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Enhanced Myosin Phosphatase and Ca²⁺-Uptake Mediate Adrenergic Relaxation of Airway Smooth Muscle

Asthma Research Group, Firestone Institute for Respiratory Health, St. Joseph's Hospital, and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Address correspondence to: Dr. Luke J. Janssen, L-314, St. Joseph's Hospital, 40 Charlton Ave. East, Hamilton, ON, L8N 4A6 Canada. E-mail: janssenl{at}mcmaster.ca

We examined the mechanisms underlying relaxations evoked by isoproterenol (Iso) in isolated porcine, bovine, or human tracheal and bronchial tissues (TSM and BSM, respectively). Iso had little effect against contractions evoked by high KCl, indicating that it does not directly suppress voltage-dependent Ca²⁺-influx nor directly inhibit myosin light chain kinase. Furthermore, Iso was equally potent against carbachol (CCh) contractions in the presence versus absence of nifedipine (10^-6 M), establishing that the primary action of Iso is not through membrane hyperpolarization. However, Iso relaxations in porcine/bovine BSM were significantly suppressed by inhibitors of the internal Ca²⁺ pump (cyclopiazonic acid; 10^-5 M) or of myosin light chain phosphatase (calyculin; 10^-6 M). Myosin light chain phosphatase activity was assayed directly (using ³²P-labeled myosin) and found to be enhanced in a time- and concentration-dependent fashion by Iso. Iso relaxations in human airway tissues, on the other hand, were not significantly affected by either calyculin or cyclopiazonic acid. Thus, we conclude that Iso acts largely in a voltage-independent fashion: in nonhuman airways, this involves enhanced Ca²⁺ pump activity (to decrease [Ca²⁺]_i) and myosin light chain phosphatase activation (to decrease Ca²⁺-sensitivity of the contractile apparatus), whereas in human airways the underlying mechanisms are still unclear.

Abbreviations: 11-2[[2-(diethylamino)methyl1]-1-piperidinyl] acetyl-5,11-dihydro-6H-pyrido-[2,3-b]-benzodiazepine-6-one, AF-DX 116 • airway smooth muscle, ASM • bronchial smooth muscle, BSM • cyclopiazonic acid, CPA • N--nitro-L-arginine, L-NNA • myosin light chain kinase, MLCK • myosin light chain phosphatase, MLCP • Rho-activated kinase, ROCK • tracheal smooth muscle, TSM • (+)-(R)-trans-4-(1-aminoethyl)-N-(pyridyl) cyclohexanecarboxamide dihydrochloride, Y27632

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