Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization

The antihypertensive flavonol quercetin (Q1) is endowedwith a cardioprotective effect againstmyocardial ischemic damage. Q1 inhibits angiotensin converting enzymeactivity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium. In the aimto overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties. Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with β-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively. Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10−8M÷10−6Mdoses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10−10M and 10−8 ÷ 10−6 M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both β1/β2-adrenergic receptors. Taking into consideration all the obtained results, the replacement of OHwith ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension

<<Ia>> catestatina migliora la risposta Frank-Starling in cuori di ratto normotesi e ipertesi agendo come attivatore fisiologico del pathway trasduzionale ossido nitrico-dipendente

Scuola di Dottorato Life Sciences, Indirizzo: Biologia animale, Ciclo XXVIII, a.a. 2015-2016The myocardial response to mechanical stretch (Frank-Starling law) is an important physiological cardiac determinant. Modulated by many endogenous substances, it is impaired in the presence of cardiovascular pathologies and during senescence. Catestatin (CST: hCgA352-372), a 21-amino-acid derivate of Chromogranin A (CgA), displays hypotensive/vasodilatory properties and counteracts excessive systemic and/or intra-cardiac excitatory stimuli (e.g., catecholamines and endothelin-1). CST, produced also by the myocardium, affects the heart by modulating inotropy, lusitropy and the coronary tone through a Nitric Oxide (NO)-dependent mechanism. This study evaluated the putative influence elicited by CST on the Frank-Starling response of normotensive Wistar Kyoto (WKY) and hypertensive (SHR) hearts by using isolated and Langendorff perfused cardiac preparations. Functional changes were evaluated on aged (18-month-old) WKY rats and SHR which mimic human chronic heart failure (HF). Comparison to WKY rats, SHR showed a reduced Frank-Starling response. In both rat strains, CST administration improved myocardial mechanical response to increased end-diastolic pressures. This effect was mediated by EE/IP3K/NOS/NO/cGMP/PKG, as revealed by specific inhibitors. CST-dependent positive Frank-Starling response is paralleled by an increment in protein S-Nitrosylation, AKT/eNOS/nNOS and PLN phosphorylations. Our data suggested CST as a NO dependent physiological modulator of the stretch-induced intrinsic regulation of the heart. This may be of particular importance in the aged hypertrophic heart, whose function is impaired because of a reduced systolic performance accompanied by delayed relaxation and increased diastolic stiffness.Università della Calabri

Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization

The antihypertensive flavonol quercetin (Q1) is endowed with a cardioprotective effect against myocardial ischemic damage. Q1 inhibits angiotensin converting enzyme activity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium. In the aim to overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties. Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with β-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1 month) on spontaneously hypertensive rats (SHRs), respectively. Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10− 8 M ÷ 10− 6 M doses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10− 10 M and 10− 8 ÷ 10− 6 M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both β1/β2-adrenergic receptors. Taking into consideration all the obtained results, the replacement of OH with ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension