3-Isobutyl-1-methylxanthine increases alpha-1-adrenergic receptor sensitivity and density in DDT1-MF2 smooth muscle cells.
The effect of chronic exposure of DDT1-MF2 smooth muscle cells to the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was investigated with regard to the dynamics of alpha-1-adrenergic receptors. After 48 hr of exposure to 750 microM IBMX, the magnitude of the maximal phospholipase C response to norepinephrine was increased approximately 2-fold and the potency of norepinephrine was increased almost 3-fold. Similar effects were noted for the response to ATP. The density of alpha-1-adrenergic receptors, as defined by [3H]-prazosin binding to membranes was increased 2-fold. In addition, chronic treatment with IBMX prevented agonist-induced desensitization of alpha-1-adrenergic receptors and enhanced the rate of receptor resensitization subsequent to desensitization by a combination of agonist and phorbol ester. These effects appear to be regulated by a cyclic AMP-dependent mechanism. Thus, chronic exposure of smooth muscle cells to phosphodiesterase inhibition may activate compensatory mechanisms that lead to enhanced sensitivity to contractile stimuli. The potential importance of such compensatory mechanisms in the treatment and etiology of smooth muscle dysfunction is briefly discussed.
Schachter
J B
JB
Department of Pharmacology, Georgetown University School of Medicine, Washington, D.C.
Wolfe
B B
BB
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D012969:Sodium Fluoride / Q000494:pharmacology; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014649:Vas Deferens
D010716:Phosphatidylinositols; D011942:Receptors, Adrenergic, alpha; D000255:Adenosine Triphosphate; D012969:Sodium Fluoride; D000242:Cyclic AMP; D010738:Type C Phospholipases; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine