Zusammenfassung
Although adenosine is known to activate K+ conduction in atrial tissue,
there is still debate as to the involvement of cAMP-dependent mechanisms.
In isolated adult guinea pig atrial myocytes, we demonstrate that
the highly A1-selective adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine
reduced basal cAMP levels by 30-40% in the absence and presence of
the nonxanthine phosphodiesterase inhibitor Ro 20-1724. Isoprenaline
caused a concentration-dependent increase in cAMP levels, which was
more pronounced in the presence of the phosphodiesterase inhibitor.
Several adenosine derivatives suppressed the isoprenaline-induced
cAMP increase by approximately 80%. The rank order of potency was
2-chloro-N6-cyclopentyladenosine (IC50, 93 nM) greater than (R)-N6-phenylisopropyladenosine
(IC50, 309 nM) greater than 5'-N-ethylcarboxamidoadenosine (IC50,
813 nM) much greater than (S)-N6-phenylisopropyladenosine (IC50,
26,300 nM). A similar but complete suppression of the isoprenaline-induced
cAMP increase was produced by the muscarinic receptor agonist carbachol
(IC50, 398 nM), which like adenosine is known to activate atrial
K+ channels. The A1-adenosine receptor-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine
antagonized the effect of 2-chloro-N6-cyclopentyladenosine concentration-dependently,
with a KB value of 9.6 nM. In atrial myocytes isolated from guinea
pigs pretreated with pertussis toxin, the inhibitory effects of adenosine
analogs on basal and isoprenaline-stimulated cAMP accumulation were
markedly attenuated. It is concluded that the adenosine receptor
in guinea pig atrial myocytes, which is known to be linked to K+
channels, is also coupled to adenylate cyclase via a pertussis toxin-sensitive
guanine nucleotide-binding protein and shows the characteristics
of the A1-adenosine receptor subtype.
Nutzer