Abstract 034: Absence Of Tachyphylaxis And Vasorelaxant Effect Induced By Nono2p, A New Nitric Oxide Donor

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2022-09, Vol.79 (Suppl_1)
• Main Authors: dos Anjos Moraes, Raiana, Alexandra de Araujo, Fênix, Barreto da Silva, Liliane, Leonne Cruz de Jesus, Rafael, Santana de Brito, Daniele, Santos de Sá, Denise, Daniel Silva da Silva, Carlos, Novais da Rocha, Zenis, Priviero, Fernanda, Webb, R C, Flavia Silva, Darizy
• Format: Article
• Language: English
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/hyp.79.suppl_1.034

Abstract only Introduction: Decreased bioavailability of nitric oxide (NO) plays a mechanistic role in hypertension and myocardial infarction. NO donors are potent vasodilators, but often exhibit toxicity or vascular tolerance. The aim of this study was to investigate the vascular activity possible tachyphylaxis of NONO2P, a novel NO donor. Methods: Male Wistar rats were euthanized, and the superior mesenteric artery was isolated for recordings of isometric force, and in vivo experiments were performed to evaluate blood pressure in non-anesthetized normotensive rats. Results: Cumulative administration of the NONO2P (10 -13 to 3x10 -6 M) induced endothelium-independent relaxation (Emax:111.51 ± 2.31%; pD2: 8.51 ± 0.08, n=9) in arterial rings pre-contracted with phenylephrine (Phe,1μM). However, the relaxation was reduced in pre-contracted rings with Phe exposed to Tyrode's solution containing 20 mM of K + (E max : 102.83 ± 2.10%; pD2: 7.73 ± 0.04, n=6), suggesting the participation of K + channels in the relaxation. The presence of the specific soluble guanylyl cyclase (sGC) inhibitor, ODQ (10μM), abolished the vasorelaxant effect (E max : 15.38 ± 11.85%, n=7). Pre-incubation with cyclopiazonic acid (CPA) (10μM), inhibitor of sarcoendoplasmic reticulum calcium ATPase (SERCA), shifted the relaxation concentration-response to the right (E max : 106.17 ± 3.06%; pD2: 7.69 ± 0.04, n=6). Interestingly, repeated NONO2P administration did not induce tachyphylaxis, and NONO2P presented similar maximum efficacy to sodium nitroprusside (SNP) (E max : 114.24 ± 3.47%; pD2: 9.40 ± 0.04, n=6). Moreover, NONO2P lowered blood pressure in normotensive rats. Conclusion: The endothelium-independent vasorelaxant effect induced by NONO2P involves both sGC, SERCA and K + channel activation, and NONO2P does not appear to cause tachyphylaxis. NONO2P is able to promote vasorelaxation with the same magnitude as SNP. Finally, NONO2P reduces blood pressure, becoming a promising molecule as a novel therapeutic alternative for the treatment of cardiovascular diseases.