes and hypertension have been associated with cardiovascular diseases and stroke. Some reports have related the coexistence of hypertension and diabetes with increase in the risk of developing vascular complications. Recently some studies have shown results suggesting that in the early stages of diabetes and hypertension exist a reduced functional response to vasopressor agents like angiotensin II (Ang II), which plays an important role in blood pressure regulation mechanism through the activation of its AT₁ and AT₂ receptors. For that reason, the aim of this work was to study the gene and protein expression of AT₁ and AT₂ receptors in aorta of diabetic SHR and WKY rats. Diabetes was induced by the administration of streptozotocin (60?mg/kg i.p.). After 4 weeks of the onset of diabetes, the protein expression was obtained by western blot and the mRNA expression by RT-PCR. Our results showed that the hypertensive rats have a higher mRNA and protein expression of AT₁ receptors than normotensive rats while the AT₂ expression remained unchanged. On the other hand, the combination of diabetes and hypertension increased the mRNA and protein expression of AT₁ and AT₂ receptors significantly. In conclusion, our results suggest that diabetes with hypertension modifies the mRNA and protein expression of AT₁ and AT₂ receptors. However, the overexpression of AT₂ could be associated with the reduction in the response to Ang II in the early stage of diabetes.     

Effects of blood pressure and the renin‐angiotensin system on platelet activation in type 2 diabetes

Aims/Introduction: Platelet‐derived microparticles (PDMP) are released from the platelets either after activation or in response to physical stimulation in vivo. The present study examined the association between blood pressure and PDMP, and the effects of high‐dose angiotensin receptor blockers (ARB) on PDMP in patients with type 2 diabetes. Materials and Methods: The study subjects consisted of 28 type 2 diabetes patients with blood pressure ≥130/80 mmHg who were treated with valsartan (80 mg daily). The patients were randomly assigned to take either 80 mg of telmisartan (Tel group) or 160 mg of valsartan (Val group) and then were followed up for 24 weeks. Thereafter, the patients were switched to combination therapy (5 mg of amlodipine with 40 mg of telmisartan [Tel group] or 80 mg of valsartan [Val group]) for 12 weeks. Results: Although the ambulatory blood pressure did not change, the PDMP levels were significantly decreased from baseline to week 24 (high dose ARB). In contrast, combination therapy reduced both blood pressure and PDMP levels compared with the baseline. Although the PDMP level was significantly correlated with the morning BP elevation at baseline and week 36 (combination therapy), this same relationship was not found at week 24. There were no significant differences in the blood pressure and PDMP levels between the two groups. Conclusions: Patients with morning hypertension might be at risk for cardiovascular diseases. High‐dose renin‐angiotensin system inhibition and blood pressure control are both considered to reduce cardiovascular events in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00048.x, 2010)     

Home Blood Pressure Control After the Great East Japan Earthquake in Patients on Chronic Hemodialysis

At 14:46 on 11 March 2011, northeastern Japan was struck by a major earthquake measuring 9.0 on the Richter scale (the Great East Japan Earthquake). Several reports have suggested a transient blood pressure (BP) increase after a major earthquake, but its impact on BP in chronic dialysis patients has not been reported. In a retrospective review of 25 hemodialysis patients who were residents of Koriyama City, changes in the morning home BP after the earthquake were investigated. Home systolic and diastolic BPs were significantly elevated 1 week after the earthquake (158 ± 16 mm Hg vs. 151 ± 13 mm Hg, P < 0.01, for systolic; 81 ± 13 mm Hg vs. 78 ± 11 mm Hg, P = 0.01, for diastolic). Mean home BP 1 week after the earthquake was unchanged from baseline in patients treated with sympatholytics and/or renin‐angiotensin system (RAS) inhibitors. BP values returned to baseline by 4 weeks after the earthquake, but percent changes in mean BP were significantly greater even 2 weeks, 4 weeks, and 6 weeks after the earthquake in patients not treated with RAS inhibitors than in those treated with RAS inhibitors (2 weeks 7.0% ± 4.5% vs. 0.2% ± 5.0%, P < 0.01; 4 weeks 4.4% ± 5.9% vs. ?1.8% ± 5.3%, P = 0.02; 6 weeks 4.6% ± 4.9% vs. ?1.9% ± 3.9%, P < 0.01). On multiple regression analysis, RAS inhibitor use had an independent relationship with percentage increases in mean BP during the 6 weeks after the earthquake. Home BP was significantly increased after a major earthquake in patients on chronic hemodialysis. Prolonged deterioration of BP control after the earthquake was associated with non‐use of RAS inhibitors.     

