Abanoquil mesylate

We have investigated the subtype of alpha2-adrenoceptor mediating prejunctional inhibition of neurotransmission in rat atrium in comparison with the alpha2-adrenoceptor mediating prejunctional inhibition in rat cerebral cortex. In rat atrium and cerebral cortex, prejunctional alpha2-adrenoceptors were investigated in terms of the ability of alpha2-adrenoceptor antagonists to increase the stimulation-evoked overflow of tritium in tissues pre-incubated with [3H]-noradrenaline. The relatively non-selective alpha2-adrenoceptor antagonist yohimbine and the alpha2D-adrenoceptor selective antagonist BRL 44408 had potencies in rat atrium which were similar to their potencies in rat cerebral cortex. The antagonists ARC 239, HV 723, WB 4101, prazosin, chlorpromazine and abanoquil, which have low affinity for alpha2D-adrenoceptors, significantly increased stimulation-evoked overflow at lower concentrations in rat atrium than rat cerebral cortex. Antagonist potency at prejunctional alpha2-adrenoceptors was correlated with antagonist affinity at alpha2-adrenoceptor ligand binding sites in membranes of rat kidney (alpha2B) and submandibular gland (alpha2D), and human recombinant alpha2C-adrenoceptors labelled with [3H]yohimbine. The correlation between ligand binding sites and the functional receptor in the rat cerebral cortex was significant only for the alpha2D-adrenoceptor ligand binding site (r=0.87, n=8, P<0.01) as compared to the alpha2B-adrenoceptor (r=0.32, n.s.) or alpha2C-adrenoceptor (r=0.12, n.s.) ligand binding sites. The correlation between ligand binding sites and the functional receptor in the rat atrium was not significant for any ligand binding site, with r=0.64, 0.68 and 0.67 for the alpha2D-, the alpha2B- and the alpha2C-adrenoceptor ligand binding sites, respectively. It is concluded that the functional prejunctional alpha2-adrenoceptor of rat cerebral cortex closely resembles the alpha2D-adrenoceptor ligand binding site of rat submandibular gland, but the rat atrium may contain two subypes of prejunctional alpha2-adrenoceptor, alpha2D and another subtype, possibly alpha2B or alpha2C.

α1‐Receptor Subtype Stimulation of Purkinje Fibers. Introduction: Previously we found that WB4101 (WB) 10‐7 M competitively blocks three α1‐adrenergic receptor‐effector responses: the increase in normal automaticity occurring in Purkinje fibers (PF) at high membrane potentials: the increase in abnormal automaticity occurring in PF at depolarized membrane potentials; and the prolongation of PF action potential duration. These observations are consistent with two different hypotheses: (1) WB blocks a single α1‐receptor subtype, which subserves different effector pathways; and (2) WB blocks different receptor subtypes, eacb of which subserves an independent patbway. The aim of this study was to test both hypotheses.Methods and Results: We used standard microelectrode techniques to study the concentration‐dependent actions of three α1‐adrenoreceptor blockers (WB (α1A≫α1D], 5‐methylurapidil [5‐MU] [α1A, ≫α1D], and UK52,046 [nonselective]) on norepinephrine (NK) effects in normal PF and in PF depolarized with a simulated ischemic solution ([K+]o= 10 mM; pO2 < 20 mmHg; pH 6.8; maximum diastolic potential ‐60 ± 1 mV). In normally polarized PF, concentration‐dependent actions of all blockers on both the positive cbronotropic response and the prolongation of action potential duration completely coincide. In contrast, the response to NE of abnormal automaticity in “ischemic” PF differs from normals: there is a bigh sensitivity to WB and 5‐MU and no response to UK52,046.Conclusions: (1) A single receptor subtype appears responsible for botb the α1‐induced prolongation of repolarization and the positive chronotropic effect in normal PF. (2) Two different receptor subtypes may be responsible for the α1‐induced effects on automaticity in normal and ischemic fibers. It is likely that the latter one is α1A, and that consideration of antiarrhythmic therapy with α1‐adrenergic blockers should focus on this subtype as a potential target.