Jp. Noveral et Mm. Grunstein, ADRENERGIC RECEPTOR-MEDIATED REGULATION OF CULTURED RABBIT AIRWAY SMOOTH-MUSCLE CELL-PROLIFERATION, The American journal of physiology, 267(3), 1994, pp. 120000291-120000299
To evaluate the potential role of adrenergic receptors in regulating a
irway smooth muscle (ASM) cell proliferation, the mitogenic effects an
d mechanisms of action of selective alpha-and beta-adrenoceptor activa
tion were investigated in cultured rabbit ASM cells. The alpha(1)-adre
noceptor agonists, phenylephrine and methoxamine, elicited significant
dose-dependent (10(-10)-10(-4) M) stimulation of ASM cell mitogenesis
, with mean +/- SE peak increases in ASM cell count amounting to 17.0
+/- 3.5 and 44.0 +/- 6.8% above unstimulated (control) levels, respect
ively. Similarly, the alpha(2)-adrenoceptor agonist clonidine (10(-8)-
10(-4)) also induced ASM cell proliferation, with a 41.1 +/- 5.5% peak
increase in cell count above control. The promitogenic responses to a
lpha-adrenoceptor activation were blocked by pertussis toxin (PT; 100
ng/ml), which ADP-ribosylates G protein negatively coupled to adenylat
e cyclase activation. In additional studies, we found that 1) treatmen
t with agents inducing intracellular adenosine 3',5'-cyclic monophosph
ate (cAMP) accumulation including the beta-adrenergic agonist, isoprot
erenol, the cAMP analogue, 8-(4-chlorophenylthio)-cAMP and forskolin,
all produced significant dose-dependent inhibition of serum-stimulated
ASM cell growth; 2) alpha-adrenoceptor activation inhibited isoproter
enol-induced cAMP accumulation; and 3) the anti-proliferative effects
of isoproterenol and PT were additive. Collectively, the above finding
s provide new evidence that adrenergic receptors exert an opposing dua
lity of action in regulating ASM cell proliferation, wherein receptors
which are negatively coupled (i.e., alpha-adrenergic) and those which
are positively coupled (i.e., beta-adrenergic) to activation of the a
denylate cyclase/cAMP signal-transduction pathway are promitogenic and
growth inhibitory to ASM cells, respectively.