Noveral J P, Grunstein M M
Division of Pulmonary Medicine, Joseph Stokes, Jr., Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104.
Am J Physiol. 1994 Sep;267(3 Pt 1):L291-9. doi: 10.1152/ajplung.1994.267.3.L291.
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.
为评估肾上腺素能受体在调节气道平滑肌（ASM）细胞增殖中的潜在作用，我们在培养的兔ASM细胞中研究了选择性α和β肾上腺素能受体激活的促有丝分裂作用及其作用机制。α1肾上腺素能受体激动剂去氧肾上腺素和甲氧明引起ASM细胞有丝分裂的显著剂量依赖性（10^(-10)-10^(-4)M）刺激，ASM细胞计数的平均±标准误峰值增加分别比未刺激（对照）水平高出17.0±3.5%和44.0±6.8%。同样，α2肾上腺素能受体激动剂可乐定（10^(-8)-10^(-4)）也诱导ASM细胞增殖，细胞计数峰值比对照增加41.1±5.5%。对α肾上腺素能受体激活的促有丝分裂反应被百日咳毒素（PT；100 ng/ml）阻断，PT可使与腺苷酸环化酶激活负偶联的G蛋白发生ADP核糖基化。在进一步的研究中，我们发现：1）用诱导细胞内3',5'-环磷酸腺苷（cAMP）积累的药物处理，包括β肾上腺素能激动剂异丙肾上腺素、cAMP类似物8-(4-氯苯硫基)-cAMP和福斯可林，均产生显著的剂量依赖性抑制血清刺激的ASM细胞生长；2）α肾上腺素能受体激活抑制异丙肾上腺素诱导的cAMP积累；3）异丙肾上腺素和PT的抗增殖作用是相加的。总体而言，上述发现提供了新的证据，表明肾上腺素能受体在调节ASM细胞增殖中发挥相反的双重作用，其中与腺苷酸环化酶/cAMP信号转导途径激活负偶联（即α肾上腺素能）的受体和正偶联（即β肾上腺素能）的受体分别对ASM细胞具有促有丝分裂和生长抑制作用。
