ABSTRACT
We have investigated the subtype of alpha 2-adrenoceptor mediating isometric contractions of human saphenous vein in comparison with alpha 2-adrenoceptor ligand binding sites. Postjunctional alpha 2-adrenoceptors in the human saphenous vein were investigated in terms of the ability of alpha 2-adrenoceptor antagonists to shift the contractile potency of noradrenaline. The following antagonists were employed (potencies, pKB, in human saphenous vein in parentheses): chlorpromazine (6.98 +/- 0.24), BDF 8933 (7.60 +/- 0.06), prazosin (6.62 +/- 0.15), ARC 239 (7.19 +/- 0.15), yohimbine (7.23 +/- 0.09), HV 723 (7.52 +/- 0.14), WB 4101 (7.90 +/- 0.06), SKF 104078 (6.55 +/- 0.08), BRL 44408 (5.72 +/- 0.21). Antagonist potency at postjunctional alpha 2-adrenoceptors was correlated with antagonist affinity at alpha 2-adrenoceptor ligand binding sites in membranes of human platelet (alpha 2A), rat kidney (alpha 2B) and Sf9 cells expressing human recombinant receptors (alpha 2C), labelled with [3H]yohimbine. The correlation with the postjunctional alpha 2-adrenoceptor mediating contraction of the human saphenous vein was best for the human recombinant alpha 2C-adrenoceptor ligand binding site (r = 0.92, n = 8, P < 0.001), as compared to correlations with the alpha 2B-adrenoceptor ligand binding site of rat kidney (r = 0.62, n = 8, n.s.) and with the alpha 2A-adrenoceptor ligand binding site of human platelet (r = 0.23, n = 8, n.s.). It is concluded that the functional postjunctional alpha 2-adrenoceptor mediating contractions of the human saphenous vein closely resembles the human recombinant alpha 2C-adrenoceptor ligand binding site.
Subject(s)
Adrenergic alpha-2 Receptor Agonists , Adrenergic alpha-Agonists/pharmacology , Muscle, Smooth, Vascular/drug effects , Norepinephrine/pharmacology , Saphenous Vein/drug effects , Adult , Animals , Aorta, Thoracic/drug effects , Blood Platelets/drug effects , Female , Humans , In Vitro Techniques , Isometric Contraction/drug effects , Kidney/drug effects , Kidney/metabolism , Kinetics , Middle Aged , Radioligand Assay , Rats , Rats, WistarABSTRACT
Chronic treatment with the D1 and D2 dopamine receptor antagonists SCH 23390 (0.5 mg/kg) and haloperidol decanoate (25 mg/kg) caused an up-regulation in D1 and D2 receptor densities, respectively, with no change in KD. Dopamine (20 microM) interacted with both receptor subtypes in a mixed competitive/non-competitive manner, causing a reduction in ligand binding affinity and an apparent decrease in receptor density. In the presence of dopamine, both vehicle-treated and SCH 23390-treated striatal preparations showed a significant loss in affinity for 3H-SCH 23390 binding to D1 receptors and a decrease in D1 receptor density of approximately 26%. Similarly, dopamine caused a substantial loss in 3H-spiperone binding affinity to D2 receptors and a 46% decrease in Bmax in both vehicle-treated and haloperidol-treated membranes. Thus, receptor up-regulation does not appear to alter the mode of interaction of dopamine with rat striatal dopamine receptors.
