title: Pharmacological evidence that potentiation of plasmalemmal Ca(2+)-extrusion is functionally coupled to inhibition of SR Ca(2+)-ATPases in vascular smooth muscle cells.
abstract: Cyclopiazonic acid (CPA), a specific inhibitor of sarcoplasmic reticulum (SR) Ca(2+)-ATPases, causes slowly developing and subsequently diminishing characteristic contractions in vascular smooth muscle, and the second application of CPA has incompletely repeatable effects, depending on the vessel type. The objective of the present study was to examine the mechanisms underlying the significant decrease of CPA-induced contractions upon the second application. A pharmacological intervention of Ca(2+) extrusion process as a strategy was performed to modulate vasoconstrictor effects of CPA in rat aortic ring preparations. CPA-induced contractions, expressed as percentages of the contractions induced by KCl (80 mM), were significantly decreased from 44.1 ± 5.7 to 7.6 ± 1.8 % (P < 0.001) upon the second application. The contractions, however, were completely repeatable in the presence of vanadate, an inhibitor of ATPases, but not of ouabain, an inhibitor of Na(+)-pumps. Strikingly, CPA-induced contractions were sustained and completely repeatable in Na(+)-free and low Na(+) medium. Furthermore, we found that the contractions were completely repeatable in the presence of 2',4'-dichlorobenzamil, an inhibitor of the forward mode of Na(+)/Ca(2+) exchangers, but not of KBR7943, an inhibitor of the reverse mode of Na(+)/Ca(2+) exchangers. Our findings indicate that CPA by inducing a transient rise in cytosolic Ca(2+) level causes a long-lasting upregulation of plasma membrane (PM) Ca(2+) extruders and thus leads to a diminished contraction upon its second application in blood vessels. This suggests that there is a functional coupling between PM Ca(2+) extruders and SR Ca(2+)-ATPases in rat aortic smooth muscle cells.
authors: Department of Medicine, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.|Program in Neurosciences & Mental Health, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada.
authors: Wen-Bo
authors: WB
authors: Zhang
authors: Department of Medicine, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada. kwancy@univmail.cis.mcmaster.ca.|Vascular Biology Research Group and Research Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung, Taiwan, 40402. kwancy@univmail.cis.mcmaster.ca.
authors: Chiu-Yin
authors: CY
authors: Kwan
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056966:Excitation Contraction Coupling / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D019831:Sodium-Calcium Exchanger; D014662:Vasoconstrictor Agents; D012964:Sodium; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium; C000543:cyclopiazonic acid
keywords: Ca2+ extrusion; Cyclopiazonic acid; Na+/Ca2+ exchanger; Plasma membrane Ca2+-ATPase; Sarcoplasmic reticulum Ca2+-ATPase; Vascular smooth muscle