O. Aprigliano et al., BETA(1)-ADRENERGIC AND BETA(2)-ADRENERGIC RECEPTORS EXHIBIT DIFFERINGSUSCEPTIBILITY TO MUSCARINIC ACCENTUATED ANTAGONISM, American journal of physiology. Heart and circulatory physiology, 41(6), 1997, pp. 2726-2735
Neonatal rat ventricular myocytes express both beta(1)- and beta(2)-ad
renergic receptors linked to enhanced intracellular adenosine 3',5'-cy
clic monophosphate (cAMP) accumulation and the modulation of contracti
le function. This study tests the hypothesis that muscarinic agonists
act via distinct mechanisms to interfere with beta(1)- and beta(2)-adr
energic receptor actions. The beta(2)-selective agonist zinterol(10(-7
) M) elicits approximately a fourfold increase in cAMP accumulation, w
hich is mimicked, both in magnitude and kinetics, by 10(-9) M of the m
ixed beta(1)-receptor agonist/beta(2)-receptor agonist isoproterenol.
At these concentrations, isoproterenol and zinterol elicit equivalent
inotropic and lusitropic (i.e., enhanced relaxation) responses. Carbac
hol inhibits all three responses (cAMP, inotropic, and lusitropic) eli
cited by isoproterenol. In contrast, carbachol does not interfere with
the effect of zinterol to augment cAMP accumulation or to induce a po
sitive inotropic response. However, carbachol inhibits the lusitropic
response to zinterol via an action at an M-2-muscarinic receptor linke
d to a pertussis toxin-sensitive pathway. Additional studies indicate
that beta(2)-receptor-dependent phosphorylation of troponin I and phos
pholamban is substantially attenuated by carbachol. We conclude that c
arbachol interferes with beta(1)-receptor actions by reducing cAMP acc
umulation. In contrast, the anti-beta(2)-receptor actions of carbachol
are mediated by a mechanism that is distinct from inhibition of cAMP
accumulation, involving an M-2-muscarinic receptor coupled to a pertus
sis toxin-sensitive G protein, which leads to inhibition of troponin I
and phospholamban phosphorylation and inhibition of the beta(2)-recep
tor-dependent lusitropic response.