血管紧张素受体阻滞药应作为卒中一级和二级预防的一线用药吗?

对于卒中的一级和二级预防,血压仍然是单个最重要的可干预危险因素.具有里程碑意义的培哚普利保护复发性卒中研究(Perindopril Protection Against Recurrent Stroke Study,PROGRESS)试验表明,卒中后至少2周开始血管紧张素转换酶抑制药(angiotensin-converting-enzyme inhibitor,ACEI)培哚普利降压治疗,可降低复发性卒中和其他心血管事件的风险.虽然大多数系统评价提示几乎所有类型的抗高血压药预防卒中的效果相似,但也存在一些重要的例外.单用替米沙坦或与雷米普利联合应用改善总体终点指标试验(Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial,ONTARGET)证实,血管紧张素受体阻滞药(angiotensin receptor blocker,ARB)替米沙坦在预防血管病或糖尿病患者的心血管事件方面与雷米普利等效;而在相似人群中,雷米普利预防卒中相当有效.人们根据ARB对肾素-血管紧张素-醛固酮系统的调节作用推测,其有优于其他降血压药的卒中保护作用.但是,多方面的临床试验提示,ARB在卒中预防中并无独特的作用.因此,对是否应将ARB作为卒中一级和二级预防的一线用药一直存在着争论.     

血管紧张素Ⅱ1型受体基因A1166C多态性与高血压肾脏损害相关性研究

目的:探讨血管紧张素Ⅱ1型受体(AT1R)A1166C多态性与高血压、高血压肾脏损害的关系。方法:入选188例原发性高血压患者进行尿微量白蛋白和AT1R基因A1166C多态性测定。结果:AA基因型与AC基因型收缩压分别为(149·1±20·8)mmHg(1mmHg=0·133kPa)和(137·8±22·6)mmHg,2组间差异有显著性(P=0·013)。AC基因型携带者尿微量白蛋白尿异常者明显增多,差异有显著性(P=0·006)。结论:AT1R基因A1166C多态性可能与原发性高血压和高血压肾脏损害有关。     

Saga of Renin‐Angiotensin System and Calcium Channels in Hypertensive Diabetics: Does it Have a Therapeutic Edge?

Current understanding of the genesis of diabetic vascular disease suggests that vascular complications, such as atherosclerosis and hypertension, are associated with changes in structural and functional parameters. Experimental and epidemiological data suggest that activation of the renin‐angiotensin‐aldosterone system plays an important role in the development of micro‐ and macro‐vascular complications. Most of the negative cardiovascular actions of angiotensin II are mediated through AT₁ receptors, whereas the AT₂ receptors mediate largely beneficial effects. Hence, compared to angiotensin converting enzyme inhibitors (ACEIs), selective AT₁ receptor blockers (ARBs) should provide additional end organ protection via AT₂ receptors activation. Although ACEIs are useful therapeutically, they are being currently displaced by ARBs. Enhanced calcium ion channel activity is reported in vascular smooth muscles from diabetic animal models. Clinical benefits of calcium channel blockers (CCBs) in diabetic hypertensive patients are controversial, but there is increasing experimental evidence for the beneficial effects of dihydropyridine‐type CCBs. Although the treatment of hypertension in diabetics reduces cardiovascular and microvascular complications, the ideal strategy for treating hypertension in diabetics has not been well defined and warrants a combination approach. Only limited clinical data regarding the use of ARBs in combination with CCBs in diabetics are available. The experimental data suggest that combination of a CCB and an AT₁ receptor blocker, or a hypothetical dual blocker of AT₁ receptors as well as of calcium channels would be an ideal regimen. There is, however, no conclusive clinical evidence to support the combined use of these drugs. This review highlights the available experimental data that support the therapeutic benefits of this combination.     

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.     

