Interaction of 5-methyl-urapidil with alpha(1)-adrenoceptors in canine blood vessels: Impact of pacing-induced heart failure

This study examines whether the alpha(1)-adrenoceptors in canine endothelium-denuded dorsal pedal artery and endothelium-denuded saphenous vein can be differentiated by 5-methyl-urapidil before (non-paced) and at end-stage heart failure induced by rapid ventricular pacing. Noradrenaline and phenylephrine produced concentration-dependent contractions of the dorsal pedal artery and the saphenous vein which were enhanced at end-stage heart failure. In non-paced animals, 5-methyl-urapidil was shown to be insurmountable against noradrenaline with the artery being more sensitive compared to the vein. At end-stage heart failure, 5-methyl-urapidil was a competitive antagonist against noradrenaline in both the artery and the vein with pA(2) values of 8.1 (7.9-8.4) and 8.6 (8.2-9.1), respectively. A different antagonist profile was seen against phenylephrine. Similar to noradrenaline, insurmountable antagonism was observed in the artery and the vein before the development of heart failure. In contrast to noradrenaline, at end-stage heart failure, no antagonism was seen with the concentrations of 5-methyl-urapidil tested against phenylephrine. These results suggest that the mechanisms mediating contractions in the dorsal pedal artery and saphenous vein to noradrenaline and phenylephrine are heterogeneous and dependent on the heart failure state.