Adrenergic receptor-mediated regulation of cultured rabbit airway smooth muscle cell proliferation.
To evaluate the potential role of adrenergic receptors in regulating airway smooth muscle (ASM) cell proliferation, the mitogenic effects and mechanisms of action of selective alpha- and beta-adrenoceptor activation were investigated in cultured rabbit ASM cells. The alpha 1-adrenoceptor 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, respectively. 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 alpha-adrenoceptor activation were blocked by pertussis toxin (PT; 100 ng/ml), which ADP-ribosylates G protein negatively coupled to adenylate cyclase activation. In additional studies, we found that 1) treatment with agents inducing intracellular adenosine 3',5'-cyclic monophosphate (cAMP) accumulation including the beta-adrenergic agonist, isoproterenol, 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 isoproterenol-induced cAMP accumulation; and 3) the anti-proliferative effects of isoproterenol and PT were additive. Collectively, the above findings provide new evidence that adrenergic receptors exert an opposing duality 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 adenylate cyclase/cAMP signal-transduction pathway are promitogenic and growth inhibitory to ASM cells, respectively.
Noveral
J P
JP
Division of Pulmonary Medicine, Joseph Stokes, Jr., Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104.
Grunstein
M M
MM
D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D011941:Receptors, Adrenergic / Q000502:physiology*; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology; D014132:Trachea / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D013873:Thionucleotides; D005576:Colforsin; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; D007545:Isoproterenol