Control of pulmonary vascular smooth muscle tone by sarcoplasmic reticulum Ca2+ pump blockers: thapsigargin and cyclopiazonic acid.

The effect of thapsigargin (TG) and cyclopiazonic acid (CPA) on the mechanical activity of the rat pulmonary artery were investigated. In chemically (beta-escin)-skinned arterial strips, application of TG (0.1-1 microM) or CPA (0.5-10 microM) prior and throughout the loading procedure of the internal Ca2+ stores (0.3 microM free Ca2+ ions for 8-10 min) concentration dependently inhibited the subsequent contractile response induced by noradrenaline (NA, 10 microM) or caffeine (25 mM). In intact strips repeatedly incubated in a Ca(2+)-containing solution (2.5 mM for 10 min), followed by incubation in a Ca(2+)-free solution 12 min before NA-stimulation, TG and CPA not only inhibited the NA-induced contraction but also increased the tension which appeared during the exposure time to Ca2+. The two phenomena developed with similar time courses. The increase in tension during the readmission of Ca2+ ions was not antagonized by verapamil (10 microM) or nifedipine (1 microM) but was blocked by La3+ (50 microM) and Co2+ (1 mM) ions. The amplitude of the verapamil-insensitive TG (or CPA)-induced contraction was dependent on the external [Ca2+] [0.1-10 mM, concentration for half maximal effect (EC50) = 0.85 mM], not modified by the reduction of the external [Na+] (from 130 to 10 mM) and decreased by depolarization of the strip using K(+)-rich (30-120 mM) solutions. Under the latter condition, 38 +/- 9 and 83 +/- 4% reduction (n = 5) was observed in the presence of 60 and 120 mM K+ respectively.(ABSTRACT TRUNCATED AT 250 WORDS)