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Background & Aims: The treatment of cardiovascular diseases (CVD) could greatly benefit from using nitric oxide (NO) donors. This study aimed to investigate the mechanisms of action of NONO2P that contribute to the observed responses in the mesenteric artery. The hypothesis was that NONO2P would have similar pharmacological actions to sodium nitroprusside (SNP) and NO., Methods: Male Wistar rats were euthanized to isolate the superior mesenteric artery for isometric tension recordings. NO levels were measured using the DAF-FM/DA dye, and cyclic guanosine monophosphate (cGMP) levels were determined using a cGMP-ELISA Kit., Results: NONO2P presented a similar maximum efficacy to SNP. The free radical of NO (NO • ) scavengers (PTIO; 100 μM and hydroxocobalamin; 30 μM) and nitroxyl anion (NO - ) scavenger (L-cysteine; 3 mM) decreased relaxations promoted by NONO2P. The presence of the specific soluble guanylyl cyclase (sGC) inhibitor (ODQ; 10 μM) nearly abolished the vasorelaxation. The cGMP-dependent protein kinase (PKG) inhibition (KT5823; 1 μM) attenuated the NONO2P relaxant effect. The vasorelaxant response was significantly attenuated by blocking inward rectifying K + channels (K ir ), voltage-operated K + channels (K V ), and large conductance Ca 2+ -activated K + channels (BK Ca ). NONO2P-induced relaxation was attenuated by cyclopiazonic acid (10 μM), indicating that sarcoplasmic reticulum Ca2+-ATPase (SERCA) activation is involved in this relaxation. Moreover, NONO2P increased NO levels in endothelial cells and cGMP production., Conclusions: NONO2P induces vasorelaxation with the same magnitude as SNP, releasing NO • and NO - . Its vasorelaxant effect involves sGC, PKG, K + channels opening, and SERCA activation, suggesting its potential as a therapeutic option for CVD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and purpose:Phosphodiesterase type-5 (PDE5) inhibitors constitute a novel and important therapeutic option for the treatment of pulmonary hypertension. The effects of the PDE5 inhibitors sildenafil, tadalafil and vardenafil on rabbit isolated pulmonary artery ring preparations and on intracellular Ca2+ concentration of thrombin-stimulated human platelets were investigated.Experimental approach:Rabbit pulmonary artery rings were mounted in 10 mL organ bath containing Krebs solution. Tissues were connected to force-displacement transducers, and changes in isometric force were recorded. Ca2+ flux in human washed platelets was measured.Key results:Sildenafil, tadalafil and vardenafil (0.0001–10 μM) concentration-dependently relaxed endothelium-intact and endothelium-denuded pulmonary artery rings. Endothelium denudation caused rightward shifts in the concentration–response curves to sildenafil, tadalafil and vardenafil (9-, 12- and 123-fold, respectively). Incubation with Nω-nitro-L-arginine methyl ester (100 μM) or ODQ (1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one) (10 μM) caused similar reductions of PDE5-induced vasorelaxations in intact rings. Sildenafil and tadalafil did not affect the phenylephrine-induced contractions, whereas vardenafil reduced the maximal responses, and shifted the phenylephrine-induced contraction curves to the right in endothelium-denuded rings (5- and 19-fold for 1 and 10 μM, respectively). Vardenafil (but neither sildenafil nor tadalafil) caused a marked rightward shift and a decrease of maximal contractile response to CaCl2. Vardenafil, but neither sildenafil nor tadalafil, significantly reduced the Ca2+ mobilization and Ca2+ influx in thrombin-stimulated washed platelets.Conclusions and implications:Our results indicate that vardenafil, in contrast to sildenafil or tadalafil, also blocked Ca2+ fluxes, thus enhancing its vasorelaxation of the pulmonary artery.British Journal of Pharmacology (2008) 154, 787–796; doi:10.1038/bjp.2008.141; published online 21 April 2008 [ABSTRACT FROM AUTHOR]