Dose-Dependent Differential Effects of In Vivo Exposure of Cadmium on Myometrial Activity in Rats: Involvement of VDCC and Ca2+-Mimicking Pathways

Abstract

Present study was undertaken to study the effect of 28-days exposure of female adult rats to cadmium (Cd) in drinking water @ 3, 10 and 30 parts per million (ppm) on myometrial responsiveness to different spasmogens and unravel the possible mechanism of alterations in myometrial activity. Cadmium and Ca levels in blood and uterus were measured by atomic absorption spectroscopy while isometric tension in myometrial strips was measured using data acquisition system-based physiograph. Dose-dependent increase in levels of cadmium was observed in both blood and uterus while calcium was increased only in the uterus as compared to those in control. Significant increase in absolute tension and mean integral tension along with non-significant increase in frequency of myometrial contraction was observed in rats of Cd-treated groups. As compared to the control, cadmium decreased and increased the effects of calcium chloride, 80 mM KCl, histamine (0.1 μM) and oxytocin (10 IU/ml) in lower-dose (3 ppm) and higher-dose groups (10 and 30 ppm), respectively. Cadmium potentiated and inhibited the relaxant response to phenylephrine in myometrium of rats at lower-dose (3 ppm) and highest-dose (30 ppm) Cd-treated groups, respectively. Results of our study revealed that Cd accumulates in the myometrium of rats and alters its responsiveness to oxytocin, histamine, 80 mM KCl, calcium chloride and phenylephrine, and these effects are differentially mediated depending on levels of exposure possibly through voltage-dependent calcium channel (VDCC) and Ca-mimicking pathways.

Vitamin D3 and calcium cosupplementation alleviates cadmium hepatotoxicity in the rat: Enhanced antioxidative and anti‐inflammatory actions by remodeling cellular calcium pathways

“…[3,4,8] Cd may also produce oxidative stress and inflammation by dysregulating several cellular Ca 2+ pathways. [6] In this respect, Cd pervaded into the targeted cells through the T-type VDCC [9,11] and concomitantly inhibited the L-type channel [12,13] to block [Ca 2+ ] E influx, [43,44] thus resulted in dose-dependent declines in rodent liver Ca 2+ levels. [35,45] Moreover, Cd provoked marked increment in [Ca 2+ ] C by releasing [Ca 2+ ] I from the ER subsequent to the activation of ITPR1 and RYR1.…”

“…Ca 2+ is pivotal for cell physiology and is controlled by stringent mechanisms that equilibrate its exchange between the extracellular ([Ca 2+ ] E ), cytosol ([Ca 2+ ] C ), and intracellular ([Ca 2+ ] I ) compartments . Ca 2+ permeates the cell membrane through several ionic channels, including the voltage‐dependent Ca 2+ channels (VDCCs) that are categorized into the transient (T)‐ and long‐lasting (L)‐types according to their voltage‐gradient requirements for stimulation . Cd commonly influxes into the cytosol through the T‐type, whereas the heavy metal inhibits Ca 2+ entry by impeding the L‐type VDCC .…”

“…[9,10] Ca 2+ permeates the cell membrane through several ionic channels, including the voltagedependent Ca 2+ channels (VDCCs) that are categorized into the transient (T)-and long-lasting (L)-types according to their voltagegradient requirements for stimulation. [11][12][13] Cd commonly influxes into the cytosol through the T-type, whereas the heavy metal inhibits Ca 2+ entry by impeding the L-type VDCC. [11][12][13] On the other hand, the endoplasmic reticulum (ER) is the main intracellular Ca 2+ store and it releases its [Ca 2+ ] I in the cytosol through store-operated channels (SOCs).…”

“…[11][12][13] Cd commonly influxes into the cytosol through the T-type, whereas the heavy metal inhibits Ca 2+ entry by impeding the L-type VDCC. [11][12][13] On the other hand, the endoplasmic reticulum (ER) is the main intracellular Ca 2+ store and it releases its [Ca 2+ ] I in the cytosol through store-operated channels (SOCs). [14,15] Ryanodine (RyRs) and inositol triphosphate receptors (ITPRs) are the main SOCs that liberate large Ca 2+ amounts after their activation by diverse stimuli, including Cd-induced cell toxicity.…”