Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure

Spinale, Francis G.; Mukherjee, Rupak; Iannini, Julie P.; Whitebread, Steve; Hebbar, Latha; Clair, Mark J.; Melton, D. Mark; Cox, Monty H.; Thomas, Patrick B.; Gasparo, Marc de

doi:10.1161/01.cir.96.7.2397

Cited by 73 publications

(46 citation statements)

References 48 publications

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“…28 Previous reports have suggested that valsartan, a highly selective antagonist of the AT 1 receptor, is useful in lowering cardiovascular risk. 18,29,30 This drug, beyond its blood pressure-lowering activity, improves heart failure in rats with myocardial infarction, reduces endothelial dysfunction and intimal thickening in atherosclerotic rabbits, and induces a significant regression of left ventricular hypertrophy in patients with essential hypertension. 18,[31][32][33] The effects of AT 1 antagonists on fibrinolytic balance, and in particular on PAI-1 and tPA plasma levels, in normal subjects as well as in patients with cardiovascular disease, are still controversial.…”

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confidence: 99%

Effect of Valsartan on Angiotensin II–Induced Plasminogen Activator Inhibitor-1 Biosynthesis in Arterial Smooth Muscle Cells

et al. 2001

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Abstract-Previous studies have shown that angiotensin II stimulates the synthesis of plasminogen activator inhibitor-1 in cultured vascular cells, which suggests that activation of the renin-angiotensin system may impair fibrinolysis. We have investigated the effects of angiotensin II and of valsartan, a recently developed angiotensin II antagonist that is highly specific and selective for the angiotensin II subtype 1 receptor, on plasminogen activator inhibitor-1 secretion by smooth muscle cells isolated from rat and human vessels. Angiotensin II induced a time-and concentration-dependent increase of plasminogen activator inhibitor activity in supernatants of rat aortic cells, which reached a plateau after 6 hours of incubation with 100 nmol/L angiotensin II (2.4Ϯ0.6-fold over control value; PϽ0.001). The angiotensin II-induced plasminogen activator inhibitor activity was inhibited, in a concentration-dependent manner, by valsartan with an IC 50 value of 21 nmol/L. Valsartan fully prevented the angiotensin II-induced increase in plasminogen activator inhibitor-1 protein and mRNA. Furthermore, angiotensin II doubled the secretion of plasminogen activator inhibitor-1 by smooth muscle cells obtained from human umbilical and internal mammary arteries, and valsartan fully prevented it. Angiotensin II did not affect the secretion of tissue plasminogen activator antigen by any of the cell systems tested. Thus, valsartan effectively inhibits angiotensin II-induced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activator in arterial rat and human smooth muscle cells. Key Words: plasminogen Ⅲ fibrinolysis Ⅲ angiotensin II Ⅲ receptors, angiotensin Ⅲ valsartan Ⅲ muscle, smooth A ctivation of the renin-angiotensin system (RAS) is associated with an increased risk of ischemic cardiovascular events independently of its effects on blood pressure. 1 Conversely, the inactivation of RAS, with angiotensinconverting enzyme (ACE) inhibitors, reduces the risk of recurrent myocardial infarction in patients with left ventricular dysfunction, 2 reduces intimal thickening after vascular injury, 3 and in experimental models decreases progression of atherosclerosis. 4 Angiotensin II (Ang II) is responsible for the RASmediated cardiovascular complications, 5 and therefore the beneficial effects of ACE inhibitors derive mainly from their reduction of the biosynthesis of this autacoid. A non-ACEdependent Ang II formation resulting from the action of a chymase enzyme occurs in the heart and in normal and to a greater extent in atherosclerotic vessel walls. 6,7 This may limit the effectiveness of ACE inhibitors.Ang II receptor antagonists, and in particular antagonists of the Ang II subtype 1 (AT 1 ) receptor, form a recently developed class of drugs that suppress both the ACE-and non-ACE-dependent vascular effects of Ang II and that are therefore better at preventing cardiovascular effects than simple ACE inhibitors. 8 Plasminogen activator inhibitor-1 (PAI-1) is a key regulator of fibrinolysis, and ac...

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Effect of Valsartan on Angiotensin II–Induced Plasminogen Activator Inhibitor-1 Biosynthesis in Arterial Smooth Muscle Cells

et al. 2001

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“…2 However, the clinical syndrome of heart failure is the final state of a wide spectrum of diseases affecting the heart 1,26 and the effects of RAS inhibition may differ according to the causation, genetic and environmental backgrounds, and disease stage. To gain insights into the in vivo effects of RAS inhibition on the development and progression of heart failure, several animal models have been utilized; [8][9][10][11][12][13][14][15][16]27 however, most do not perfectly represent human heart failure, 28 and the effects of RAS inhibition are unknown in a mouse model of DCM caused by mutations affecting the cytoskeleton and sarcomere. In this regard, we are the first to analyze the preventive effects of AT1a receptor blockade on progression of heart failure in MLP-deficient cardiomyopathic mice.…”

Section: Discussionmentioning

confidence: 99%

“…2,6 These cellular alterations that occur within the heart would promote left ventricular (LV) remodeling and contribute to the progression of heart failure. However, the effects of the AT1 receptor have been experimentally verified only in animal models of heart failure, such as a myocardial infarction model produced by coronary artery ligation, 7-9 a pacing-induced heart failure model, 10 Dahl salt-sensitive rats, 11 a pressure-overloaded model, 12,13 a shunt-induced volume-overloaded model, 14 experimental myocarditis, 15 and doxorubicininduced cardiomyopathy. 16 A number of reports have suggested that inhibition of the AT1 receptor prevents LV remodeling after myocardial infarction, 2,7-9 but it remains unknown whether it is also beneficial for dilated cardiomyopathy (DCM).…”

