AN IN VITRO STUDY OF INTERACTIONS BETWEEN DOXAZOSIN AND ENALAPRILAT AT VASCULAR α₁‐ADRENOCEPTORS

Abstract

1. Isolated perfused male Sprague-Dawley rat tail artery segments were used to investigate interactions between the alpha-1-adrenoceptor antagonist, doxazosin, and the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, using phenylephrine (PE) as the alpha 1-adrenoceptor agonist. 2. In concentrations of up to 10(-5) mol/L, enalaprilat had no effect on arterial responses to PE. 3. Doxazosin produced a concentration-dependent competitive alpha 1-adrenoceptor antagonism, yielding a mean pA2 value of 8.72. 4. In the continuous presence of 10(-6) mol/L enalaprilat, doxazosin with a pA2 value of 9.10 was a 2.4-fold more potent alpha 1-adrenoceptor antagonist than in the absence of enalaprilat. 5. These results are interpreted to indicate that endogenously produced angiotensin II can modulate the activity of alpha 1-adrenoceptors in vascular smooth muscle.

The INTERACTION BETWEEN ENALAPRILAT AND SELECTED Α‐ADRENOCEPTOR ANTAGONISTS IN ISOLATED RAT TAIL ARTERIES

“…A notable exception to this potentiation was the highly specific al-adrenoceptor antagonist prazosin: this will be discussed separately. The present findings are consistent with the hypothesis (Tierney et al 1989;Marwood et al 1991a,b) that A11 modulates the activity of a]-adrenoceptors; in the absence of A11 (resulting from ACE inhibition by enalaprilat) al-adrenoceptor antagonists were more potent than in the presence of AII.…”

“…The present work, in which a series of a-adrenoceptor antagonists were shown to be potentiated by the ACE inhibitor enalaprilat, confirms and extends previous work (Tierney et al 1989;Marwood et al 1991a,b;Kyncl et al 1992;Marwood et al 1992). A notable exception to this potentiation was the highly specific al-adrenoceptor antagonist prazosin: this will be discussed separately.…”

“…In support of this concept, Smith et al (1991) have suggested that A11 affects the pressor action of noradrenaline at its vascular receptor. In previous work (Tierney et al 1989;Marwood et al 1991a,b) it was postulated that A11 may in some way affect the tertiary structure of the al-adrenoceptor. The present work extends this concept: enalaprilat-induced inhibition of A11 production effectively removes A11 from either the a*-adrenoceptor or the cell membrane around/ near the receptor and may induce a conformational change, thereby allowing antagonists freer access to, or a better 'fit' with, the receptor.…”

Ramipril prevents hypersensitivity to phenylephrine in aorta from streptozotocin-induced diabetic rats

“…These data are supported by Rosendorff et al [43] who reported that cilazapril, an ACE inhibitor, does not affect the affinity of phenylephrine for o~-adrenergic receptors. Similarly, Tierney et al [44] reported no effect of enalaprilat on responses to phenylephrine in segments from rat tail arteries.…”

INVESTIGATIONS INTO INTERACTIONS BETWEEN DOXAZOSIN AND ENALAPRILAT AT α1‐ADRENOCEPTORS IN ANAESTHETIZED RATS

“…Furthermore, the lack of effect of enalaprilat on doxazosin in arteries from DOCA-treated rats reflected the fact that the DOCAsaline treatment had already prevented AII production by depriving the ACE of its substrate, AI. On the basis of these results we proposed that A11 modulates the activity of vascular al-adrenoceptors (Tierney et al 1989;Marwood et al 1991).…”