Cardiovascular characterization of the novel organic mononitrate NDIBP in rats

• Published in: Nitric oxide 2022-02, Vol.119, p.50-60
• Main Authors: Cavalcanti, Airlla Laana de Medeiros, Rocha, Patrícia Keytth Lins, Zhuge, Zhengbing, Montenegro, Marcelo F., Paulo, Luciano Leite, Mendes-Júnior, Leônidas das Graças, Brandão, Maria Cláudia Rodrigues, Athayde-Filho, Petrônio F., Lundberg, Jon O., Weitzberg, Eddie, Carlström, Mattias, Braga, Valdir de Andrade
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - metabolism; Antihypertensive Agents - therapeutic use; Cytochrome P-450 Enzyme System - metabolism; Female; Hypertension - drug therapy; Hypertension - metabolism; Male; Medicin och hälsovetenskap; Mesenteric Arteries - drug effects; Mesenteric artery; Nitrates - metabolism; Nitrates - therapeutic use; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Donors - metabolism; Nitric Oxide Donors - therapeutic use; Organic nitrate; Potassium Channels - metabolism; Rats; Rats, Wistar; Renovascular hypertension; Signal Transduction - drug effects; Soluble Guanylyl Cyclase - metabolism; Vasodilator Agents - metabolism; Vasodilator Agents - therapeutic use; Vasorelaxation; Xanthine Dehydrogenase - metabolism
• ISSN: 1089-8603; 1089-8611; 1089-8611
• DOI: 10.1016/j.niox.2021.12.007

Organic nitrates are widely used to restore endogenous nitric oxide (NO) levels reduced by endothelial nitric oxide synthase dysfunction. However, these drugs are associated with undesirable side effects, including tolerance. This study aims to investigate the cardiovascular effects of the new organic nitrate 1,3-diisobutoxypropan-2-yl nitrate (NDIBP). Specifically, we assessed its effects on blood pressure, vascular reactivity, acute toxicity, and the ability to induce tolerance. In vitro and ex vivo techniques showed that NDIBP released NO both in a cell-free system and in isolated mesenteric arteries preparations through a process catalyzed by xanthine oxidoreductase. NDIBP also evoked endothelium-independent vasorelaxation, which was significantly attenuated by 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO, 300 μM), a nitric oxide scavenger; 1-H-[1,2,4] oxadiazolo–[4,3-a]quinoxalin-1-one (ODQ, 10 μM), a soluble guanylyl cyclase inhibitor; tetraethylammonium (TEA, 3 mM), a potassium channel blocker; febuxostat (500 nM), a xanthine oxidase inhibitor; and proadifen (10 μM), an inhibitor of cytochrome P450 enzyme. Furthermore, this organic nitrate did not induce tolerance in isolated vessels and presented low toxicity following acute oral administration. In vivo changes on cardiovascular parameters were assessed using normotensive and renovascular hypertensive rats. NDIBP evoked a reduction of blood pressure that was significantly higher in hypertensive animals. Our results suggest that NDIBP acts as a NO donor, inducing blood pressure reduction without having the undesirable effects of tolerance. Those effects seem to be mediated by activation of NO-sGC-cGMP pathway and positive modulation of K+ channels in vascular smooth muscle. •NDIBP releases NO through a metabolic process catalyzed by XOR and CYP450.•NDIBP induces an endothelium-independent vasorelaxant effect.•NDIBP presents a low oral acute preclinical toxicity.•NDIBP induces hypotension and a dual chronotropic effect in rats.