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.

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.

The cannabinoid receptors, CB1 and CB2, are expressed in the heart, but their role under pathological conditions remains controversial. This study examined the effect of CB1 receptor blockade on cardiovascular functions after experimental MI and in experimental metabolic syndrome. MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with the CB1 receptor antagonist rimonabant (10 mg/kg i.p. daily) started 7 days before or 6 h after MI and continued for 6 weeks. Haemodynamic parameters were measured via echocardiography and intracardiac Samba catheter. CB1 blockade improved systolic and diastolic heart function, decreased cardiac collagen and hydroxyproline content and down-regulated TGF-β1. Additionally, rimonabant decreased arterial stiffness, normalised QRS complex duration and reduced brain natriuretic peptide levels in serum. In primary cardiac fibroblasts, rimonabant decreased MMP-9 activity and TGF-β1 expression. Furthermore, rimonabant improved depressed systolic function of spontaneously hypertensive obese rats and reduced weight gain. Blocking of CB1 receptor with rimonabant improves cardiac functions in the early and late stages after MI, decreases arterial stiffness and reduces cardiac remodelling. Rimonabant also has cardioprotective actions in rats characterised by the metabolic syndrome. Inhibition of proteolysis and TGF-β1 expression and reduced collagen content by rimonabant may attenuate destruction of the extracellular matrix and decrease fibrosis after MI.

The expression pattern of angiotensin AT2 receptors with predominance during fetal life and upregulation under pathological conditions during tissue injury/repair process suggests that AT2 receptors may exert an important action in injury/repair adaptive mechanisms. Less is known about AT2 receptors in acute ischemia-induced cardiac injury. We aimed here to elucidate the role of AT2 receptors after acute myocardial infarction. Double immunofluorescence staining showed that cardiac AT2 receptors were mainly detected in clusters of small c-kit1 cells accumulating in peri-infarct zone and c-kit1AT21 cells increased in response to acute cardiac injury. Further, we isolated cardiac c-kit1AT21 cell population by modified magnetic activated cell sorting and fluorescence activated cell sorting. These cardiac c-kit1AT21 cells, represented $0.19% of total cardiac cells in infarcted heart, were characterized by upregulated transcription factors implicated in cardiogenic differentiation (Gata-4, Notch-2, Nkx-2.5) and genes required for self-renewal (Tbx-3, c-Myc, Akt). When adult cardiomyocytes and cardiac c-kit1AT21 cells isolated from infarcted rat hearts were cocultured, AT2 receptor stimulation in vitro inhibited apoptosis of these cocultured cardiomyocytes. Moreover, in vivo AT2 receptor stimulation led to an increased c-kit1AT21 cell population in the infarcted myocardium and reduced apoptosis of cardiomyocytes in rats with acute myocardial infarction. These data suggest that cardiac c-kit1AT21 cell population exists and increases after acute ischemic injury. AT2 receptor activation supports performance of cardiomyocytes, thus contributing to cardioprotection via cardiac c-kit1AT21 cell population.