Comparison of contractions produced by carbachol, thapsigargin and cyclopiazonic acid in the guinea-pig tracheal muscle

Abstract

1. Thapsigargin (TPG, 3 μM) and cyclopiazonic acid (CPA, 10 μM) slowly increased muscle tone in the guinea-pig isolated tracheal muscle. A large sustained contraction was produced when 2.4 mM Ca²⁺ was readmitted after 10 min exposure to Ca²⁺-free solution following 30 min treatment with TPG or CPA.

2. The sustained contraction after Ca²⁺ readmission was partially inhibited by nifedipine (3 μM) and highly dependent on external Ca²⁺. The TPG- and CPA-induced sustained contractions were 75% and 67%, respectively, of the sustained contraction produced by carbachol (Cch, 1 μM, EC₈₀) in the presence of nifedipine.

3. The contractions produced by Cch, TPG and CPA were all inhibited by isoprenaline (ISO) and sodium nitroprusside (SNP). In the presence of nifedipine, the IC₅₀ of ISO was 11, 17, and 23 nM and that of SNP was 0.5, 1, 0.8 μM for Cch-, TPG-, and CPA-induced contractions, respectively. The contraction produced by 60 mM K⁺ was only weakly inhibited by ISO and SNP. As with ISO and SNP, the Cch-, TPG- and CPA-induced contractions were also similarly inhibited by SKF 96365 (100 μM) and cadmium (Cd²⁺, 100 μM).

4. It was concluded that TPG and CPA increased Ca²⁺ influx probably via a mechanism activated by Ca²⁺ depletion of the sarcoplasmic reticulum. The susceptibility of the contraction produced by TPG, CPA and Cch to inhibition by ISO and SNP and also by SKF-96365 and Cd²⁺ suggests that the contractions use common pathways for increasing intracellular Ca²⁺, and that the contractions produced by K⁺ involve a different mechanism.

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