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

• Published in: Pharmacological research Vol. 78; pp. 1 - 9
• Main Authors: Martelli, A., Testai, L., Anzini, M., Cappelli, A., Di Capua, A., Biava, M., Poce, G., Consalvi, S., Giordani, A., Caselli, G., Rovati, L., Ghelardini, C., Patrignani, P., Sautebin, L., Breschi, M.C., Calderone, V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-12-2013
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-inflammatory drugs; Blood Pressure - drug effects; Coronary Vessels - drug effects; COX2-inhibitors; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Endothelial dysfunction; Endothelium - drug effects; Endothelium - pathology; Endothelium-Dependent Relaxing Factors - administration & dosage; Endothelium-Dependent Relaxing Factors - pharmacology; Hypertension; Hypertension - blood; Hypertension - drug therapy; Male; Nitrates - blood; Nitrates - chemistry; Nitrates - pharmacology; Nitric Oxide - administration & dosage; Nitric Oxide - pharmacology; Nitric oxide-releasing drugs; Nitrites - blood; Pharmacodynamic hybrids; Pyrroles - chemistry; Pyrroles - pharmacology; Rats; Rats, Inbred SHR; Rats, Wistar; Regional Blood Flow - drug effects; NO; NR; DMSO; ACh; VIGOR; HR; APPROVe; tNSAIDs; BP; SHRs; SNP; ANOVA; Pharmacodynamic hybrids; NSAIDs; Endothelial dysfunction; COX2; COXIBs; NO-naproxen (PubChem CID: 9884642); VA694; GC; ODQ; VA692; Hypertension; SBP; Anti-inflammatory drugs; COX2-inhibitors; IL-1β; CINOD; RB; CV; NA; Nitric oxide-releasing drugs; LVDP; 2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethyl nitrate (PubChem CID: 56929588); SEM; 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; cyclooxygenase-2; systolic blood pressure; sodium nitroprusside; left ventricular developed pressure; blood pressure; nitric oxide; spontaneously hypertensive rats; interleukine-1β; resuspending buffer; COX-selective inhibitors; nitrate reductase bars; standard error of the mean; 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one; dimethylsulphoxide; 2-[2-[1-(4-Fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyrrol-3-yl]ethoxy]ethanol; COX-inhibitors; Vioxx Gastrointestinal Outcome studies; Adenomatous Polyp PRevention On Vioxx study; analysis of variance; noradrenaline; traditional non-steroidal anti-inflammatory drugs; COX-inhibiting nitric oxide donor; heart rate; non-steroidal anti-inflammatory drugs; cardiovascular; COX; guanylate cyclase; acetylcholine
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2013.09.008

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.