The Inhibitory Effect of Li+ on Contractile Elements of Intestinal Smooth Muscle

Abstract

ABSTRACT-The mechanism of the inhibitory effect of Li+ on contraction was examined in guinea pig ileal longitudinal smooth muscle. Li+-substitution (68.4 mM) reversed contractions induced by high K+ (45.4 mM), carbachol (1 teM) and histamine (1 tM) without changing the cytosolic Ca" level. Li+ also had no effect on the increase in 45Ca2+ uptake stimulated by high K+. High K+ transiently increased myosin light chain (MLC) phosphorylation, reaching a peak at 6-9 sec. Li+-substitution inhibited the high K+-induced MLC phosphorylation. In permeabilized ileal strips, contraction induced by 1 1iM Ca 2+ was inhibited by 10 mM Lit The inhibitory effect was antagonized by increasing the concentration of Ca 2+ or calmodulin. In the permeabilized muscle in which MLC was previously thiophosphorylated with 1 mM ATPIS and 3 PM Ca2+, ATP induced contraction in Ca 21 free buffer. Li+ added during this contraction did not show an inhibitory effect. In contrast, when 30 mM Li+ was added during the thiophosphorylation, the contraction induced by the subsequent addition of ATP was inhibited. Li+ (30 mM) changed neither the rate of relaxation induced by removing external Ca 21 in permeabilized muscle nor the rate of dephosphorylation of MLC induced by crude phosphatase extracted from the ileum. Li+ (15 mM), on the other hand, inhibited the rate of phosphorylation of MLC caused by crude MLC kinase extracted from the ileum. Li+ did not inhibit the calmodulin activity as measured with the (Ca 2+ + Mg2+)-ATPase activity of the erythrocyte membrane. These results suggest that the inhibitory effect of Li+ on contractions is attributable to the inhibition of MLC kinase in guinea pig ileum. Keywords: Li+ (lithium ion), Smooth muscle (intestine), Contractile element, Myosin light chain kinase, Cytosolic Ca 2+ levelLi+ has been shown to have various biological actions such as inhibition of phosphatidylinositol turnover (1, 2) and adenylate cyclase (3, 4). In intestinal smooth muscle, Li+ relaxes contractions induced by high concentrations of KCl and receptor agonists (5 -7). Treatment of guinea pig ileal muscle with 68.4 mM Li+ solution increased the cellular Li+ content to 10-20 mmol/kg wet wt. in 30-60 min (8) and the inhibitory effect increased with the accumulation of Li+ in the cell (9-11). Recently, we have reported that Li+-induced relaxation is not due to a decrease in cytosolic Ca 2+ level ([Ca2+];) and that Li+ relaxes Ca 2+-induced contraction in permeabilized tissue (11). The purpose of the present experiments is to further clarify the mechanism for the inhibitory effect of Li+ in guinea pig ileal smooth muscle. Preparations and solutionsIleum was isolated from male guinea pigs (300 -400 g) after stunning by a sharp blow on the neck and exsanguination. Longitudinal smooth muscle strips, approximately 5-mm-wide and 10-mm-long, were prepared. Normal physiological salt solution (PSS) contained: 136.9 mM NaCl, 5.4 mM KCI, 1.5 mM CaC12, 1.0 MM MgC12, 23.8 mM NaHCO3 and 5.5 mM glucose. High K+ solutions were made by hyperosmotically add...

Antinociceptive effect of chronic lithium on visceral hypersensitivity in a rat model of diarrhea‐predominant irritable bowel syndrome: The role of nitric oxide pathway

“…Some studies, which were conducted to clarify the impacts of lithium on enteric smooth muscle, have demonstrated contradictory results. One showed spasmogenic effects 46 and another showed relaxant effects of lithium on the ileal smooth muscle of guinea pigs 47 . Kuiken et al .…”

“…One showed spasmogenic effects 46 and another showed relaxant effects of lithium on the ileal smooth muscle of guinea pigs. 47 Kuiken et al's study excluded a possible post-junctional effect of NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) on the smooth muscle. 42 In these three studies, lithium has some effects on enteric muscle, but these effects are not mediated through the NO pathway.…”

Weakening of ion-channel interactions of Na + and Li + in acetylcholine-receptor channels of frog skeletal muscle with an increase in agonist concentration

“…4). Further examples are also available showing that Li + and Mg 2+ exert opposing effects on other factors that regulate phosphorylation, such as calmodulin [27,45] and cytosolic phophatases [27,34], and it seems doubtful in general that exhaustive review will turn up instances where Na + , Li + , 822 Competitive interactions of Na + and Li + currents Another consequence of transient binding of permeating cations with channel sites is that the presence of one ion species in the channel must at some level inhibit the movement of a second ion [26], and one might thus expect to see something of this competitive interaction by comparing the single-ion currents of Na + and Li + with currents generated in bath media containing a mixture of these ions. Results suggesting an ion competition effect were found first in the low-carb tests in Fig.…”