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Telmisartan (Micardis, Pritor), a highly selective angiotensin II (AII) type 1 (AT1) receptor antagonist, is approved for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents. The long elimination half-life of telmisartan ensures the drug provides effective reductions in blood pressure (BP) across the entire 24-hour dosage interval. Extensive evidence from well designed clinical trials and the clinical practice setting indicates that telmisartan, either as monotherapy or in combination with other antihypertensive agents, provides long-term antihypertensive efficacy and is well tolerated in a broad spectrum of hypertensive patients, including the elderly and those with coexisting type 2 diabetes mellitus, metabolic syndrome and/or renal impairment. Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 6 hours of this period. Independent of its effect on BP, telmisartan displays favourable effects on insulin resistance, lipid levels, left ventricular hypertrophy (LVH) and renal function. The consistent antihypertensive efficacy during the entire 24-hour dosage interval and sustained BP-lowering effect in the long term, combined with its favourable tolerability profile, mean that telmisartan is a valuable first-line treatment option for the management of essential hypertension.
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PMID:Telmisartan: a review of its use in the management of hypertension. 1639 68

Reference data on the function of renin-angiotensin-aldosterone system (RAAS) and pharmacological correction of its hyperactivity are summarized and analyzed in the paper. RAAS plays important role in the development and worsening of hypertension, facilitates proliferation of smooth muscle and heart cells. The hyperactivity of RAAS promotes the development of cardiovascular complications, such as myocardial infarction, stroke, increases cardiovascular mortality and morbidity. Pharmacological correction of RAAS hyperactivity decreases hypertension, prevents occlusion of heart and blood vessels, provides anti-ischemic action, vascular and cardiac protection, improves life style, prevents cardiovascular mortality, such as fatal stroke, myocardial infarction and sudden death. b-blocker inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin AT1-receptors blockers are reviewed as first line therapy of essential hypertension and congestive heart failure. ACT inhibitors, AT1- receptor blockers decrease total cholesterol, LDL, but increase HDL, beta-blockers decrease HDL. AT1-blockers are alternative drugs for treatment of cardiovascular diseases in those cases where ACE inhibitors are contraindicated or intolerance exists.
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PMID:[Pharmacological correction of hyperactivity of renin-angiotensin-aldosterone system]. 1644 43

Hypertension produces pathophysiological changes that are often responsible for the mortality associated with the disease. It is evident that overactive renin-angiotensin systems play a central role in the development of hypertension and target organ damage associated with hypertension. We have previously found that a novel angiotensin II receptor (AT1) vaccine-ATR12181 attenuated the development of high blood pressure (BP) in spontaneously hypertensive rat (SHR) model of human essential hypertension. Our objective was to determine whether this attenuation of high BP is associated with prevention of target organ damage induced by hypertensive state. SHRs were immunized against a peptide (coded ATR12181) from the extracelluar portion of the AT1A receptor by repeated subcutaneous injections of peptide-tetanus-toxoid complex in combination with Freund's adjuvant. A 64 weeks long-term observation was performed. Repeated vaccinations resulted in the induction of anti-ATR12181 antibodies. At the end of observation, vaccinated SHRs manifested lower BP, decreased cardiac hypertrophy and attenuation of kidney injuries. mRNA levels of c-fos and c-jun in heart and kidneys were decreased in vaccinated SHRs. Since a self antigen was used, safety of vaccine was concerned. However, the signs of autoimmune diseases were not observed in the sections of heart and kidney. These data demonstrated that repeated immunization against a domain of the extracellular portion of the AT1 receptor was able to cause a target organ protection against hypertension. Active immunization against the AT1 receptor may be considered as a promising new strategy in the treatment of hypertension.
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PMID:Target organ protection from a novel angiotensin II receptor (AT1) vaccine ATR12181 in spontaneously hypertensive rats. 1669 97

The renin-angiotensin-aldosterone system (RAAS) plays a relevant role not only in the pathophysiology of essential hypertension, but also in the development of hypertensive target organ damage. Different drugs acting on RAAS components are now available: angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II AT1 receptors blockers (ARBs), non-selective and selective aldosterone antagonists. The review will focus on their effects on hypertensive organ damage. In fact, apart from the well known efficacy in reducing blood pressure, all these drugs have been demonstrated to protect against target organ damage, reversing or preventing its development. The main issues addressed will be: effects of the RAAS blockade on heart and kidney disease, protective action against arterial wall damage, with a focus on the endothelial protection. The comparison among ACE inhibitors, ARBs and aldosterone antagonists will be discussed, with specific reference to different class and/or drug effects and to the results of few studies evaluating the effects of combination therapy with different drugs blocking the RAAS.
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PMID:Blockade of the renin-angiotensin-aldosterone system: effects on hypertensive target organ damage. 1684 7

