1. The novel anti-inflammatory agent VA694, endowed with both NO-releasing and COX2-selective inhibiting properties, exhibits NO-mediated positive effects on blood pressure, coronary flow and endothelium in an experimental model of hypertension and endothelial dysfunction
- Author
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Carla Ghelardini, Antonio Giordani, Andrea Cappelli, Giovanna Poce, Mariangela Biava, Alma Martelli, Gianfranco Caselli, Maurizio Anzini, Sara Consalvi, L. Sautebin, A. Di Capua, Vincenzo Calderone, Maria Cristina Breschi, P. Patrignani, Lucio Claudio Rovati, Lara Testai, Martelli, A, Testai, L, Anzini, M, Cappelli, A, Di Capua, A, Biava M., A, Poce, G., Consalvi, S, Giordani, A, Caselli, G, Rovati, L, Ghelardini, C, Patrignani, P, Sautebin, Lidia, Breschi, Mc, and Calderone, V.
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2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethyl nitrate ,Male ,resuspending buffer ,systolic blood pressure ,Vascular smooth muscle ,Wistar ,Blood Pressure ,Prostacyclin ,Pharmacology ,Rats, Inbred SHR ,2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethyl nitrate (PubChem CID: 56929588) ,HR ,left ventricular developed pressure ,heart rate ,COX-inhibiting nitric oxide donor ,GC ,NO-naproxen (PubChem CID: 9884642) ,sodium nitroprusside ,ANOVA ,VIGOR ,Pharmacodynamic hybrids ,cardiovascular ,APPROVe ,Nitric oxide-releasing drugs ,COX2-inhibitors ,Inbred SHR ,Endothelium ,SHRs ,Endothelium-Dependent Relaxing Factors ,Nitric Oxide ,traditional non-steroidal anti-inflammatory drugs ,COX(2) ,BP ,VA692 ,In vivo ,VA694 ,Pyrroles ,Rats, Wistar ,SBP ,COX(2)-selective inhibitors ,Cyclooxygenase 2 Inhibitors ,2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethanol ,LVDP ,medicine.disease ,1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one ,2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethanol (PubChem CID: 56929591) ,ACh ,Adenomatous Polyp PRevention On Vioxx study ,Anti-inflammatory drugs ,CINOD ,COX(2)-inhibitors ,COXIBs ,CV ,DMSO ,Endothelial dysfunction ,Hypertension ,IL-1β ,NA ,NO ,NR ,NSAIDs ,ODQ ,RB ,SEM ,SNP ,Vioxx Gastrointestinal Outcome studies ,acetylcholine ,analysis of variance ,blood pressure ,cyclooxygenase-2 ,dimethylsulphoxide ,guanylate cyclase ,interleukine-1β ,nitrate reductase bars ,nitric oxide ,non-steroidal anti-inflammatory drugs ,noradrenaline ,spontaneously hypertensive rats ,standard error of the mean ,tNSAIDs ,Animals ,Anti-Inflammatory Agents, Non-Steroidal ,Coronary Vessels ,Nitrates ,Nitrites ,Rats ,Regional Blood Flow ,Blood pressure ,Cyclooxygenase ,Anti-Inflammatory Agents ,biology ,Chemistry ,Anti-inflammatory drugs, Pharmacodynamic hybrids, COX2-inhibitors, Nitric oxide-releasing drugs, Hypertension, Endothelial dysfunction ,medicine.anatomical_structure ,Non-Steroidal ,medicine.drug ,4]Oxadiazolo[4 ,medicine ,1H-[1 ,biology.protein ,3-a]quinoxalin-1-one - Abstract
Selective cyclooxygenase 2 (COX2) inhibitors (COXIBs) are effective anti-inflammatory and analgesic drugs with improved gastrointestinal (GI) safety compared to nonselective nonsteroidal anti-inflammatory drugs known as traditional (tNSAIDs). However, their use is associated with a cardiovascular (CV) hazard (i.e. increased incidence of thrombotic events and hypertension) due to the inhibition of COX2-dependent vascular prostacyclin. Aiming to design COX2-selective inhibitors with improved CV safety, new NO-releasing COXIBs (NO-COXIBs) have been developed. In these hybrid drugs, the NO-mediated CV effects are expected to compensate for the COXIB-mediated inhibition of prostacyclin. This study evaluates the potential CV beneficial effects of VA694, a promising NO-COXIB, the anti-inflammatory effects of which have been previously characterized in several in vitro and in vivo experimental models. When incubated in hepatic homogenate, VA694 acted as a slow NO-donor. Moreover, it caused NO-mediated relaxant effects in the vascular smooth muscle. The chronic oral administration of VA694 to young spontaneously hypertensive rats (SHRs) significantly slowed down the age-related development of hypertension and was associated with increased plasma levels of nitrates, stable end-metabolites of NO. Furthermore, a significant improvement of coronary flow and a significant reduction of endothelial dysfunction were observed in SHRs submitted to chronic administration of VA694. In conclusion, VA694 is a promising COX2-inhibiting hybrid drug, showing NO releasing properties which may mitigate the CV deleterious effects associated with the COX2-inhibition.
- Published
- 2013
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