Antagonism of endothelin actions

Abstract

The mechanism of hypertension following acute NO synthase blockade is via endothelin-mediated vasoconstriction. Thus, NO appears to inhibit endothelin activity by blocking its expression and not as a chronic direct acting vasodilator. Administration of an endothelin antagonist to a patient in a ‘normal’ physiological state may result in specific regional vasodilation. This treatment finds utility in the treatment of erectile dysfunction.

What is claimed is:  
     
         1 . A method for treating physiological conditions in which NO production is at least partially inhibited, comprising the step of administering to a patient in need thereof an effective amount of an agent which will antagonize the actions of endothelin, in a pharmaceutically acceptable carrier therefor.  
     
     
         2 . A method as claimed in  claim 1  wherein said agent is selected from the group consisting of peptidal endothelin antagonists, non-peptidal endothelin antagonists, inhibitors of endothelin converting enzyme, and antisense oligonucleotides which block translation of endothelin mRNA.  
     
     
         3 . A method as claimed in  claim 2  wherein said peptidal endothelin antagonist is an ET A /ET B  receptor antagonist.  
     
     
         4 . A method as claimed in  claim 2  wherein said non-peptidal endothelin antagonist is bosentan.  
     
     
         5 . A method as claimed in  claim 2  wherein said inhibitor of endothelin converting enzyme is phosphoramidon.  
     
     
         6 . A method as claimed in  claim 2  wherein said anti-sense oligonucleotide is complementary to at least a portion of preproendothelin mRNA.  
     
     
         7 . A method as claimed in  claim 1  wherein said physiological condition is selected from the group consisting of hypertension and erectile dysfunction.  
     
     
         8 . A method as claimed in  claim 2  wherein said agent is administered orally.  
     
     
         9 . A method as claimed in  claim 2  wherein said agent is administered intraperitoneally.  
     
     
         10 . A method as claimed in  claim 3  wherein said ET A /ET B  receptor antagonist is PD145065.  
     
     
         11 . A method as claimed in  claim 10  wherein said PD145065 is administered intraperitoneally.  
     
     
         12 . A composition for use in the treatment of physiological conditions in which NO production is at least partially inhibited, comprising an effective amount of an agent which will antagonize the action of endothelin, in admixture with a pharmaceutically acceptable carrier therefor.  
     
     
         13 . A composition as claimed in  claim 12  wherein said agent is selected from the group consisting of peptidal endothelin antagonists, non-peptidal endothelin antagonists, inhibitors of endothelin converting enzyme and antisense oligonucleotides which block translation of endothelin mRNA.  
     
     
         14 . A composition as claimed in  claim 13  wherein said peptidal endothelin antagonist is an ET A /ET B  receptor antagonist.  
     
     
         15 . A composition as claimed in  claim 14  wherein said ET A /ET B  receptor antagonist is PD145065.  
     
     
         16 . A composition as claimed in  claim 13  wherein said non-peptidal endothelin antagonist is bosentan.  
     
     
         17 . A composition as claimed in  claim 13  wherein said inhibitor of endothelin converting enzyme is phosphoramidon.  
     
     
         18 . A composition as claimed in  claim 13  wherein said antisense oligonucleotide is complementary to at least a portion of preproendothelin mRNA.  
     
     
         19 . A composition as claimed in  claim 13  wherein said agent is an ET A  receptor antagonist.  
     
     
         20 . A composition as claimed in  claim 13  wherein said agent is an ET B  receptor antagonist.  
     
     
         21 . A method for down regulating local endothelin-mediated vasoconstrictor tone and vascular growth activity in a patient independently of any normal or abnormal systemic physiology, comprising the step of administering an effective amount of endothelin antagonist agent in a pharmaceutically acceptable carrier therefor.  
     
     
         22 . A method as claimed in  claim 21  wherein said agent is selected from the group consisting of peptidal endothelin antagonists, non-peptidal endothelin antagonists, inhibitors of endothelin converting enzyme, and antisense oligonucleotides which block translation of endothelin mRNA.  
     
     
         23 . A method as claimed in  claim 22  wherein said peptidal endothelin antagonist is an ET A /ET B  receptor antagonist.  
     
     
         24 . A method as claimed in  claim 21  wherein said vasoconstrictor tone is selected from the set consisting of the tone of the pudendal vasculature, the tone of the arteries feeding the pudendal vasculature, and a combination thereof.  
     
     
         25 . A composition for use in down regulation of local endothelin-mediated vasoconstrictor tone and vascular growth activity in a patient independently of any normal or abnormal systemic physiology, comprising an effective amount of an agent which will antagonize the action of endothelin, in admixture with a pharmaceutically acceptable carrier therefor.  
     
     
         26 . A composition as claimed in  claim 25  wherein said agent is selected from the group consisting of peptidal endothelin antagonists, non-peptidal endothelin antagonists, inhibitors of endothelin converting enzyme and antisense oligonucleotides which block translation of endothelin mRNA.  
     
     
         27 . A composition as claimed in  claim 26  wherein said peptidal endothelin antagonist is an ET A /ET B  receptor antagonist.  
     
     
         28 . A composition as claimed in  claim 25  wherein said vasoconstrictor tone is selected from the set consisting of the tone of the pudendal vasculature, the tone of the arteries feeding the pudendal vasculature, and a combination thereof.