Essential hypertension is a common disease, yet its pathogenesis is not well understood. Altered control of sodium excretion in the kidney may be a key causative feature, but this has been difficult to test experimentally, and recent studies have challenged this hypothesis. Based on the critical role of the renin-angiotensin system (RAS) and the type I (AT1) angiotensin receptor in essential hypertension, we developed an experimental model to separate AT1 receptor pools in the kidney from those in all other tissues. Although actions of the RAS in a variety of target organs have the potential to promote high blood pressure and end-organ damage, we show here that angiotensin II causes hypertension primarily through effects on AT1 receptors in the kidney. We find that renal AT1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. When AT1 receptors are eliminated from the kidney, the residual repertoire of systemic, extrarenal AT1 receptors is not sufficient to induce hypertension or cardiac hypertrophy. Our findings demonstrate the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications. Further, they suggest that the major mechanism of action of RAS inhibitors in hypertension is attenuation of angiotensin II effects in the kidney.
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PMID:Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. 1709 Jun 78

Although polymorphisms in renin-angiotensin-aldosterone (RAA) system genes for angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE I/D), angiotensin II type 1 receptor (AT1 A/C1166), and aldosterone synthase (CYP11B2-344T/C) have been major targets for genetic investigation in association with essential hypertension (EH), the influence of these genetic factors is still to be determined. Because patients with young-onset EH are thought to possess a stronger genetic background than EH patients who show elevated BP relatively late in life, the targeted screening of hypertensive students in Tohoku University was completed for the selection of subjects for genetic investigation. Out of 16,434 students (12,794 males and 3,670 females) younger than 30, 22 students showed a high blood pressure (BP) (systolic and diastolic BP of 140 and/or 90 mmHg or greater, respectively, on two occasions and more than 135 and/or 85 mmHg, respectively, at a third measurement during casual BP measurements at the Tohoku University Health Center. These 22 students were asked to measure their BP at home (HBP). Six of the students had a systolic HBP of more than 135 mmHg and/or a diastolic HBP of more than 85 mmHg, and these students subsequently received medical examinations at Tohoku University Hospital and were diagnosed with EH. Genotyping for the four major genetic polymorphisms mentioned above was performed on the six students with EH and on 12 of the remaining 16 students whose HBP was within the normal range (white coat hypertension: WCH). Neither the EH nor the WCH students showed a different distribution of genotypes and allelic frequencies, compared to those found in the general Japanese population. Hence, the present study suggests that none of the major genetic polymorphisms in the RAA system strongly influence the onset of EH.
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PMID:Investigation of major genetic polymorphisms in the Renin-Angiotensin-aldosterone system in subjects with young-onset hypertension selected by a targeted-screening system at university. 1719 Jul 32

Essential hypertension is considered a multifactorial trait resulting from a combination of environmental and genetic factors. The angiotensin II type 1 receptor mediates the vasoconstrictor and growth-promoting effects of Ang II. The A1166C polymorphism of the AT1 receptor gene may be associated with cardiovascular phenotypes, such as high arterial blood pressure, aortic stiffness, and increased cardiovascular risk. We investigated the association between this A1166C polymorphism and hypertension in hypertense and normotense subjects from San Luis (Argentina) by mismatch PCR-RFLP analysis. Hypertense patients exhibited significant increases in lipid related values and body mass index. The frequency of occurrence of the C1166 allele was higher among patients with hypertension (0.19) than in the control group (0.06). No significant association was found between this polymorphism and essential hypertension in the study population, although the AC genotype prevalence was higher in patients with hypertension and positive family history of hypertension (32%) than in control subjects (12%). Patients with the A1166C polymorphism exhibited higher levels of serum total cholesterol, LDL-cholesterol and BMI than in control subjects. Taken together the genotype and biochemical parameters and considering the restrictive selection criteria used, the present results suggest a correlation between AT1 A1166C gene polymorphism and risk of cardiovascular disease.
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PMID:Angiotensin II type 1 receptor A1166C gene polymorphism and essential hypertension in San Luis. 1737 65

