Modulation of evoked contractions in rat arteries by ryanodine, thapsigargin, and cyclopiazonic acid.

The contribution of sarcoplasmic reticulum (SR) Ca2+ release to evoked tension in rat arterial rings was studied by comparing the effects of ryanodine (an SR Ca2+ channel opener) and thapsigargin and cyclopiazonic acid (CPA) (two Ca(2+)-ATPase inhibitors). Isometric tension was evoked by serotonin (5-HT), 30-50 mM external K+, and 10 mM caffeine in rings of aorta and a small (second-order) branch of the superior mesenteric artery (SMA). Resting tension was unaffected by 10 microM ryanodine or 1-5 microM thapsigargin, but 20 microM CPA raised resting tension in aortic rings and evoked spontaneous contractions in some SMA rings. Ryanodine (10 microM) or 1-5 microM thapsigargin partially depleted the SR Ca2+ stores (indicated by reduced caffeine-evoked contractions) and attenuated 5-HT- and high K(+)-evoked contractions in aortic rings but augmented 5-HT- and high K(+)-evoked contractions in SMA. Caffeine completely emptied the SR Ca2+ stores in the presence of ryanodine but not thapsigargin in both the aorta and SMA; thus, thapsigargin may selectively affect one component of a heterogeneous SR. When the aortic Ca2+ stores were empty (i.e., caffeine contractions were abolished), the 5-HT- and high K(+)-evoked contractions in the aorta were also augmented. CPA rapidly emptied the SR Ca2+ stores in both the aorta and SMA. CPA augmented the 5-HT-evoked contractions in the SMA and in five of nine aortic rings but attenuated evoked contractions in the remaining aortic rings. The attenuation or abolition of the caffeine contractions implies that ryanodine, thapsigargin, and CPA all deplete the SR Ca2+ stores. The attenuated responses to 5-HT and high K+ observed when the aortic SR Ca2+ stores were only partially depleted are consistent with the idea that evoked SR Ca2+ release is a large component of the Ca2+ transient in the aorta. The augmentation of 5-HT- and high K(+P)-evoked responses after partial (SMA) or complete (aorta) depletion of the SR Ca2+ stores suggests that evoked release of SR Ca2+ normally regulates Ca2+ entry by negative feedback and/or that the SR normally buffers the evoked rise in cytosolic Ca2+.