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EFFICACY OF CALCIUM ANTAGONISTS: Calcium-channel blockers (CCBs) have long been recognized as potent agents for hypertensive therapy, with substantial blood pressure reduction in all age groups and races. CCBs improve endothelial function, may positively influence atherosclerosis in carotid arteries, reduce left ventricular hypertrophy, and hypertrophy of the resistance vessels, and improve arterial compliance. They do not adversely affect lipids and serum glucose. USE IN PRACTICE: CCBs are also a heterogenous class of drugs composed of the phenylalkylamine verapamil, the benzothiazepine diltiazem, and the large group of dihydropyridines (DHPs) with the prototype nifedipine, and an increasing number of newer agents (e. g. nitrendipine, nisoldipine, amlodipine, felodipine, lacidipine and lercanidipine). DHPs are primarily vasodilators, lowering blood pressure by decreasing peripheral vascular resistance at the level of the small arterioles which can be followed by an autonomic counterregulation especially in drugs with a rapid onset of action. This is markedly reduced or abolished in the treatment with the modern long acting DHPs and is also not the case in the treatment with non-DHPs. Prospective randomized controlled outcome studies demonstrated a significant reduction in stroke in elderly patients with isolated systolic hypertension compared with placebo (Syst-Eur [Syst-China]), and no significant differences in cardiovascular mortality and combined morbidity compared with diuretics, beta blockers or ACE-Inhibitors (STOP-2, INSIGHT, NORDIL, ALLHAT, INVEST). To normalize the blood pressure it is mostly necessary to combine antihypertensive drugs. Here are CCBs ideal partners for a therapy with ACE-inhibitors, AT1 antagonists or beta blockers (DHP) and diuretics (verapamil). With respect to the antihypertensive differential therapy the author recommends CCBs based on studies with the evidence grade 1-3; especially for elderly hypertensives (with isolated systolic neuhypertension and a high risk of stroke), for patients with COPD and asthma bronchiale, Raynaud's syndrome or Prinzmetal-angina, patients with diastolic function disturbances including diastolic heart failure or hypertensives with massive left ventricular hypertrophy (in combination with ACE or AT1 inhibitors).
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PMID:[Differential therapy with calcium antagonists]. 1468 11

The pathophysiologic mechanisms of myocardial remodeling in heart failure (HF) remain poorly understood. Using differential mRNA display of myocardial tissue from rats with ischemic HF vs. controls we identified robust myocardial induction of the mRNA encoding connective tissue growth factor (CTGF). The aim of this study was to investigate the sites of synthesis and the mechanisms of induction of CTGF in failing myocardial tissue. The study demonstrates that myocardial expression of CTGF mRNA and protein is substantially elevated in non-ischemic tissue from both the left and the right ventricles of rats with experimentally induced myocardial infarction (MI). The induction of myocardial CTGF mRNA was shown to transcend from early post-infarction HF to chronic HF. In situ hybridization and immunohistochemical analysis of myocardial tissue sections demonstrated expression of CTGF confined to fibroblasts and endothelial cells of non-ischemic myocardial tissue. In subsequent experiments rats subjected to MI were randomized to treatment with the AT1 angiotensin receptor antagonist losartan (12.5 mg/kg b.i.d. per os) or vehicle. Losartan attenuated ventricular hypertrophy, improved hemodynamics, and prevented the induction of myocardial CTGF mRNA observed in rats post-MI. To provide the cellular basis of Ang II-stimulated CTGF mRNA expression, primary cultures of rat myocardial fibroblasts were stimulated with Ang II (10(-7) M). Real-time reverse transcription-polymerase chain reaction and western blot analysis demonstrate that Ang II induces rapid, AT1 receptor-mediated elevations of CTGF mRNA and protein in rat cardiac fibroblasts. Furthermore, CTGF was shown to stimulate fibroblast proliferation in vitro. In conclusion, this study demonstrates that CTGF is a myocardial effector of Ang II-induced myocardial remodeling in HF mediated via AT1 receptors situated on cardiac fibroblasts.
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PMID:Connective tissue growth factor--a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats. 1501 Feb 78