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Angiotensin II Type 1a Receptor Signals are Involved in the Progression of Heart Failure in MLP-Deficient Mice

Yamamoto

Akazawa

Ito

et al. 2007

Circ J

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growing body of evidence suggests that blockade of the renin -angiotensin system (RAS) leads to a decrease in the morbidity and mortality of patients with congestive heart failure. 1 In addition to the systemic effects, including elevation of blood pressure (BP), sodium and water retention, and activation of the sympathetic nervous system, the activated RAS has unfavorable direct effects on the heart. 2 Most of the known functions of angiotensin II (Ang II) in the cardiovascular system are mainly mediated through the Ang II type 1 (AT1) receptor. 3 In mice or rats, the AT1 receptor has 2 subtypes (AT1a and AT1b), but the AT1a receptor is predominantly expressed and functionally important in cardiomyocytes. 4,5 According to the results of in vitro experiments, activation of the AT1 receptor stimulates diverse intracellular signaling cascades and produces reactive oxygen species, which evoke hypertrophic responses in cardiomyocytes and enhance cellular proliferation and production of extracellular matrix proteins, such as collagen, in cardiac fibroblasts. 2,6 These cellular alterations that occur within the heart would promote left ventricular (LV) remodeling and contribute to the progression of heart failure. However, the effects of the AT1 receptor have been experimentally verified only in animal models of heart failure, such as a myocardial infarction model produced by coronary artery ligation, 7-9 a pacing-induced heart failure model, 10 Dahl salt-sensitive rats, 11 a pressure-overloaded model, 12,13 a shunt-induced volume-overloaded model, 14 experimental myocarditis, 15 and doxorubicininduced cardiomyopathy. 16 A number of reports have suggested that inhibition of the AT1 receptor prevents LV remodeling after myocardial infarction, 2,7-9 but it remains unknown whether it is also beneficial for dilated cardiomyopathy (DCM).Mice deficient for the gene for muscle LIM protein (MLP) have been characterized as a good model of human DCM. 17 MLP, a member of the LIM-only proteins, 18 is involved in organization of cytoarchitecture 17 and is proposed to function as a mechanosensor. 19 Approximately 35% of MLP-deficient mice (offspring of homozygous breeders) exhibit an early phenotype with marked hypertrophy and death within 10-11 days, and remainder survive into adulthood and exhibit a number of phenotypic features of human DCM (adult phenotype). 17 In the present study, we used MLP-deficient mice as a model of DCM and examined the effects of AT1 receptor blockade on disease progression using AT1a-deficient mice. Methods AnimalsG1 pups generated from an MLP +/-heterozygote× AT1a -/-homozygote cross were mated to created the MLP +/-/ AT1a +/-double heterozygotes (G2). G4 offspring were genCirc J 2007; 71: 1958 -1964 (Received March 29, 2007 revised manuscript received July 20, 2007; accepted July 31, 2007 Background Angiotensin II (AT) is implicated in the development of cardiac remodeling, which leads to heart failure, and pharmacological inhibition of the AT type 1 (AT1) receptor has improved mortality and morbi...

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“…As previously described, myocardial ACE activity was determined with the synthetic substrate Hip-His-Leu by a modified procedure. 12 All assays were performed in duplicate.…”

Section: Measurement Of the Components Of Rasmentioning

confidence: 99%

Angiotensin II Type 1 Receptor Blockade Prevents Alcoholic Cardiomyopathy

Cheng

Cunningham

et al. 2006

Circulation

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Background-Activation of the renin-angiotensin system (RAS) may contribute to the development of alcoholic cardiomyopathy. We evaluated the effect of angiotensin II (Ang II) type 1 receptor (AT 1 ) blockade on the development of alcoholic cardiomyopathy. Methods and Results-We serially evaluated left ventricular (LV) and cardiomyocyte function and the RAS over 6 months in 3 groups of instrumented dogs. Eight animals received alcohol (once per day orally, providing 33% of total daily caloric intake); 6 received alcohol and irbesartan (5 mg · kg Ϫ1 · d Ϫ1 PO); and 8 were controls. Compared with controls, alcohol ingestion caused sustained RAS activation with progressive increases in plasma levels of Ang II, renin activity, LV angiotensin-converting enzyme activity, and LV myocyte Ang II AT 1 receptor expression. The RAS activation was followed by a progressive fall in LV contractility (E ES , alcohol-fed dogs 3.9Ϯ0.

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Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure

Cited by 73 publications

References 48 publications

Effect of Valsartan on Angiotensin II–Induced Plasminogen Activator Inhibitor-1 Biosynthesis in Arterial Smooth Muscle Cells

Effect of Valsartan on Angiotensin II–Induced Plasminogen Activator Inhibitor-1 Biosynthesis in Arterial Smooth Muscle Cells

Angiotensin II Type 1a Receptor Signals are Involved in the Progression of Heart Failure in MLP-Deficient Mice

Angiotensin II Type 1 Receptor Blockade Prevents Alcoholic Cardiomyopathy

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