In a rat model of human essential hypertension (SHR), the chronic increase in cerebral arteriolar blood pressure is accompanied by remodelling with wall hypertrophy and a fall in diameter. The latter produces an increase in cerebrovascular resistance which maintains cerebral blood flow autoregulation at high systemic blood pressure levels, but accentuates hypoperfusion at low arterial pressures such as those observed during and following cerebral ischemia. Using ACE inhibitors and AT1 blockers we have shown that the normalisation of wall thickness is pressure-dependent but that the normalisation of arteriolar diameter relates to a pressure-independent mechanism involving aldosterone. This raises the possibility of new drug targets for arteriolar remodelling involving intracellular sodium-dependent modulation of protein metabolism.
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PMID:[Renin-angiotensin-aldosterone system: an old system offering new drug targets for the cerebral circulation]. 1748 76

Causal relationship between sodium and hypertension has been proposed and various changes in Na+,K+-ATPase (sodium pump) activity have been described in established primary hypertension. A number of direct vascular effects of estradiol have been reported, including its impact on the regulation of sodium pump activity and vasomotor tone. The effects of estradiol involve the activation of multiple signaling cascades, including phosphatydil inositol-3 kinase (PI3K) and p42/44 mitogen-activated protein kinase (p42/44(MAPK)). In addition, some of the effects of estradiol have been linked to activity of cytosolic phospholipase A(2) (cPLA(2)). One possible cardioprotective mechanism of estradiol involves of the interaction between estradiol and the rennin-angiotensin system (RAS). Elevated circulating and tissue levels of angiotensin II (Ang II) have been implicated in the development of hypertension and heart failure. The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump, in vascular smooth muscle cells (VSMC). The aim of our investigation was to elucidate the signaling mechanisms employed by estradiol and Ang II in mediating sodium pump activity/expression in VSMC, with particular emphasis on PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. Our primary hypothesis is that estradiol stimulates sodium pump activity/expression in VSMC via PI3K/cPLA(2)/p42/44(MAPK) dependent mechanism and, that impaired estradiol-stimulated sodium pump activity/expression in hypertensive rodent models (i.e. SHR), Ang II-mediated vascular impairment of estradiol is related to a decrease ability of estradiol to stimulate the PI3K/cPLA(2)/p42/44(MAPK) signaling pathways. An important corollary to this hypothesis is that in hypertensive state (i.e. SHR rats) the decreasing in ACE enzyme activity and/or AT1 receptor expression caused by administration of estradiol is accompanying with abrogated ability of Ang II to decrease IRS-1/PI3K association, and consequent PI3K/cPLA(2)/p42/44(MAPK) activity and associated sodium pump activity/expression. A clear characterization of how Ang II attenuates estradiol signaling may lead to a better understanding of the molecular mechanism(s) underlying pathophysiological conditions such as hypertension and to understanding how certain pathophysiological situations affect sodium pump activity/expression in VSMC.
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PMID:Hypothetical mechanism of sodium pump regulation by estradiol under primary hypertension. 1830 83

Angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers have long been considered as two classes of drugs with strictly comparable effect in cardiovascular diseases, on the assumption that both classes act on the renin-angiotensin-aldosterone system. The results of large clinical intervention trials, which failed to demonstrate any significant difference between the effects of these two pharmacological classes in patients with essential hypertension, acute myocardial infarction and heart failure, supported this concept. The recent observation that a combination of ACE-inhibitors and AT1 receptor blockers improves the prognosis of these pathological conditions better than monotherapy at higher doses focused on the difference between their mechanisms of action. The results of pathophysiological studies have suggested that in the heart, as well as in the kidney, AT1 receptor blockers act in the early stages of the disease, improving left ventricular dysfunction in hypertensive patients and preventing microalbuminuria in diabetic animals. It seems reliable to suggest that AT1 receptor blockers are to be preferred to ACE-inhibitors for an early prevention of cardiovascular and renal disease. The new inhibitors of renin activity may further amplify our chances, also blocking the negative effects mediated by angiotensin II escape and by stimulation of the prorenin/renin receptors.
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PMID:[Renin-angiotensin system modulation: instructions for use]. 1838 70


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