1. Myocardial infarction (MI) poses a significant risk for sudden cardiac death. The effectiveness of angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockade in attenuating unfavourable post-MI outcomes indicates an important role for angiotensin (Ang) II signalling in the post-MI remodelling process. 2. AT1 and AT2 receptor expression is known to be altered during the early postinjury period and at the later failure stage in the infarcted heart. The aim of the present investigation was to characterize AngII receptor expression shifts in the intermediate, adaptive phases of post-MI hypertrophic remodelling. 3. The present study investigated relative cardiac AT1 and AT2 receptor expression levels using semiquantitative reverse transcription-polymerase chain reaction (GAPDH normalized) in rats at 4 and 20 weeks after ligation of the left anterior descending coronary artery. 4. Heart weight and normalized heart weight were significantly higher in the MI group than in the sham group 4 weeks post-MI, with significant hypertrophy of the left ventricle, left atrium and right ventricle in MI rats. At 20 weeks post-MI, left ventricular hypertrophy remained significant, whereas the mass of the other cardiac tissues was not different to that of sham controls. 5. AT2 receptor expression was markedly reduced in both the non-infarct and infarcted areas of the left ventricular wall in the MI group compared with the sham-operated group 4 weeks after surgery. Expression levels were reduced to 8 and 13% of sham values in the viable and scar tissue regions, respectively. By 20 weeks post-MI, there was no evidence of AT2 receptor expression suppression in the left ventricle. No significant relative changes in AT1 receptor mRNA levels were observed at either 4 or 20 weeks post-MI. 6. The present study demonstrates, for the first time, a selective downregulation of left ventricular AT2 receptor expression in the intermediate phase of post-MI ventricular remodelling in the rat. This downregulation may provide an enhanced AT1 receptor-mediated compensatory progrowth signal in the early adaptive post-MI growth phase. A more detailed understanding of the time-course of differential AT1 and AT2 receptor expression regulation post-MI may potentially identify an optimal window for targeted pharmacological intervention in the treatment of MI.
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PMID:Transitory reduction in angiotensin AT2 receptor expression levels in postinfarct remodelling in rat myocardium. 1529 43

The angiotensin II receptor blockers (ARBs), are highly selective for the AT1 subtype and will block the effects of angiotensin II on peripheral vessels. Several short- and long-term studies have shown these agents to be safe and effective antihypertensive drugs. Since monotherapy of hypertension may be ineffective in lowering the blood pressure to goal, the use of an ARB, especially in combination with a diuretic or another medication, is frequently necessary to bring the blood pressure <140/90 mm Hg (<130/80 mm Hg among people with diabetes mellitus or chronic renal failure), according to JNC 7 guidelines. Besides hypertension, the ARBs have been shown to reduce left ventricular hypertrophy in hypertensive patients. Other benefits of these medications, as well as the angiotensin I converting enzyme inhibitors (ACEIs), include a decrease in cardiovascular morbidity and mortality in patients with heart failure, or hypertensive diabetic nephropathy with proteinuria. Some of the beneficial effects noted with the ACEIs and ARBs (congestive heart failure, left ventricular hypertrophy), have also been demonstrated with the use of b blockers alone and in combination with a diuretic. These drugs, i.e., b blockers, ARBs, and ACEIs, seem to exert their beneficial action through the blockade of the renin-angiotensin-aldosterone system. The role of this system in cardiovascular remodeling and its blockade will be discussed in this review, which will specifically summarize data with the ARB, valsartan.
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PMID:Clinical experience with angiotensin receptor blockers with particular reference to valsartan. 1530 83

Irbesartan (Aprovel) belongs into the new group drugs for the cardiovascular system which exert an antagonistic effect at the level of angiotensin II, but experimental pilot studies as well as clinical studies draw also attention to the possible therapeutic potential of AT1 receptor blockers in the treatment of chronic heart failure. Irbesartan has a marked antihypertensive effect as is apparent from a recent clinical study in 139 patients with mild and moderate hypertension--implemented in the Czech Republic. Twelve-week treatment with Irbesartan led to a marked drop of the systolic and diastolic blood pressure (159.2 +/- 14 vs. 137 +/- 13 mmHg/99.2 +/- 7 vs. 85.3 +/- 7 mmHg, p < 0.01). A very favourable therapeutic effect was recorded in this investigation also in 24-hour monitoring of the blood pressure. The use of irbesartan in patients with arterial hypertension has according to other studies also a favourable effect on organ complications of hypertension and diabetes (regression of left ventricular hypertrophy, reduction of albuminuria). Irbesartan may prove due to its favourable effect a suitable alternative in conditions associated with intolerance of ACE-inhibitors in patients with moderate and severe forms of arterial hypertension, in chronic heart failure and in diabetic nephropathy.
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PMID:[Irbesartan in the treatment of arterial hypertension]. 1564 39

The effect of antihypertensive therapy on arrhythmias is controversial. An initial study in patients with chronic heart failure indicated that losartan, an angiotensin II receptor antagonist, may possess antiarrhythmic properties. However, the effect of AT1 receptor antagonists on arrhythmias of subjects with good systolic function has never been evaluated. Thirty-nine men with primary hypertension (18 without left ventricular hypertrophy [LVH], and 21 with LVH, aged 48.2 +/-8.6 and 50.5 +/-6.0 years, respectively), 15 healthy normotensive subjects (47.9 +/-8.5 years), and 14 highly trained athletes (34.1 +/-1.6 years) were studied. Transthoracic echocardiography and 24-hour Holter ambulatory monitoring were performed at baseline (without treatment). Hypertensive patients underwent the same examinations after 8 months of losartan administration. The prevalence and complexity of ventricular arrhythmias, and the frequency of supraventricular arrhythmias were increased in hypertensive patients with LVH compared to normotensive controls and athletes, at baseline. A similar significant reduction of blood pressure (BP) was noted in both groups of patients (p < 0.001). The LVH was reduced in hypertensives with LVH (the left ventricular mass index by 12%, the interventricular septum by 8.1%, the posterior wall by 7%, all p < 0.01). However, the arrhythmias did not change in either group of patients, even if all hypertensives were considered as 1 group. In conclusion, an 8-month course with losartan was effective in lowering BP and reducing LVH. However, the increased arrhythmias, which were registered in hypertensive patients with LVH at baseline, did not change.
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PMID:Losartan controlled blood pressure and reduced left ventricular hypertrophy but did not alter arrhythmias in hypertensive men with preserved systolic function. 1607 26

