Antagonism of Ca2+ and other actions of verapamil in guinea‐pig isolated trachealis

Abstract

1 In trachealis bathed by a K⁺-rich, Ca²⁺-free physiological salt solution, calcium chloride (CaCl₂) at 0.01 to 10 mmol l⁻¹ evoked concentration-dependent spasm. Verapamil (0.1 to 10 μmol l⁻¹) was an effective antagonist of CaCl₂. 2 Spasm evoked by acetylcholine, histamine, potassium chloride (KCl) and tetraethylammonium (TEA) was studied in trachealis bathed by normal Krebs solution. Verapamil (0.1 to 10 μmol l⁻¹) markedly suppressed spasm evoked by KCl and TEA. In contrast the actions of acetylcholine and histamine were much less affected by verapamil. 3 Spasm evoked by prostaglandin E₂ was studied in trachealis bathed by Krebs solution containing indomethacin (2.8 μmol l⁻¹). Verapamil (0.1 to 10 μmol l⁻¹) had little or no effect against prostaglandin E₂-induced spasm. 4 Verapamil (0.1 to 10 μmol l⁻¹) had relatively little effect on the tone of trachealis bathed by normal Krebs solution. In contrast bathing in Krebs solution lacking CaCl₂ caused almost complete tone loss. 5 Extracellular electrophysiological recording showed that verapamil (10 μmol l⁻¹) suppressed not only TEA-evoked spasm but also TEA-evoked slow waves and spike potentials. Verapamil also abolished the transient period of slow wave activity associated with the spasm evoked by KCl. 6 Intracellular electrophysiological recording showed that TEA-induced spike activity was resistant to tetrodotoxin (3 μmol l⁻¹). However, verapamil (10 μmol l⁻¹) abolished the tetrodotoxin-resistant spikes without increasing the resting membrane potential. 7 It is concluded that verapamil suppresses TEA- or KCl-induced spasm, slow waves or spikes by inhibition of Ca²⁺ influx. Spasm evoked by acetylcholine, histamine and prostaglandin E₂ depends on mechanisms for increasing the cytoplasmic concentration of free Ca²⁺ which are resistant to verapamil. The failure of verapamil markedly to depress tissue tone is consistent with the proposal that tone results from the activity of endogenous prostaglandins.