Enhanced myosin phosphatase and Ca(2+)-uptake mediate adrenergic relaxation of airway smooth muscle.
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 Ca(2+)-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 Ca(2+) 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 (32)P-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 Ca(2+) pump activity (to decrease [Ca(2+)](i)) and myosin light chain phosphatase activation (to decrease Ca(2+)-sensitivity of the contractile apparatus), whereas in human airways the underlying mechanisms are still unclear.
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D001993:Bronchodilator Agents / Q000494:pharmacology; D002118:Calcium / Q000493:pharmacokinetics*; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002417:Cattle; D018678:Cholinergic Agents / Q000494:pharmacology; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D043263:Myosin-Light-Chain Phosphatase / Q000187:drug effects / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013045:Species Specificity; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D018678:Cholinergic Agents; D007211:Indoles; D011189:Potassium Chloride; D002217:Carbachol; D043263:Myosin-Light-Chain Phosphatase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D002118:Calcium; C000543:cyclopiazonic acid