Losartan (Cozaar) is an angiotensin AT1 receptor antagonist. It is approved in numerous countries for the treatment of hypertension and has been approved in the UK, the US and several European countries for stroke risk reduction in patients with hypertension and left ventricular hypertrophy (LVH). Losartan is recommended for use alone or with hydrochlorothiazide, but it can also be administered with other antihypertensive medications. In patients with hypertension, losartan effectively lowers blood pressure and also leads to regression of LVH. In the large, well designed LIFE (Losartan Intervention For Endpoint reduction in hypertension) study in patients with hypertension and LVH, losartan was more effective than atenolol in reducing the composite primary endpoint of cardiovascular (CV) mortality, stroke or myocardial infarction (MI). This was mainly due to a significant 25% reduction in the risk of stroke in the losartan group. Losartan recipients also had a significantly lower incidence of new-onset diabetes mellitus compared with atenolol recipients. Similar benefits were observed in several patient subgroups from the LIFE study, but not in the subgroup of Black patients. Losartan is well tolerated and is a cost effective alternative to atenolol in the setting of stroke reduction. Comparative data on clinical outcomes in hypertensive patients for losartan versus other antihypertensive agents would be of interest. Nonetheless, in addition to its established antihypertensive and end organ effects, the LIFE study indicates that, with the possible exception of Black patients, losartan can reduce the risk of stroke in patients with hypertension and LVH.
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PMID:Losartan: a review of its use in stroke risk reduction in patients with hypertension and left ventricular hypertrophy. 1639 83

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

Left ventricular hypertrophy (LVH) prevalence is very high in end stage renal disease (ESRD). It's a predictor of cardiac death in peritoneal dialysis patients. Noradrenalin, Angiotensin II and aldosterone are involved incardiac hypertrophy. Dopamine, acting at DA2 receptors inhibits norephinephrin release, antagonizes aldosterone and down-regulates AT1 receptor numbers, suggesting that DA2 agonists, like bromocriptine (BEC) could regress LVH. The objective of this study was to evaluate the changes in left ventricular mass in patients with ESRD in continuous ambulatory peritoneal dialysis (CAPD), by adding BEC to the treatment. An open clinical trial was conducted. Twenty patients were enrolled. Five formed the control group. Fifteen patients in the experimental group received BEC 2.5 mg three times daily over three months. M mode echocardiography and prolactin plasma levels were measured at the beginning and at the end of the study. The statistical analysis was performed using Student t test. The echocardiography reports showed a 24.4% decreased in left ventricular mass index (LVMI); the interventricular septum decreased 11.3%, the ejection fraction was not modified. The control group showed no difference. BEC-mediated decreases in left-ventricular mass in LVH patients on dialysis suggest that Dopaminergic agonists could be useful in caring for patients with ESRD and LVH.
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PMID:Bromocriptine induces regression of left ventricular hypertrophy in peritoneal dialysis patients. 1641 76

Left ventricular hypertrophy refers to a pathologic increase in left ventricular mass and is associated with an increased risk of subsequent cardiovascular morbidity and mortality from any cause. In the development of left ventricular hypertrophy there is growth of cardiomyocytes and accumulation of extracellular matrix and fibrosis. The actions are partly induced by angiotensin II, the principal effector of the renin-angiotensin-aldosterone system, binding to the AT1 receptor. Biochemical markers, some implicated in inflammatory changes, correlate with changes in left ventricular mass. The reduction in left ventricular mass brought about with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ARB) therapy correlates with a reduction in these inflammatory changes, monitored by brain natriuretic peptide. Recent studies incorporating trials of ARBs have found ARBs to be more effective in reducing left ventricular mass than beta blockers and possibly more effective than calcium antagonists. Initial studies suggest that ARBs and angiotensin-converting enzyme inhibitors may have similar effects in terms of reducing left ventricular hypertrophy, and the combination of angiotensin-converting enzyme inhibitors and ARBs is thought to be synergistic due to a more complete inhibition of the renin-angiotensin-aldosterone system. In conclusion, these agents are efficacious in antihypertensive therapy and can play an important role in the prevention or regression of left ventricular hypertrophy due to hypertension.
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PMID:Mechanism of angiotensin II type 1 receptor blocker action in the regression of left ventricular hypertrophy. 1684 2


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