piperidines and 5-methylurapidil

1 Alpha1-Adrenoceptor (alpha1-AR) subtypes were characterized in isolated omental arteries obtained after abdominal surgery in patients with end-stage renal disease (ESRD) or with Diabetes Mellitus type 2 plus ESRD (ESRD-DM). 2 Omental arteries from patients with ESRD and ESRD-DM elicited a significant increase in sensitivity to phenylephrine with a pD(2) (-log EC50) of 6.7 and 6.6, respectively, vs. the control (5.8, P < 0.001). 3 Stimulation with phenylephrine was conducted in the presence or absence of selective alpha1-AR competitive antagonists: 5-methylurapidil (alpha1A-), AH11110A (1-[biphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2-ol; alpha1B-) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4.5] decane-7,9-dione; alpha(1D)-). The relative abundance of mRNA for all three alpha(1)-ARs was determined. 4 The maximal contractile responses to phenylephrine were: E(max) 1.59 +/- 0.17, 1.48 +/- 0.08 and 1.55 +/- 0.14 g for the ESRD, ESRD-DM and control groups, respectively. 5 Functionally, there was an increment in the affinity for the alpha(1A)-AR antagonist (pA2: control 7.45, ESRD 8.36, ESRD-DM 8.0; P < 0.01), and a reduction in the alpha1B-AR antagonist affinity (8.3 for controls, 7.6 for ESRD and 7.3 for ESRD-DM; P < 0.01) associated with renal disease. The affinities for the alpha1D-AR antagonist were similar among the studied groups (8.5 for the controls, 8.7 for the ESRD and 8.1 for the ESRD-DM groups). 6 Renal disease increased mRNA expression of alpha(1B)-ARs and reduced both alpha1A- and alpha(1D)-ARs subtypes in ESRD and ESRD-DM patients. 7 The results suggest that human omental arteries exposed to chronic uraemia show vascular hypersensitivity to phenylephrine, because of functional alpha1-AR changes.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adult; Arteries; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Humans; Imines; Kidney Failure, Chronic; Male; Middle Aged; Omentum; Phenylephrine; Piperazines; Piperidines; Receptors, Adrenergic, alpha-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasoconstriction; Vasoconstrictor Agents

1 We have characterized the alpha(1)-adrenoceptor subtypes present in isolated aorta of the alpha(1D)-adrenoceptor knockout (KO) mice, by chloroethylclonidine (CEC)-induced alkylation and their protection by selective alpha(1)-adrenoceptor antagonists. 2 The alpha(1D)-adrenoceptor is involved in the contractile response to noradrenaline in wild type (WT) mouse aorta. 3 In WT mice 5-methylurapidil (5-MU, an alpha(1A)-adrenoceptor antagonist) or BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-8-azaspiro[4.5] decane-7,9 dione, a selective alpha(1D)-adrenoceptor antagonist), protected the receptors from CEC-induced (alpha(1B/D)-adrenoceptor) alkylation, the combination of both antagonists resulted in complete protection, while AH11110A (1-[biphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2-ol, an alpha(1B)-adrenoceptor antagonist) did not protect. 4 In aorta of KO mice there was a 19-fold rightward shift in noradrenaline effective concentration (EC(50)) compared with WT; while 5-MU alone or in combination with AH11110A protected alpha(1)-adrenoceptors to the same extent. 5 The data indicate that alpha(1A)-adrenoceptors mediate contraction and suggest their role in maintaining homeostasis in the alpha(1D)-adrenoceptors KO mice.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Aorta; Clonidine; Dose-Response Relationship, Drug; Imines; In Vitro Techniques; Mice; Mice, Knockout; Norepinephrine; Piperazines; Piperidines; Receptors, Adrenergic, alpha-1; Vasoconstriction; Vasoconstrictor Agents

The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the alpha 1-adrenoceptor. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the alpha 1-adrenoceptor subtypes. Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively).

Topics: Adrenergic alpha-Antagonists; Animals; Antipsychotic Agents; Binding Sites; Dioxanes; Hippocampus; In Vitro Techniques; Isoxazoles; Male; Phentolamine; Piperazines; Piperidines; Prazosin; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Risperidone; Spleen