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Title: 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
Authors: Martelli, A
Testai, L
Anzini, Maurizio 
Cappelli, Andrea 
DI CAPUA, Angela
Biava, M
Poce, G
Consalvi, S
Giordani, A
Caselli, G
Rovati, L
Ghelardini, C
Patrignani, P
Sautebin, L
Breschi, M. C
Calderone, V.
Keywords: 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; 2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethanol (PubChem CID: 56929591); 2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethyl nitrate; 2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethyl nitrate (PubChem CID: 56929588); ACh; ANOVA; APPROVe; Adenomatous Polyp PRevention On Vioxx study; Anti-inflammatory drugs; BP; CINOD; COX(2); COX(2)-inhibitors; COX(2)-selective inhibitors; COX-inhibiting nitric oxide donor; COXIBs; CV; DMSO; Endothelial dysfunction; GC; HR; Hypertension; IL-1β; LVDP; NA; NO; NO-naproxen (PubChem CID: 9884642); NR; NSAIDs; Nitric oxide-releasing drugs; ODQ; Pharmacodynamic hybrids; RB; SBP; SEM; SHRs; SNP; VA692; VA694; VIGOR; Vioxx Gastrointestinal Outcome studies; acetylcholine; analysis of variance; blood pressure; cardiovascular; cyclooxygenase-2; dimethylsulphoxide; guanylate cyclase; heart rate; interleukine-1β; left ventricular developed pressure; nitrate reductase bars; nitric oxide; non-steroidal anti-inflammatory drugs; noradrenaline; resuspending buffer; sodium nitroprusside; spontaneously hypertensive rats; standard error of the mean; systolic blood pressure; tNSAIDs; traditional non-steroidal anti-inflammatory drugs; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Coronary Vessels; Cyclooxygenase 2 Inhibitors; Endothelium; Endothelium-Dependent Relaxing Factors; Hypertension; Male; Nitrates; Nitric Oxide; Nitrites; Rats; Rats, Inbred SHR; Rats, Wistar; Regional Blood Flow
Issue Date: 2013
Project: None 
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.
ISSN: 1043-6618
DOI: 10.1016/j.phrs.2013.09.008
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