Angiotensin II (Ang II), the biologically active component of renin-angiotensin system (RAS), acts through two receptor subtypes, the AT1 and the AT2 receptor. All classic physiological effects of Ang II, such as vasoconstriction, aldosterone and vasopressin release, sodium and water retention and sympathetic facilitation, are mediated by the AT1 receptor. Ang II, via its AT1 receptor, is also involved in cell proliferation, left ventricular hypertrophy, nephrosclerosis, vascular media hypertrophy, endothelial dysfunction, neointima formation and processes leading to athero-thrombosis. Recent investigations have established a role for the AT2 receptor in cardiovascular, brain and renal function as well as in the modulation of various biological processes involved in development, cell differentiation, tissue repair and apoptosis. This review summarizes new insights in the regulation, signalling and (patho-) physiological functions of AT1 and AT2 receptors. An extensive review on angiotensin receptors has been published recently (de Gasparo M et al., Pharmacol Rev 2000; 52: 415-72).

Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer.

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Background-This study is the first to examine the effect of direct angiotensin II type 2 (AT 2 ) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT 2 receptor agonist compound 21 (C21). Methods and Results-Myocardial infarction (MI) was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.01, 0.03, 0.3 mg/kg per day IP) was started 24 hours after MI and was continued until euthanasia (7 days after MI). Infarct size was assessed by magnetic resonance imaging, and hemodynamic measurements were performed via transthoracic Doppler echocardiography and intracardiac Millar catheter. Cardiac tissues were analyzed for inflammation and apoptosis markers with immunoblotting and real-time reverse transcription polymerase chain reaction. C21 significantly improved systolic and diastolic ventricular function. Scar size was smallest in the C21-treated rats. In regard to underlying mechanisms, C21 diminished MI-induced Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect. Phosphorylation of the p44/42 and p38 mitogen-activated protein kinases, both involved in the regulation of cell survival, was strongly reduced after MI but almost completely rescued by C21 treatment. Furthermore, C21 decreased MI-induced serum monocyte chemoattractant protein-1 and myeloperoxidase as well as cardiac interleukin-6, interleukin-1␤, and interleukin-2 expression, suggesting an antiinflammatory effect. Conclusions-Direct

Studying the angiotensin type 2 receptor (AT 2 ) has been problematic in the past because a pharmacological tool for direct, specific in vitro and in vivo stimulation of the receptor has been lacking. Consequently, current knowledge about AT 2 receptor signalling and function had to be obtained by indirect approaches, like studying animals or cells with genetically altered AT 2 receptor expression levels, inhibitory experiments using specific AT 2 receptor antagonists, stimulation with angiotensin II under concomitant angiotensin II type 1 receptor blockade or stimulation with the peptide agonist CGP42112A, which has additional AT 2 receptor antagonistic properties. The recently developed non-peptide AT 2 receptor agonist Compound 21 now, for the first time, allows direct, selective and specific AT 2 receptor stimulation in vitro and in vivo. This new tool will certainly revolutionise AT 2 receptor research, enable many new insights into AT 2 receptor function and may also have the potential to become a future medical drug. This article reviews milestone findings about AT 2 receptor functional properties obtained by 'conventional' experimental approaches within the last 20 years. Moreover, it provides an overview of the first results obtained by direct AT 2 receptor stimulation with Compound 21, comprising effects on alkaline secretion, neurite outgrowth, blood pressure and post-infarct cardiac function.

Background-The concentration of gadopentetate dimeglumine in myocardium and blood can be assessed from T1 measurements and can be used to calculate the extracellular volume (ECV) of the myocardium. We hypothesized that diffuse myocardial fibrosis in a small-animal model could be quantitatively assessed by measuring myocardial ECV using small-animal Look-Locker inversion recovery T1 mapping. Methods and Results-Sprague-Dawley rats (nϭ10) were subjected to continuous angiotensin-2 (AT2) infusion for 2 weeks via a subcutaneously implanted minipump system. Magnetic resonance imaging (MRI) was performed both before and after AT2 infusion. The MRI protocol included multislice cine imaging and before-and-after contrast small-animal Look-Locker inversion recovery T1 mapping and late gadolinium enhancement imaging. Myocardial ECV was calculated from hematocrit and T1 values of blood and myocardium. During the course of AT2 infusion, the meanϮSD systolic blood pressure increased from 122Ϯ10.9 to 152Ϯ27.5 mm Hg (Pϭ0.003). Normalized heart weight was significantly higher in AT2-treated animals than in control littermates (Pϭ0.033

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The renin-angiotensin system (RAS) plays an important role in the initiation and progression of cardiovascular and renal diseases. These actions mediated by AT1 receptor (AT1R) are well established and led to development of selective AT1R blockers (ARBs). In contrast, there is scientific evidence that AT2 receptor (AT2R) mediates effects different from and often opposing those of the AT1R. Meagrely expressed in healthy tissue the AT2R is upregulated in injuries providing an endogenous protection to inflammatory, oxidative and apoptotic processes. Interestingly the beneficial effects mediated by AT2R can be further enhanced by pharmacological intervention using the recently developed AT2R agonists. This review article summarizes our current knowledge about regulation, signalling and effects mediated by AT2R in health and disease, with emphasis on cardiac and renal systems. At the end a novel concept of natural protective systems will be introduced and discussed as an attractive target in drug development.