Role of the calcium channel in blastocyst implantation: a novel contraceptive target

Abstract

The proinflammatory blastocyst implantation cascade involves important mediators like prostaglandins (PG). The influx of calcium via the calcium channel acts as a trigger for the activation of the PG synthesis pathway. Hence, it was hypothesized that calcium channel blockers that are known to possess anti-inflammatory activity may interfere with normal implantation. Pregnant Swiss albino mice (Mus musculus) were treated with diltiazem (1) 4 mg/kg, po on days 1-6 of pregnancy, n=6/day) or (2) at the implantation site (25 microg/animal) via intrauterine injection in the right horn at 5:00 pm on day 4. The intact uterus was used to assay lipid peroxidation and superoxide dismutase activity as markers of membrane fluidity or to observe the day 15 fetus. Oral diltiazem treatment in therapeutic dosage before and during the implantation period did not cause any change in normal uterine milieu during the window of implantation. When injected into the uterine lumen 12-14 h before the average implantation time, however, a complete failure in implantation was observed. Thus, the site specific action of diltiazem may be blocking prostaglandin synthesis, hence causing implantation failure. Oral diltiazem treatment did not mimic this action, indicating that although orally safe in pregnancy in therapeutic dosage, calcium channel blockers may provide a new and yet unknown target in female contraceptive research.

Hormonal Crosstalk with Calcium Channel Blocker during Implantation

“…1) whereas implantation was completely inhibited in the diltiazem treated animals and no implantation sites were observed as previously reported [Banerjee et al 2009]. The levels of 17β-estradiol and progesterone were similar to earlier reported values for the initial days of pregnancy in mice (Fig.…”

“…Accordingly, the previously reported inhibition of blastocyst implantation cascade by calcium channel blockers during the 'implantation window' seems to be an independent mechanism interfering with uterine receptivity without any direct estrogen-progesterone control [Banerjee et al 2009]. This makes it essential now to understand the alternate mechanism controlling calcium channel regulation during blastocyst implantation and is the subject of further research.…”

“…In one group of pregnant female mice on d 4 of pregnancy, at 5:00 p.m. both uterine horns of the animals were injected with the test drug (diltiazem in 0.9% normal saline; 25 µg/ animal) through a ventral incision under ketamine:xylazine anesthesia (80:10mg/kg) [Banerjee et al 2009]. …”

“…Previous experiments have shown that the calcium channel played a significant role in blastocyst implantation and that intra-uterine delivery of calcium channel blockers like diltiazem at about 10-12 h prior to implantation causes implantation failure [Banerjee et al 2009]. Thus the inflammatory cascade responsible for prostaglandin synthesis activated by the rate limiting mobilization of cPLA 2 was shown to be under the control of the rise in intracellular calcium levels just prior to the onset of implantation.…”

The roles of endoplasmic reticulum stress response in female mammalian reproduction

“…Consistent with the Grp78 mRNA level, Grp78 protein significantly increases in the pregnant mouse uterus on day 5, especially in the implantation site Reid and Heald 1970), and these results suggest that increased Grp78 in the pregnant mouse uterus plays important roles in embryo implantation t hrough the UPR and ERS. Additionally, the upregulation of the calcium-binding protein S100P in the human uterine epithelium during embryo implantation (Tong et al 2010;, the embryo implantation failure caused by the downregulation of the calcium-binding protein S100A11 , and the abundant expression of calcium-transport genes in reproductive tissues in a distinct manner suggest that calcium regulates embryo implantation, and that calcium-channel blockers might provide new targets for female contraceptives (Banerjee et al 2009(Banerjee et al , 2011. Nevertheless, ERS is triggered by a disturbance of Ca 2+ homeostasis, and ERS and the UPR play an important role in the maintenance of Ca 2+ homeostasis (Dai et al 2012;Park et al 2010).…”