Abstract
Tonic contraction of the lower esophageal sphincter (LES) prevents gastroesophageal reflux. LES tone is produced both by cholinergic nerve and myogenic activities. The Ca++ sources for LES tone and carbachol-induced contraction in canine LES strips were determined from the effect on contractile activity of extracellular Ca++level modulation, Ca++ entrance blockade or enhancement with nifedipine or BayK8644 respectively, and/or inhibition of Ca++ store refilling using the sarcoplasmic reticulum Ca++ pump inhibitor, cyclopiazonic acid. LES tone disappeared when a Ca++-free physiological saline solution or nifedipine was applied. Sustained Ca++ free contractions to carbachol were prevented/abolished by nifedipine or increased Ca++ chelation and enhanced by BayK8644. Inhibition of sarcoplasmic reticulum Ca++ pumps by cyclopiazonic acid reduced Ca++ free contractions to carbachol; BayK8644 restored cyclopiazonic acid-reduced Ca++ free contractions to carbachol. Therefore, some Ca++ stores can be refilled by mechanisms not requiring activity of the sarcoplasmic reticulum Ca++ pump. A preferred pathway may exist whereby Ca++ enters stores directly through L-Ca++channels. The proposed Ca++ store refilling mechanism involves continuous Ca++ entry through L-Ca++channels from sites not equilibrated with external Ca++. Therefore, diverse Ca++ stores exist in canine LES which are dependent on Ca++ influx through L-Ca++channels.
Footnotes
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Send reprint requests to: Dr. E. E. Daniel, Professor Emeritus, Department of Biomedical Sciences, McMaster University, Faculty of Health Sciences, 1200 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
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↵1 This study was supported by a grant from the Medical Research Council of Canada.
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↵2 Current address: Playfair Neurosciences Unit, The Toronto Hospital (Western Division), 399 Bathurst St., Toronto, Ontario M5T 2S8, Canada.
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A.M.S. was a recipient of a Research/Travel Awards for abstracts of this work which were supported by the AGA Foundation at Digestive Diseases Week (New Orleans, LA, 1994) and the XIIth International Congress of Pharmacology (Montreal, Canada, 1994). A.L. was supported by the AGA Foundation as summer Student for part of this work.
- Abbreviations:
- ACh
- acetylcholine
- BayK
- BayK 8644
- KCa
- Ca++-activated K+ channel
- CFCC
- Ca++ free contractions to carbachol
- CCh
- carbachol
- CPA
- cyclopiazonic acid
- DAG
- diacyl glycerol
- DMSO
- dimethylsulfoxide
- GE
- gastroesophageal
- L-Ca++
- L-type Ca++
- LES
- lower esophageal sphincter
- NIF
- nifedipine
- CPLC
- phospholipase
- PSS
- physiological saline solution
- PM
- plasma membrane
- C-PKC
- protein kinase C
- SR
- sarcoplasmic reticulum
- SBB
- superficial buffer barrier
- TPSS
- tone in physiological saline solution
- [Ca++]i
- intracellular Ca++
- STOC
- spontaneous transient outward currents
- IP3
- inositol 1,4,5-trisphosphate
- PLC
- phospholipase C
- EGTA
- ethylene ethylene glycol-bis (b-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- ANOVA
- analyses of variance
- Received December 9, 1997.
- Accepted May 28, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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