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1 Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
2 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
3 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: ndiamant{at}uhnres.utoronto.ca.
Within the muscular equivalents of the cat lower esophageal sphincter (LES), the circular muscle develops greater spontaneous tone whereas the sling muscle is more responsive to cholinergic stimulation. Smooth muscle contraction involves a combination of calcium release from stores and of calcium entry via several pathways. We hypothesized that there are differences in the sources of Ca2+ utilized for contraction in sling and circular muscles and that these differences could contribute to the functional asymmetry observed within the LES. Contraction of muscle strips from the circular and sling regions of the LES was assessed in the presence of tetrodotoxin. In Ca2+ free Krebs, tone was inhibited to a greater degree in circular than sling muscle. L-type Ca2+ channel (LCa) blockade with nifedipine or verapamil inhibited tone in LES circular, but not sling muscle. The sarcoplasmic reticulum (SR) Ca2+-ATPase inhibitor, cyclopiazonic acid (CPA), caused greater increase in tone in sling than in circular muscle. The phospholipase-C (PLC) inhibitor U-73122 and the SR inositol triphosphate (IP3) receptor blocker 2-amino-ethoxy-diphenyl borate (2-APB) inhibited tone in circular and sling demonstrating continuous release of Ca2+ from IP3 sensitive stores is important in tone generation in both muscles. In Ca2+ free Krebs, acetylcholine-induced contractions (AChC) were inhibited to a greater degree in sling than circular muscles. However, nifedipine and verapamil greatly inhibited AChC in the circular muscle but not sling. Depletion of SR Ca2+ stores with CPA, or inhibition of IP3 mediated store release with either U-73122 or 2-APB inhibited AChC in both muscles. These studies demonstrate that LES circular and sling muscle a) utilize intracellular and EC Ca2+ sources to different degrees in the generation of spontaneous tone and AChC, and b) use different Ca2+ entry pathways. These differences hold the potential for selective modulation of LES tone in health and disease.
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