1. Cyclic nucleotide-dependent phosphodiesterases (PDEI) inhibition by muscarinic antagonists in bovine tracheal smooth muscle.
- Author
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Guerra de González L, González de Alfonzo R, Lippo de Bécemberg I, and Alfonzo MJ
- Subjects
- Animals, Atropine pharmacology, Cattle, Cell-Free System, Cyclic AMP metabolism, Muscle, Smooth enzymology, Muscle, Smooth metabolism, Purinones pharmacology, Rolipram pharmacology, Trachea cytology, Vinca Alkaloids pharmacology, Cyclic GMP metabolism, Muscarinic Antagonists pharmacology, Muscle, Smooth drug effects, Phosphodiesterase Inhibitors pharmacology, Phosphoric Diester Hydrolases metabolism
- Abstract
In bovine tracheal smooth muscle (TSM) strips, muscarinic antagonists (atropine, 4-DAMP, AFDX-116 and methoctramine) were able to increase simultaneously and a similar fashion the intracellular levels of cyclic nucleotides, with a cAMP/cGMP ratio higher than 2.0. These original pharmacological responses were time-and dose-dependent, exhibiting maximal values at 15 min, with a pEC(50) of 7.4 +/- 0.2 for atropine and 4-DAMP. These effects on cAMP and cGMP levels were similar to the ones obtained with isobutyl-methylxantine (IBMX, 10 microM), a non-selective cyclic nucleotide phosphodiesterase (PDE) inhibitor, suggesting the involvement of PDEs in these muscarinic antagonist responses. Neither, rolipram (10 microM), a specific PDEIV inhibitor, nor zaprinast (10 microM), a PDEV inhibitor, exhibited this "atropine-like" responses. Instead, atropine enhanced the increments of cAMP levels induced by rolipram and cGMP levels by zaprinast. However, vinpocetine (20 microM), a non-calmodulin dependent PDEIC inhibitor was able to mimic these muscarinic antagonist responses in intact smooth muscle strips. In addition, in cell free systems, muscarinic antagonists inhibited the membrane-bound PDEIC activity whereas soluble (cytosol) PDEIC activity was not affected by these muscarinic drugs. These results indicate that muscarinic antagonists acting possibly as inverse agonists on M(2)/M(3)mAChRs anchored to sarcolemma membranes can initiate a new signal transducing cascade leading to the PDEIC inhibition, which produced a simultaneous rise in both cAMP and cGMP intracellular levels in tracheal smooth muscle.
- Published
- 2004
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