Tonic potentiation and attenuation produced by membrane depolarization in guinea-pig trachealis

1. We studied how membrane depolarization directly affected intracellular Ca2+ signalling when voltage-operated Ca2+ channels (VOCC) were not available in guinea-pig tracheal smooth muscle. To block VOCC, we used 3 micromol/L verapamil, which completely abolished high K+ (20-60 mmol/L)-induced contraction, and elevation of fura-2 signal. 2. Muscle tone was generated by adding Ca2+ to the extracellular Ca2+-free solution containing prostaglandin (PG)E2 (100 nmol/L) after abolishing basal tone with indomethacin (1 micromol/L). 3. In the absence of verapamil, high K+ (20-60 mmol/L) solution potentiated 2.4 mmol/l Ca2+-induced sustained contractions. Even in the presence of 3 micromol/L verapamil, replacement with 20 and 40 mmol/L K+ solution induced tonic potentiation, which was changed to attenuation with a higher K+ solution (60 mmol/L), lower extracellular Ca2+ concentration (Ca2+]o) and pretreatment with cyclopiazonic acid (10 micromol/L), a Ca2+ sequestration inhibitor. 4. These results indicate that the balance between depolarization-dependent Ca2+ release and receptor-operated cation channel inhibition may determine whether tonic potentiation or attenuation is manifested, depending on the availability of VOCC, the magnitude of the depolarization, Ca2+]o and Ca2+ content in the sarcoplasmic reticulum.