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)
Gonzalez De La Fuente
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P
Laboratoire de Physiologie, Université de Bordeaux 2, France.
Savineau
J P
JP
Marthan
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D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D004928:Escin / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013324:Strontium / Q000494:pharmacology; D013729:Terpenes / Q000494:pharmacology*; D019284:Thapsigargin
D007211:Indoles; D013729:Terpenes; D002110:Caffeine; D019284:Thapsigargin; D004928:Escin; D011505:Protein-Tyrosine Kinases; D000252:Calcium-Transporting ATPases; D002118:Calcium; D009638:Norepinephrine; C000543:cyclopiazonic acid; D013324:Strontium