PHARMACOLOGICAL PROPERTIES OF THE CLONED ALPHA(1A D)-ADRENOCEPTOR SUBTYPE ARE CONSISTENT WITH THE ALPHA(1A)-ADRENOCEPTOR CHARACTERIZED IN RAT CEREBRAL-CORTEX AND VAS-DEFERENS/
Ba. Kenny et al., PHARMACOLOGICAL PROPERTIES OF THE CLONED ALPHA(1A D)-ADRENOCEPTOR SUBTYPE ARE CONSISTENT WITH THE ALPHA(1A)-ADRENOCEPTOR CHARACTERIZED IN RAT CEREBRAL-CORTEX AND VAS-DEFERENS/, British Journal of Pharmacology, 111(4), 1994, pp. 1003-1008
1 The pharmacological characteristics of cloned mammalian alpha1A/D-,
alpha1B- and alpha1C-adrenoceptor subtypes expressed in rat 1 fibrobla
sts were determined in comparison to the binding and functional proper
ties of these subtypes in rat tissues. 2 Analysis of [H-3]-prazosin bi
nding to membrane homogenates from rat 1 fibroblast cells expressing e
ach of the alpha1-subtypes indicated high affinity binding to a single
population of binding sites. Binding affinities were similar for alph
a1A/D-, alpha1B-, and alpha1C-subtypes (K(d)s: 0.13, 0.10 and 0.15 nm
respectively) although a higher density of alpha1B- and alpha1C-recept
ors (B(max): 4068 and 10,323 fmol mg-1 protein respectively) were expr
essed in comparison to alpha1A/D (838 fmol mg-1). 3 Displacement of [H
-3]-prazosin from membranes expressing cloned alpha1-adrenoceptor subt
ypes revealed that 5-methyl-urapidil, WB4101, benoxathian and phentola
mine displayed high affinity and selectivity for alpha1A/D- over alpha
1B-subtypes. These compounds also had high affinity and selectivity fo
r alpha1C- over alpha1B-subtypes. 5-Methyl-urapidil showed selectivity
for alpha1C (K(i) 0.60 +/- 0.16 nM) over both alpha1A/D (K(i), 9.8 +/
- 2.8 nm) and alpha1B (K(i) 57.2 +/- 12 nm) subtypes. Prazosin and dox
azosin were not subtype selective. 4 In comparison to [H-3]-prazosin a
similar pharmacological profile was obtained with [I-125]-HEAT using
cloned alpha1/D-, alpha1B- and alpha1C-adrenoceptors expressed in rat
1 fibroblasts. 5 The affinities of prazosin, WB 4101, 5-methyl-urapidi
l, phentolamine and benoxathian at cloned alpha1A/D-receptors were con
sistent with alpha1A affinities determined with chlorethylclonidine-tr
eated rat cortical membranes. Affinities at cloned alpha1B-receptors w
ere consistent with alpha1B affinities determined with rat liver membr
anes. 6 Using the epididymal rat vas deferens as a functional measure
of alpha1A affinity, prazosin (pA2 9.23 +/- 0.28), WB 4101 (pA2 9.58 /- 0.12), phentolamine (pK(B) 7.90 +/- 0.16), benoxathian (pK(B) 9.21
+/- 0.21) and 5-methyl-urapadil (pK(B) 8.51 +/- 0.16) were potent anta
gonists of noradrenaline-induced contractions. 7 At present, evidence
from cloning studies suggests the existence of at least three alpha1-a
drenoceptor subtypes. In contrast to the recent proposal for alpha1-ad
renoceptor classification, the pharmacology of the cloned alpha1A/D (o
r alpha1D)-adrenoceptor is more consistent with that of an alpha1A-adr
enoceptor characterized in rat cerebral cortex and vas deferens.