心肌梗死后β2受体对心肌细胞L型钙通道电流的调控作用

目的研究β2肾上腺素受体（β2受体）对心肌梗死后心肌细胞L型钙通道电流（‰）的调控作用。方法Wistar大鼠随机分为正常对照和心肌梗死组，制作心肌梗死模型。分离心肌细胞，应用全细胞膜片钳技术，观察心肌梗死后ICaL变化，先后给予β2受体激动剂salbutamol（10μmol／L）及β2受体阻滞剂ICI118，551（0．1μmol／L）后再观察ICaL的变化。结果心肌梗死后8周ICaL显著减低37．0％（P〈0.05）。在正常和梗死后8周后心肌细胞，β2受体激动剂均显著增加ICaL（P〈0．05），心肌梗死后对ICaL的调节作用较正常心肌细胞增强（23．4％±1．7％对33．1％±3．3％，P〈0.05），这种作用可被抑制型G调节蛋白（Gi蛋白）抑制剂放大，被环磷酸腺苷依赖蛋白激酶（PKA）拈抗剂抑制。结论β2受体对ICaL具有调节作用，且心肌梗死后这种调节作用增强，提示心肌梗死后β2受体在恶性心律失常发生中的作用可能提高。     

Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells

Both renin–angiotensin systems and insulin participate in kidney-involved blood pressure regulation. Activation of angiotensin II type 2 receptor (AT₂R) decreases sodium reabsorption in renal proximal tubule (RPT) cells, whereas insulin produces the opposite effect. We presume that AT₂R has an inhibitory effect on insulin receptor expression in RPT cells, which may affect renal sodium transport and therefore be of physiological or pathological significance. Our present study found that activation of AT₂R inhibited insulin receptor expression in a concentration and time-dependent manner in RPT cells from Wistar-Kyoto (WKY) rats. In the presence of a protein kinase C (PKC) inhibitor (PKC inhibitor peptide 19–31, 10^?6 mol/L) or a phosphatidylinositol 3 kinase inhibitor (wortmannin, 10^?6 mol/L), the inhibitory effect of AT₂R on insulin receptor was blocked, indicating that both PKC and phosphatidylinositol 3 kinase were involved in the signaling pathway. There was a linkage between AT₂R and insulin receptor which was determined by both laser confocal microscopy and coimmunoprecipitation. However, the effect of AT₂R activation on insulin receptor expression was different in RPT cells from spontaneously hypertensive rats (SHRs). Being contrary to the effect in WKY RPT cells, AT₂R stimulation increased insulin receptor in SHR RPT cells. Insulin (10^?7 mol/L, 15 minutes) enhanced Na⁺-K⁺-ATPase activity in both WKY and SHR RPT cells. Pretreatment with CGP42112 decreased the stimulatory effect of insulin on Na⁺-K⁺-ATPase activity in WKY RPT cells, whereas pretreatment with CGP42112 increased it in SHR RPT cells. It is suggested that activation of AT₂R inhibits insulin receptor expression and function in RPT cells. The lost inhibitory effect of AT₂R on insulin receptor expression may contribute to the pathophysiology of hypertension.     

Angiotensin receptor blockers: evidence for preserving target organs

Hypertension is a major problem throughout the developed world. Although current antihypertensive treatment regimens reduce morbidity and mortality, patients are often noncompliant, and medications may not completely normalize blood pressure. As a result, current therapy frequently does not prevent or reverse the cardiovascular remodeling that often occurs when blood pressure is chronically elevated. Blockade of the renin-angiotensin system (RAS) is effective in controlling hypertension and treating congestive heart failure. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit the activity of the RAS, but these two classes of antihypertensive medications have different mechanisms of action and different pharmacologic profiles. Angiotensin-converting enzyme inhibitors block a single pathway in the production of angiotensin II (Ang II). In addition, angiotensin I is not the only substrate for ACE. The ACE inhibitors also block the degradation of bradykinin that may have potential benefits in cardiovascular disease. Bradykinin is, however, the presumed cause of cough associated with ACE inhibitor therapy. Data from clinical trials on ACE inhibitors serve to support the involvement of the RAS in the development of cardiovascular disease. Angiotensin receptor blockers act distally in the RAS to block the Ang II type 1 (AT1) receptor selectively. Thus, ARBs are more specific agents and avoid many side effects. Experimental and clinical trials have documented the efficacy of ARBs in preserving target-organ function and reversing cardiovascular remodeling. In some instances, maximal benefit may be obtained with Ang II blockade using both ARBs and ACE inhibitors. This review describes clinical trials that document the efficacy of ARBs in protecting the myocardium, blood vessels, and renal vasculature.