Effects of amitriptyline, a tricyclic antidepressant, on smooth muscle reactivity in isolated rat trachea.
OBJECTIVE
This study was designed to investigate the action of amitriptyline, a tricyclic antidepressant, on airway smooth muscle reactivity and its underlying mechanisms.


METHODS
In isolated rat trachea, isometric force was recorded to examine the effects of amitriptyline on the contractile response to acetylcholine (ACh), electrical field stimulation (EFS), calyculin A (a myosin light chain phosphatase inhibitor), and sphingosylphosphorylcholine (SPC; a Rhokinase activator). In addition, inositol monophosphate (IP1) accumulation was measured to examine its effects on inositol 1, 4, 5-trisphosphate (IP(3)) production during stimulation with ACh.


RESULTS
Amitriptyline inhibited the contractile responses to ACh, EFS, calyculin A, and SPC, with the concentrations of amitriptyline (mean +/- SD) required to exert 50% inhibition (IC(50)) being 4.3 +/- 1.3 microM, 3.2 +/- 1.6 microM, 256.4 +/- 106.4 microM, and 98.2 +/- 21.8 microM, respectively. In addition, amitriptyline (10 microM) eliminated the ACh (10 microM)-induced IP(1) accumulation.


CONCLUSIONS
The results suggest that amitriptyline does not influence tracheal smooth muscle reactivity at clinical concentrations (<1 microM), but attenuates the reactivity at supraclinical concentrations (> or =1 microM). The attenuated response to ACh brought about by amitriptyline is presumably due, at least in part, to the inhibition of phosphatidylinositol (PI) metabolism. The ability of amitriptyline to inhibit the calyculin Ainduced contraction suggests that amitriptyline also inhibits the Ca(2+)-calmodulin-myosin light chain pathway independently of the inhibition of PI metabolism. Finally, the difference between the IC(50) values for SPC-induced contraction and those for calyculin A-induced contraction suggests that amitriptyline may also inhibit the Rho-kinase pathway.
Matsunaga
Shoji
S
Department of Anesthesiology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
Shibata
Osamu
O
Nishioka
Kenji
K
Tsuda
Atsushi
A
Makita
Tetsuji
T
Sumikawa
Koji
K
D000109:Acetylcholine / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007293:Inosine Triphosphate / Q000378:metabolism; D007537:Isometric Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D014132:Trachea / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D018759:Adrenergic Uptake Inhibitors; D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D010716:Phosphatidylinositols; D007293:Inosine Triphosphate; D000639:Amitriptyline; D054460:rho-Associated Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009219:Myosin-Light-Chain Kinase; D043263:Myosin-Light-Chain Phosphatase; D000109:Acetylcholine; D009638:Norepinephrine
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