Control of pulmonary vascular smooth muscle tone by sarcoplasmic reticulum ca2+ pump blockers: thapsigargin and cyclopiazonic acid |
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Authors: | Patrick Gonzalez De La Fuente Jean -Pierre Savineau Roger Marthan |
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Institution: | (1) Laboratoire de Physiologie, Université de Bordeaux 2, 146 rue Léo Saignat, F-33076 Bordeaux, France |
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Abstract: | The effect of thapsigargin (TG) and cyclopiazonic acid (CPA) on the mechanical activity of the rat pulmonary artery were investigated. In chemically (-escin)-skinned arterial strips, application of TG (0.1–1 M) or CPA (0.5–10 M) prior and throughout the loading procedure of the internal Ca2+ stores (0.3 M free Ca2+ ions for 8–10 min) concentration dependently inhibited the subsequent contractile response induced by noradrenaline (NA, 10 M) or caffeine (25 mM). In intact strips repeatedly incubated in a Ca2+-containing solution (2.5 mM for 10 min), followed by incubation in a Ca2+-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 M) or nifedipine (1 M) but was blocked by La3+ (50 M) 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. This contraction was also concentration dependently inhibited by the tyrosine kinase inhibitors genistein (0.5–50 M) and tyrphostin (2–50 M). Sr2+ ions, which contracted both depolarized intact and skinned strips, failed to replace Ca2+ ions in the verapamil-insensitive contraction induced by TG or CPA (n=4). Finally, TG (1 M) and CPA (10 M) did not modify the pCa tension relationship in skinned strips (n=5). These results show that the main action of TG and CPA in rat pulmonary artery is to prevent the refilling of the internal Ca2+ store. TG and CPA also seem to facilitate a Ca2+ influx through a specific verapamil-insensitive pathway. The biophysical and molecular characteristics of this pathway remain to be elucitated, although it appears to involve a tyrosine kinase activity. |
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Keywords: | Thapsigargin Cyclopiazonic acid Pulmonary artery Vascular smooth muscle -Escin" target="_blank">gif" alt="beta" align="MIDDLE" BORDER="0">-Escin Skinned strips Verapamil-insensitive contraction Tyrosine kinase inhibitors |
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