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Calcium Channels, Rho-Kinase, Protein Kinase-C, and Phospholipase-C Pathways Mediate Mercury Chloride-Induced Myometrial Contractions in Rats

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Abstract

Adverse effects of mercury on female reproduction are reported; however, its effect on myogenic activity of uterus and mechanism thereof is obscure. Present study was undertaken to unravel the mechanistic pathways of mercuric chloride (HgCl2)-induced myometrial contraction in rats. Isometric tension in myometrial strips of rats following in vitro exposure to HgCl2 was recorded using data acquisition system-based physiograph. HgCl2 produced concentration-dependent (10 nM–100 μM) uterotonic effect which was significantly (p < 0.05) reduced in Ca2+-free solution and inhibited in the presence of nifedipine (1 μM), a L-type Ca2+ channel blocker, thus suggesting the importance of extracellular Ca2+ and its entry through L-type calcium channels in HgCl2-induced myometrial contractions in rats. Cumulative concentration-response curve of HgCl2 was significantly (p < 0.05) shifted towards right in the presence of Y-27632 (10 μM), a Rho-kinase inhibitor, suggesting the involvement of Ca2+-sensitization pathway in mediating HgCl2-induced myometrial contraction. HgCl2-induced myometrial contraction was also significantly (p < 0.05) inhibited in the presence of methoctramine or para-fluoro-hexahydro-siladifenidol, a selective M2 and M3 receptor antagonists, respectively, which evidently suggest that mercury also interacts with M2 and M3 muscarinic receptors to produce myometrial contractions. U-73122 and GF-109203X, the respective inhibitors of PLC and PKC-dependent pathways, downstream to the receptor activation, also significantly (p < 0.05) attenuated the uterotonic effect of HgCl2 on rat uterus. Taken together, present study evidently reveals that HgCl2 interacts with muscarinic receptors and activates calcium signaling cascades involving calcium channels, Rho-kinase, protein kinase-C, and phospholipase-C pathways to exert uterotonic effect in rats.

Graphical abstract depicting the mechanism of mercury-induced myometrial contraction in rats. M receptor: Muscarinic receptor; PIP2: phospho-inositol bisphosphate; PLC: phospholipase-C; DAG: diacyl glycerol; IP3: inositol triphosphate; IP3R: inositol triphosphate receptor; PKC; protein kinase-C; MLCP: myosin light chain phosphatise; MYPT: myosin phosphatase; SR: sarco-endoplasmic reticulum

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Acknowledgements

Research work presented in this manuscript was undertaken in the research project funded by Indian Council of Agricultural Research, New Delhi, India, under Niche Area of Excellence Programme (Grant No. 10 (10)/2012-EPD dated 23rd march 2012) to Department of Veterinary Pharmacology and Toxicology, DUVASU, Mathura, India. Financial assistance from ICAR is thankfully acknowledged.

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  1. Experimental Pharmacology Laboratory, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan (DUVASU), Mathura, 281001 (U.P.), India

    Swati Koli, Atul Prakash, Soumen Choudhury, Rajesh Mandil & Satish K. Garg

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  1. Swati Koli
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  2. Atul Prakash
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Correspondence to Satish K. Garg.

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Koli, S., Prakash, A., Choudhury, S. et al. Calcium Channels, Rho-Kinase, Protein Kinase-C, and Phospholipase-C Pathways Mediate Mercury Chloride-Induced Myometrial Contractions in Rats. Biol Trace Elem Res 187, 418–424 (2019). https://doi.org/10.1007/s12011-018-1379-x

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