Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used 
to treat pulmonary arterial hypertension. We tested the hypothesis that a 
selective endothelin type A receptor antagonist (ambrisentan) and a 
phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax 
endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial 
rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L 
ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, 
whereas both drugs in combination acted synergistically to relax arterial rings 
by 83±6%. The nonselective endothelin type A and B receptor antagonists bosentan 
(100 nmol/L) and macitentan (30 nmol/L) alone relaxed endothelin-contracted 
rings by 30±5% and 24±3%, respectively. Combinations of 30 nmol/L tadalafil with 
100 nmol/L bosentan or 30 nmol/L macitentan relaxed endothelin-contracted rings 
by 53±5% or 46±7%, respectively; these values are similar to the calculated sums 
of the individual effects of these compounds. Denudation of endothelium from 
pulmonary arterial rings abolished the vasodilator response to 30 nmol/L 
tadalafil and the synergistic vasorelaxant effect of tadalafil with ambrisentan. 
In the presence of 1 μmol/L BQ-788, a selective endothelin type B receptor 
antagonist, the vasorelaxant effects of 10 nmol/L ambrisentan and 30 nmol/L 
tadalafil were additive but not synergistic. These data can be interpreted to 
suggest that ambrisentan and tadalafil synergistically inhibit 
endothelin-1-induced constriction of rat intrapulmonary arteries and that 
endothelin type B receptors in endothelium are necessary to enable a synergistic 
vasorelaxant effect of the drug combination.