Effects of cyclopiazonic acid on contraction and intracellular Ca2+ in oesophageal striated muscle of normotensive and spontaneously hypertensive rats

1 The effects of cyclopiazonic acid (CPA), a selective inhibitor of sarcopl asmic reticulum (SR) Ca2+-ATPase, on twitch contraction and on the resting state of tension and intracellular Ca2+ level ([Ca2+](i)) of the oesophagea l striated muscle of stroke-prone spontaneously hypertensive rats (SHRSP) a nd normotensive Wistar Kyoto rats (WKY) were compared. 2 CPA (10 mu M) augmented the twitch contraction of oesophageal striated mu scle preparations from both SHRSP and WKY, reducing the rate of relaxation (-dT/dt), and thus resulting in the prolongation of the time to 80% relaxat ion. The effect was significantly smaller in the SHRSP preparations. 3 In the resting state, CPA caused a sustained elevation of [Ca2+](i). The elevation was greater in the WKY preparations. Tension development accompan ied by the elevation was observed in WKY preparations, but not in SHRSP pre parations. 4 The sustained elevation of [Ca2+](i) induced by CPA was eliminated by the removal of extracellular Ca2+. Both the elevated [Ca2+](i) and tension in the preparations from WKY were reduced by flufenamic acid (100 mu M), mefen amic acid (100 mu M), lanthanum (La3+, 100 mu M), gadolinium (Gd3+, 100 mu M) and SK&F 96365 (100 mu M) but not by verapamil (10 mu M). 5 Thapsigargin (3 mu M), another SR Ca2+-ATPase inhibitor, produced similar effects on basal tension to those of CPA, although it reduced the amplitud e of twitch contraction. 6 These results suggest that in the rat oesophageal striated muscle, (1) CP A extends the sequestrating time of Ca2+ into the SR, (2) CPA induces a Ca2 + influx mediated through verapamil-insensitive pathways, possibly nonselec tive cation channels, and (3) the mechanism of [Ca2+](i) modulation due to CPA-sensitive SR Ca2+-ATPase is deteriorated in the oesophageal striated mu scle from SHRSP as compared with WKY preparations.