The Classification of Adrenoceptors (Adrenergic Receptors). An Evaluation from the Standpoint of Receptor Theory

1 The actions of the a 1 -adrenoceptor antagonist indoramin have been examined against the contractions induced by noradrenaline in the rat vas deferens and aorta taking into account a putative neuronal uptake blocking activity of this antagonist which could result in self-cancelling actions.2 Indoramin behaved as a simple competitive antagonist of the contractions induced by noradrenaline in the vas deferens and aorta yielding pA 2 values of 7.38+0.05 (slope=0.98+0.03) and 6.78+0.14 (slope=1.08+0.06), respectively. 3 When the experiments were repeated in the presence of cocaine (6 mM) the potency (pA 2 ) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72+0.07 (slope=1.10+0.05) while its potency remained unchanged in the aorta (pA 2 =6.69+0.12; slope=1.04+0.05). 4 In denervated vas deferens, indoramin antagonized the contractions to noradrenaline with a potency similar to that found in the presence of cocaine (8.79+0.07; slope=1.09+0.06). 5 It is suggested that indoramin blocks a 1 -adrenoceptors and neuronal uptake in rat vas deferens resulting in Schild plots with slopes not di erent from unity even in the absence of selective inhibition of neuronal uptake. As a major consequence of this double mechanism of action, the pA 2 values for this antagonist are underestimated when calculated in situations where the neuronal uptake is active, yielding spurious pK B values.

Section: Discussionmentioning

confidence: 55%

Effects of indoramin in rat vas deferens and aorta: concomitant α₁‐adrenoceptor and neuronal uptake blockade

Pupo

Cavenaghi

Campos

et al. 1999

“…The maximal contractions induced by phenylephrine, 5-HT and KCl in each preparation were taken as 100%, and nonlinear regression analyses were applied to sigmoid concentration-response curves for contractile agonists. The pK B value was determined for a single concentration of antagonist by the concentration-ratio method (Furchgott, 1972). Binding data were first fitted to a one-and then a twosite model, and if the residual sums of squares were statistically less for a two-site fit of the data than for a one-site, as determined by an F-test comparison, then the two-site model was accepted.…”

Section: Discussionmentioning

confidence: 99%

Alpha‐1D adrenoceptors are involved in reserpine‐induced supersensitivity of rat tail artery

Taki

Tanaka

Zhang

et al. 2004

1 We examined reserpine-induced chemical denervation supersensitivity with special reference to alpha-1 adrenoceptor (AR) subtypes. 2 Chronic treatment with reserpine for 2 weeks depleted noradrenaline in the tail artery and spleen of rats. Noradrenaline in the thoracic aorta was negligible before and after reserpine treatment. 3 The treatment with reserpine produced supersensitivity in the contractile responses of the rat tail artery to phenylephrine, 5-HT and KCl, resulting in leftward shift of concentration-response curves (11.6-, 2.5-and 1.1-fold at EC 50 value, respectively). These results suggest a predominant sensitization of the alpha-1 AR-mediated response by reserpine treatment. 4 BMY 7378 at a concentration (30 nM) specific for blocking the alpha-1D AR subtype, but not KMD-3213 at a concentration (10 nM) selective for blocking the alpha-1A AR subtype, inhibited the supersensitivity of the phenylephrine-induced response in the reserpine-treated artery. On the other hand, the response to phenylephrine in reserpine-untreated artery was selectively inhibited by the same concentration of KMD-3213, but not by BMY 7378. Prazosin, a subtype-nonselective antagonist, blocked the responses to phenylephrine with the same potency, regardless of reserpine treatment. 5 In the thoracic aorta and spleen, no supersensitivity was produced in the responses to phenylephrine by reserpine treatment. 6 In a tissue segment-binding study using [ 3 H]-prazosin, the total density and affinity of alpha-1 ARs in the rat tail artery were not changed by treatment with reserpine. However, alpha-1D AR with high affinity for BMY 7378 was significantly detected in reserpine-treated tail artery, in contrast to untreated artery. Decreases in alpha-1A AR with high affinity for KMD-3213 and alpha-1B AR with low affinities for KMD-3213 and BMY 7378 were also estimated in reserpine-treated tail artery. 7 Alpha-1D AR mRNA in rat tail artery increased to three-folds by reserpine treatment, whereas the levels of alpha-1A and 1B mRNAs were not significantly changed. 8 The present results suggest that chronic treatment with reserpine affects the expression of alpha-1 AR subtypes of rat tail artery and that the induction of alpha-1D ARs with high affinity for catecholamines is in part associated with reserpine-induced supersensitivity.

“…The agonist concentrationratio (CR) in the presence and absence of the antagonist was determined at the level of 50% of the maximum response. Using the agonist concentration ratio produced by the lowest e ective concentration of the antagonist (one producing a 3 ± 5 fold rightward displacement of the agonist concentration response curve), an estimate of the negative logarithm of the dissociation constant (logK B ) was determined by the method of Furchgott (1972). logK B log CR 1 log Antagonist…”

Section: Discussionmentioning

confidence: 99%

Rilmenidine reveals differences in the pharmacological characteristics of prejunctional α₂‐adrenoceptors in the guinea‐pig, rat and pig

Ali

Cheng

Ting

et al. 1998

1 The a 2A and a 2D -adrenoceptor subtypes are thought to be species homologs most easily di erentiated on the basis of the potency of antagonists. In the present study we have compared the e ect of rilmenidine with two other selective a 2 -adrenoceptor agonists, UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) and clonidine, against electrically-evoked contractions in ®ve isolated preparations from the rat, guinea-pig and pig, and, where possible, determined the receptor subtype involved. 2 UK-14034, clonidine and rilmenidine produced concentration-dependent inhibition of the electricallyevoked contractions of the rat isolated vas deferens and tail artery and the guinea-pig ileum. These inhibitory e ects were reversed by the selective a 2 -adrenoceptor antagonist, RX-811058 (1 mM), except in the rat tail artery preparations where the remaining neurogenic response was inhibited; evidence for the involvement of`innervated' a 2 -adrenoceptors. Both clonidine and UK-14304 produced concentrationdependent inhibition of responses in the porcine isolated tail artery and urinary bladder but clonidine was markedly less e cacious in these preparations. In contrast, rilmenidine failed to inhibit the neurogenic contractions in either preparation. 3 Although rilmenidine failed to elicit a detectable response in either the porcine isolated tail artery or urinary bladder, it (10 mM and 30 mM, respectively) competitively antagonised the inhibitory e ects of UK-14304 with an estimated dissociation constant of (pK B ) 5.82 and 5.93, respectively. 4 Prazosin (1 mM) failed to alter the e ect of UK-14304 against neurogenic contractions in the porcine isolated urinary bladder, while rauwolscine (pK B 8.87) was 10 fold more potent than phentolamine (pK B 7.56). On the other hand, phentolamine (pK B 8.42) was only marginally more potent than rauwolscine (pK 8.05) against clonidine-induced inhibition of electrically-evoked contractions of the guinea-pig isolated ileum. This pharmacological evidence with antagonists supports the presence of a 2D -adrenoceptors in the rat and guinea-pig and the a 2A -adrenoceptors in the pig. 5 We have demonstrated that rilmenidine, unlike clonidine and UK-14304, is devoid of any agonist activity at prejunctional a 2A -adrenoceptors in the pig, but is an e cacious agonist at a 2D -adrenoceptors in the rat and guinea-pig.