Nitroxyl Progenitors in the Treatment of Heart Failure

Abstract

Administration of an HNO/NO − donating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NO − donating compound isopropylamine (IPA)/NO (Na(CH 3 ) 2 CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NO − donating compound Angeli's salt. Additionally, in contrast to the effects observed with NO donors, administration of an HNO/NO − donor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NO − exerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

1 .- 25 . (canceled) 
     
     
         26 . A method of treating heart failure comprising;
 administering to a subject experiencing heart failure, a therapeutically effective dose of at least one nitroxyl donating compound, wherein the nitroxyl donating compound is not Angeli's salt and is not administered in the presence of a potassium-channel activator, and wherein the dose is effective to increase myocardial contractility.   
     
     
         27 . The method of  claim 26 , wherein the nitroxyl donating compound comprises a compound having the formula 
       
         
           
           
               
               
           
         
         wherein J is an organic or inorganic moiety, M +x  is a pharmaceutically acceptable cation, wherein x is the valence of the cation, a is 1 or 2, b and c are the smallest integers that result in a neutral compound, and wherein the compound releases the nitroxyl under physiological conditions. 
       
     
     
         28 . The method of  claim 27 , wherein the nitroxyl donating compound comprises a derivative or analog of IPA/NO. 
     
     
         29 . The method of  claim 26 , wherein the heart failure is not acute congestive heart failure. 
     
     
         30 . A method of treating heart failure comprising;
 administering to a subject experiencing heart failure and receiving beta-adrenergic receptor antagonist therapy, a therapeutically effective dose of at least one nitroxyl donating compound, wherein the dose is effective to increase myocardial contractility.   
     
     
         31 . The method of  claim 30 , wherein the nitroxyl donating compound comprises a compound having the formula 
       
         
           
           
               
               
           
         
         wherein J is an organic or inorganic moiety, M I ′ is a pharmaceutically acceptable cation, wherein x is the valence of the cation, a is 1 or 2, b and c are the smallest integers that result in a neutral compound, and wherein the compound releases the nitroxyl under physiological conditions. 
       
     
     
         32 . The method of  claim 31 , wherein the nitroxyl donating compound comprises a derivative or analog of IPA/NO. 
     
     
         33 . The method of  claim 31 , wherein the nitroxyl donating compound comprises Angeli's salt. 
     
     
         34 . The method of  claim 30  wherein the beta-adrenergic receptor antagonist therapy comprises administration of propranolol to the subject.