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
| Autor: | 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 |
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| Přispěvatelé: | 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, Calderone, V. |
| Rok vydání: | 2013 |
| Předmět: |
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 |
| Zdroj: | Pharmacological Research. 78:1-9 |
| ISSN: | 1043-6618 |
| DOI: | 10.1016/j.phrs.2013.09.008 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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