The modulatory role of vascular endothelium in the interaction of agonists and antagonists with alpha-adrenoceptors in the rat aorta.

1. We have examined the effect of endothelium on the antagonistic action of prazosin, doxazosin, yohimbine and phentolamine against phenylephrine, clonidine and noradrenaline. 2. The action of prazosin against phenylephrine was similar to that earlier reported against noradrenaline, acting as a non-competitive antagonist in the presence of endothelium and as a competitive antagonist in the absence of endothelium. Prazosin also acted as a non-competitive antagonist against clonidine in the absence of endothelium. 3. Doxazosin behaved in a similar way to prazosin against noradrenaline, phenylephrine and clonidine acting as a non-competitive antagonist in the presence of endothelium and as competitive antagonist after removal of endothelium. In contrast, yohimbine and phentolamine acted as competitive antagonists both in the presence and in the absence of endothelium. 4. Analysis of the concentration-response curves for noradrenaline, phenylephrine and clonidine in the presence and in the absence of endothelium showed that the affinity for all three agonists was the same but not the efficacy and the receptor reserve, both of which were lower in the presence than in the absence of endothelium. 5. The rank order of agonist potency in the absence of endothelium was noradrenaline greater than phenylephrine greater than clonidine. The rank order of antagonist potency was prazosin greater than or equal to doxazosin greater than phentolamine greater than yohimbine. 6. The results show that vascular endothelium modulates the contractile response to alpha-adrenoceptor agonists and also modifies the action of the antagonists prazosin and doxazosin but not that of yohimbine and phentolamine. This effect of endothelium was related to a change in agonist efficacy and receptor reserve. These results also suggest that the alpha-adrenoceptors of the isolated aorta of the rat are predominantly, if not exclusively of the alpha 1-subtype

Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta.

The effect of endothelium on the adrenolytic action of prazosin was studied in the rat isolated aorta. Prazosin showed a non-competitive type of antagonism in preparations with intact endothelium while in preparations where endothelium had been removed, prazosin at concentrations between 0.3 nM-10 nM acted as a competitive antagonist. Methylene blue, used to decrease tissue levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP), converted prazosin from a non-competitive antagonist into an apparently competitive antagonist in the presence of endothelium. Increasing tissue levels of cyclic GMP by incubation with 8-bromo-cyclic GMP converted prazosin from an apparently competitive antagonist into a non-competitive antagonist in the absence of endothelium. Analysis of concentration-response curves for noradrenaline in the presence and absence of endothelium showed that the affinity for noradrenaline was the same but the efficacy, measured by estimating the receptor reserve, was not; it was lower in the presence than in the absence of endothelium. It was concluded that the change in the mode of antagonism of prazosin after endothelium removal could be related to an alteration in the efficacy of the agonist, brought about by a change in the tissue levels of cyclic GMP