COMPARISON OF CONTRACTIONS PRODUCED BY CARBACHOL, THAPSIGARGIN AND CYCLOPIAZONIC ACID IN THE GUINEA-PIG TRACHEAL MUSCLE

1 Thapsigargin (TPG, 3 mu M) and cyclopiazonic acid (CPA, 10 mu M) slo wly increased muscle tone in the guinea-pig isolated tracheal muscle. A large sustained contraction was produced when 2.4 mM Ca2+ was readmi tted after 10 min exposure to Ca2+-free solution following 30 min trea tment with TPG or CPA. 2 The sustained contraction after Ca2+ readmiss ion was partially inhibited by nifedipine (3 mu M) and highly dependen t on external Ca2+. The TPG- and CPA-induced sustained contractions we re 75% and 67%, respectively, of the sustained contraction produced by carbachol (Cch, 1 mu M, EC80) in the presence of nifedipine. 3 The co ntractions produced by Cch, TPG and CPA were all inhibited by isoprena line (ISO) and sodium nitroprusside (SNP). In the presence of nifedipi ne, the IC50 of ISO was 11, 17, and 23 nM and that of SNP was 0.5, 1, 0.8 mu M for Cch-, TPG-, and CPA-induced contractions, respectively. T he contraction produced by 60 mM K+ was only weakly inhibited by ISO a nd SNP. As with ISO and SNP, the Cch-, TPG- and CPA-induced contractio ns were also similarly inhibited by SKF 96365 (100 mu M) and cadmium ( Cd2+, 100 mu M). 4 It was concluded that TPG and CPA increased Ca2+ in flux probably via a mechanism activated by Ca2+ depletion of the sarco plasmic reticulum. The susceptibility of the contraction produced by T PG, CPA and Cch to inhibition by ISO and SNP and also by SKF-96365 and Cd2+ suggests that the contractions use common pathways for increasin g intracellular Ca2+, and that the contractions produced by K+ involve a different mechanism.