Pharmacological Characterization of Α‐adrenoreceptor Subtypes in Rat Isolated Thoracic 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. 5The rank order of agonist potency in the absence of endothelium was noradrenaline > phenylephrine > clonidine. The rank order of antagonist potency was prazosin > doxazosin > phentolamine > yohimbine. 6 The results show that vascular endothelium modulates the contractile response to a-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 a-adrenoceptors of the isolated aorta of the rat are predominantly, if not exclusively of the a1-subtype.

Section: Discussionsupporting

confidence: 79%

The modulatory role of vascular endothelium in the interaction of agonists and antagonists with α‐adrenoceptors in the rat aorta

Alosachie

Godfraind

1988

“…85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. Though the present functional evaluations did not provide the most precise estimates of the antagonists affinity, owing to the limited series of experiments and at least in some cases the narrow range of concentrations tested, the pA2 value of prazosin (or the apparent pKB = 9.5) derived is in agreement with previously reported data showing affinity values (pA2) of 10.42 (Hamed et al, 1983), 10.30 (Martinotti et al, 1991), 9.89 (Muramatsu et al, 1990), 9.45 (Aboud et al, 1993) and 10.6 (Oriowo et al, 1990). Also our pA2 values for phentolamine and 5-methylurapidil are similar to those previously obtained by other authors (Muramatsu et al, 1990;Hamed et al, 1983;Aboud et al, 1993).…”

Section: Affinity For the M)aand Ac8-adrenoceptor Subtypessupporting

confidence: 88%

Mediation of noradrenaline‐induced contractions of rat aorta by the (α_1B‐adrenoceptor subtype

Testa

Guarneri

Poggesi

et al. 1995

1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible alpha 1B-adrenoceptor antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the alpha 1B-adrenoceptor subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population.

“…We used the rat aorta and anococcygeus for postjunctional a,-adrenoceptors and the rabbit saphenous vein for postjunctional x2-adrenoceptors. Rat aorta was chosen because it is now generally accepted that only a,-adrenoceptors are located there (Downing et al, 1983;Digges & Summers, 1983a;Hamed et al, 1983;Ruffolo, 1985). Rat anococcygeus is also believed to contain only a,-adrenoceptors (McGrath, 1984).…”

mentioning

confidence: 99%

Activities of octopamine and synephrine stereoisomers on α‐adrenoceptors

Brown¹,

McGrath

Midgley

et al. 1988

100

1 The activities of the (-)-and (+ )-forms of m-and p-octopamine and m-and p-synephrine on a,-adrenoceptors from rat aorta and anococcygeus and a2-adrenoceptors from rabbit saphenous vein were compared with those of noradrenaline (NA).2 The rank order of potency of the (-)-forms on cx,-adrenoceptors from rat aorta and a2-adrenoceptors was NA > m-octopamine = m-synephrine > p-octopamine = p-synephrine. The two m-compounds were 6 fold less active than NA on x,-adrenoceptors from rat aorta and 150 fold less active on x,-adrenoceptors. The two p-compounds were 1,000 fold less active than NA on both oqadrenoceptors from rat aorta and x2-adrenoceptors. The rank order ofpotency ofthe (-)-forms on oqadrenoceptors from rat anococcygeus was NA = m-synephrine > m-octopamine >p-octopamine = p-synephrine. m-Octopamine was 4 fold less active than NA and (-)-m-synephrine. The two pcompounds were 30 fold less active than NA. 3 The rank order of potency of the (+)-forms was NA>m-octopamine>m-synephrine>p-octopamine >p-synephrine on both a,-and M2-adrenoceptors. The potency ofeach ( + )-form was 1-2 orders of magnitude less than that of the (-) counterpart, the differences being greater for the stereoisomers of synephrine than for those of octopamine on both a,-and M2-adrenoceptors. 4 The yohimbine diastereoisomer antagonists, rauwolscine and corynanthine, were tested against (-)-NA and (-)-m-octopamine-induced contractions in both preparations. Based upon the known selectivities of these isomers for a-adrenoceptor subtypes, it is concluded that the rat aorta contains only a,-adrenoceptors while the rabbit saphenous vein possesses predominantly M2-adrenoceptors.5 Ligand binding data for the octopamine and synephrine stereoisomers at oq-and a2-binding sites from rat cerebral cortex was also obtained. (-)-Forms were more active than (+ )-forms. The rank order of affinity of the (-)-forms for both a,-and M2-binding sites was NA > m-octopamine = msynephrine >p-synephrine >p-octopamine. The relative affinities ofthe members ofthe series against a,-binding sites were very similar to their relative functional activities on rat aorta. However, the affinities of both m-and p-compounds relative to that of ( -)-NA were much greater at the x2-binding sites than were the relative activities in rabbit saphenous vein, possibly suggesting low intrinsic efficacy. Functional antagonist responses to NA by the (-)-octopamine and synephrines could not, however, be demonstrated on rat aorta or rabbit saphenous vein. 6 The activities of m-octopamine and m-synephrine were not significantly different from each other on either a,-adrenoceptors from rat aorta or x2-adrenoceptors; however, m-synephrine is more active than m-octopamine on a,-adrenoceptors from rat anococcygeus. Both m-octopamine and msynephrine can be considered to be naturally occurring x,-selective amines. However, if m-and poctopamine are co-released with NA in amounts proportional to their concentration, it is concluded that their activities on m,-and x2-adrenoceptors are too low to be ...