We investigated the structure-activity relationships regarding vascular and antioxidant activity of a range of synthetic flavonols and flavones with 3 or fewer hydroxyl (OH) or methoxyl substitutions. The relaxant responses and ability of the flavones/flavonols to inhibit phenylephrine (PE)- and Ca-induced contraction was determined in rat isolated thoracic aorta. The ability of these compounds to reduce the level of superoxide and preserve endothelium-dependent relaxation in the presence of oxidative stress was also examined. Four compounds impaired contraction to PE or Ca, in the potency order 3'-hydroxyflavonol>3',4'-dihydroxyflavonol>7,4'-dihydroxyflavonol>3',4'-dihydroxyflavone. Flavonol, 3',4'-dimethoxyflavonol, and flavone were significantly less active. The flavonoids caused concentration-dependent reductions in superoxide produced by rat aorta in the presence of NADPH. The most active compounds, 3',4'-dihydroxyflavonol and 7,4'-dihydroxyflavonol, preserved endothelium-dependent relaxation in the presence of oxidative stress caused by pyrogallol or xanthine/xanthine oxidase. The results indicate that the catechol group is not critical for vascular relaxant or antioxidant activity, but rather, the important determinants for higher vascular and antioxidant activity of these compounds are the presence of a C3 OH group and the total number of OH substituents, respectively. These results have allowed the identification of the structural characteristics that promote vascular and antioxidant activity of flavonols, which may lead to the development of agents useful in treatment of cardiovascular disease.

Background: Perinatal glucocorticoid treatment is associated with hypertrophic cardiomyopathy, but the cellular mechanism is controversial. An underlying interaction between glucocorticoids and the renin-angiotensin system may be important, but whether glucocorticoids modulate angiotensin II (AngII)-dependent cardiomyocyte growth responses in the neonate has not been investigated. Objectives: The major aim of this investigation was to determine whether glucocorticoids modulate the neonatal cardiomyocyte growth response to AngII. In particular we sought evidence to determine whether angiotensin II type 2 (AT₂) receptor co-expression with angiotensin II type 1 (AT₁) receptor is of specific importance in this modulatory function. Methods: In this study, we used AT₁ and AT₂ receptor-expressing adenoviruses (Ad-AT₁ and Ad-AT₂) in a well-defined in vitro neonatal cardiomyocyte culture model to assess whether glucocorticoids affect cardiomyocyte growth responses (i.e. total protein content). Results: Following addition of AngII (0.1 µmol/l) to neonatal cardiomyocytes infected with Ad-AT₁ alone, a significant growth response was measured (133.2 ± 4.8%). Expression of Ad-AT₂ alone induced a ∼20% increase in total cellular protein content, which was unaffected by addition of AngII. Neither corticosterone (1 µmol/l) nor dexamethasone (1 µmol/l) had any significant effect on the AT₁- or AT₂-mediated growth responses. In contrast, the growth response to AngII was augmented following co-expression of AT₂ and AT₁ receptors (149.2 ± 4.2%), which was reduced by ∼20% in the presence of either corticosterone or dexamethasone (p < 0.05). Conclusions: The present study provides novel evidence that glucocorticoids suppress neonatal cardiomyocyte growth responsiveness when AT₂ and AT₁ receptor subtypes are co-expressed.

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device. Despite initial symptomatic improvement, both subsequently developed severe PH within 2 years, one patient being now deceased and the other requiring dual therapy for PH. The remaining patient, a 45-year-old woman with mean PAp of 28 mmHg, PVRI 3.04 m 2 and Qp:Qs of 2.1:1, surprisingly progressed to severe PH and despite therapy is also recently deceased. Conclusion: Transcatheter closure of ASDs in patients with PH may shorten life expectancy, even in the era of novel therapies for PH. Full haemodynamic evaluation of these patients is mandatory and indications for closure should be carefully reviewed.