Potentiation ofIsosorbide Dinitrate Effects WithN-Acetlcysteine inPatients With Chronic HeartFailure

Background Supply ofsulfhydryl groups withtheadministration ofN-acetylcysteine (NAC)hasbeenreported toreverse tolerance tonitroglycerin butnottoisosorbide dinitrate (ISDN). Lackofinteraction between NAC andISDNwas suggested asanexplanation forthese findings. Thepresent study wastherefore designed tofurther evaluate this hypothesis. Forthis purpose, wecompared thehemodynamic and hormonal effects ofISDNwhengiven alone andincombination withNAC. Methods andResults We performed arandomized, crossoverdesign evaluation ofthehemodynamic andhormonal effects ofISDNandISDN+NACin14patients withchronic congestive heart failure duetoleft ventricular systolic dysfunction. Thefindings ofthis study demonstrated asubstantial NAC-mediated potentiation ofISDNeffect onmeanright atrial pressure (-11±21% versus -38±27%, -17±20% versus-34±27%, and-7±20%versus -25±26%at2,3,and4 hours, respectively; all P<.05), meanpulmonary artery wedge pressure (-18±16% versus-33±14%, -15±25%versus -33±19%, -14±22%versus -25±22%, and-16±16% versus-26±16%at2,3,4,and5hours, respectively; all P<.05), meanpulmonary artery pressure (-8±11%versus -20±15% at3hours, P<.05), andcardiac output (anincrease of2±16% versus 25±20%at4hours, P<.05). Although there wereno significant changes inserumcatecholamine levels andplasma renin concentration with bothregimens, ISDN+NACresulted inagreater fall inplasma levels ofatrial natriuretic peptide (296±251 pg/mLafter ISDNversus 202±118pg/mLafter ISDN+NAC,P<.05). Conclusions Theresults ofthis study provide strong evidencefortheexistence ofaninteraction between thiols and ISDNandfurther support therole ofsulfhydryl groups inthe activation andtherapeutic action oforganic nitrates. The discrepancy between theresults ofthis study demonstrating NAC-induced potentiation ofISDNeffects andaprevious study showing failure toreverse ISDNtolerance withNAC maysuggest thatISDN-NACinteraction requires normal intracellular levels ofsulfhydryl groups anddoesnotoccur after intracellular sulfhydryl groupdepletion. (Circulation. 1994;89:2595-2600.)