Title

 

Authors

A. Arcipreti¹, A. Martelli¹, L. Testai¹, M.C. Breschi¹, M. Anzini², A. Di Capua², M. Biava³, S. Alfonso³, C. Ghelardini⁴, A. Giordani⁵, L. Rovati⁵, V. Calderone^1
 
1Dip. di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa; via Bonanno, 6, I-56126 Pisa, Italy.
²Dip. Farmaco Chimico Tecnologico, Università degli Studi di Siena; via Alcide de Gasperi 2, I-53100 Siena, Italy
³Dip. di Studi di Chimica e Tecnologie del Farmaco, Università di Roma “La Sapienza”; piazzale Aldo Moro 5, I-00185 Roma, Italy
⁴Dip. di Farmacologia, Università di Firenze; viale G. Pieraccini 6, I-50139 Firenze, Italy
⁵Rottapharm SpA, via Valosa di Sopra 7, I-20052 Monza, Italy 

 

Abstract

Selective inhibitors of COX2 (Coxibs) were projected to reduce the  gastric complications typically associated with the classical non-steroidal anti-inflammatory drugs (NSAIDs), which are due to the inhibition of mucosal prostanoids deriving from COX1. The improved gastroenteric safety of Coxibs has been generally shown by clinical studies. Nevertheless, strong evidence indicates an increased cardiovascular toxicity of Coxibs. This feature is associated with an imbalance in the activities of different prostanoids endowed with important and opposite roles in the cardiovascular system. Indeed, Coxibs do not influence the biosynthesis of vasocontractile and platelet activating prostanoids, such as the COX1-derived TXA2; by contrast, they inhibit the COX2-mediated production of PGI2, which plays vasorelaxing and anti-platelet effects [1,2]. In order to attenuate such a cardiovascular toxicity, a new class of “bi-functional” drugs has been designed. In these molecules (called CINODs), which show both COX2 Inhibiting and Nitric Oxide (NO)-releasing properties, the release of NO (and the consequent anti-platelet and vasodilator activity) would compensate the impaired PGI2-mediated effects [3]. The CINOD derivative VA 694  was selected for a preliminary investigation. In agreement with the pharmacological profile of a NO-donor compound, VA 694 caused concentration-dependent vasorelaxing effects on isolated endothelium-denuded aortic rings of normotensive Wistar rats; these effects were abolished by ODQ (an inhibitor of guanylate cyclase). Thereafter, the effects of VA 694 were also tested on Spontaneously Hypertensive Rats (SHR). 2-Months old SHR rats, submitted to a chronic (32 days) oral administration of vehicle, exhibited a significant age-dependent progression of the hypertensive status, in agreement with widely reported experimental data. By contrast, the chronic oral administration of VA 694 almost completely arrested such a progressive exacerbation of hypertension. At the end of the above chronic treatment on the two experimental groups, endothelium-intact thoracic aortic rings and hearts of the SHR rats were isolated and submitted to functional studies. The isolated aortic rings of the chronically vehicle-treated SHR rats showed modest vasorelaxing responses to Acetylcholine. This feature is considered a clear indication of endothelial dysfunction, because the vasodilator effects of Acetylcholine are obligatorily mediated by the release of endogenous NO from endothelium. By contrast, the Acetylcholine-induced vasorelaxing responses were improved in aortic rings from the SHR rats submitted to the chronic oral administration of VA 694, suggesting a reduced progression of endothelial dysfunction. As concerns the coronary circulation, Langendorff-perfused isolated hearts from SHR rats showed a coronary flow lower than that exhibited by hearts of normotensive animals; by contrast, the coronary flow of hearts of SHR rats submitted to the sub-chronic oral administration of VA 694 was significantly increased. These results seem to indicate that this compound, a prototype of hybrid drugs endowed with both COX-2-inhibiting and NO-releasing properties, shows beneficial cardiovascular effects probably due to the NO-mediated component. Therefore, such a NO-releasing pharmacodynamic property can be viewed as a complementary aspect of great potential usefulness for counterbalancing the cardiovascular negative effects of Coxibs and improving their toxicological profile.
 
References
[1] Capone ML, Tacconelli S, Rodriguez LG, Patrignani P. NSAIDs and cardiovascular disease: transducing human pharmacology results into clinical read-outs in the general population. Pharmacol. Rep.,2010;62:530-5
[2] Martínez-González J, Badimon L. Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks. Curr. Pharm. Des., 2007; 13:2215-27
[3] Patent “Nitroesteri di 1,5-diaril-2-alchil-pirroli-3-sostituiti”, TO2010A000739