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

tSelective cyclooxygenase 2 (COX2) inhibitors (COXIBs) are effective anti-inflammatory and anal-gesic drugs with improved gastrointestinal (GI) safety compared to nonselective nonsteroidalanti-inflammatory drugs known as traditional (tNSAIDs). However, their use is associated with a car-diovascular (CV) hazard (i.e. increased incidence of thrombotic events and hypertension) due to theinhibition of COX2-dependent vascular prostacyclin. Aiming to design COX2-selective inhibitors withimproved CV safety, new NO-releasing COXIBs (NO-COXIBs) have been developed. In these hybriddrugs, the NO-mediated CV effects are expected to compensate for the COXIB-mediated inhibition ofprostacyclin. 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 invivo 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 admin-istration of VA694 to young spontaneously hypertensive rats (SHRs) significantly slowed down theage-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 signifi-cant reduction of endothelial dysfunction were observed in SHRs submitted to chronic administration ofVA694. In conclusion, VA694 is a promising COX2-inhibiting hybrid drug, showing NO releasing propertieswhich may mitigate the CV deleterious effects associated with the COX2-inhibition.