Abstract
Some beta1- and beta2-adrenoceptor-blocking agents, such as (-)-CGP
12177, cause cardiostimulant effects at concentrations considerably
higher than those that antagonise the effects of catecholamines.
The cardiostimulant effects of these non-conventional partial agonists
are relatively resistant to blockade by (-)-propranolol and have
been proposed to be mediated through putative beta4-adrenoceptors
or through atypical states of either beta1- or beta2-adrenoceptors.
We investigated the effects of (-)-CGP 12177 on sinoatrial rate and
left atrial contractile force as well as the ventricular binding
of (-)-3HCGP 12177 in tissues from wild-type, beta2-adrenoceptor
knockout and beta1/beta2-adrenoceptor double knockout mice. The cardiostimulant
effects of (-)-CGP 12177 were present in wild-type and beta2-adrenoceptor
knockout mice but were absent in beta1/beta2-adrenoceptor double
knockout mice. Thus, the presence of beta1-adrenoceptors is obligatory
for the cardiostimulant effects of (-)-CGP 12177. It appears therefore
that an atypical state of the beta1-adrenoceptor contributes to the
mediation of the cardiostimulant effects induced by non-conventional
partial agonists. Ventricular beta1- and beta2-adrenoceptors, labelled
in wild-type with a K(D) approximately 0.5 nmol/l (approximately
16 fmol/mg protein), were absent in beta1/beta2-adrenoceptor double
knockout mice. However, a high density binding site (approximately
154-391 fmol/mg protein) that did not saturate completely (K(D) approximately
80-200 nM) was labelled by (-)-3HCGP 12177 in the three groups
of mice, being distinct from beta1- and beta2-adrenoceptors, as well
as from the site mediating the agonist effects of (-)-CGP 12177.
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