HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Transient Receptor Potential Melastatin-8 Activation Induces Relaxation of Pulmonary Artery by Inhibition of Store-Operated Calcium Entry in Normoxic and Chronic Hypoxic Pulmonary Hypertensive Rats.

Abstract
Pulmonary hypertension (PH) is characterized by enhanced vasoconstriction and vascular remodeling, which are attributable to the alteration of Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). It is well established that store-operated Ca2+ entry (SOCE) is augmented in PASMCs during PH and that it plays a crucial role in PH development. Our previous studies showed that the melastatin-related transient receptor potential 8 (TRPM8) is down-regulated in PASMCs of PH animal models, and activation of TRPM8 causes relaxation of pulmonary arteries (PAs). However, the mechanism of TRPM8-induced PA relaxation is unclear. Here we examined the interaction of TRPM8 and SOCE in PAs and PASMCs of normoxic and chronic hypoxic pulmonary hypertensive (CHPH) rats, a model of human group 3 PH. We found that TRPM8 was down-regulated and TRPM8-mediated cation entry was reduced in CHPH-PASMCs. Activation of TRPM8 with icilin caused concentration-dependent relaxation of cyclopiazonic acid (CPA) and endothelin-1 contracted endothelium-denuded PAs, and the effect was abolished by the SOCE antagonist Gd3+ Application of icilin to PASMCs suppressed CPA-induced Mn2+ quenching and Ca2+ entry, which was reversed by the TRPM8 antagonist N-(3-aminopropyl)-2-([(3-methylphenyl)methyl])-oxy-N-(2-thienylmethyl)benzamide hydrochloride salt (AMTB). Moreover, the inhibitory effects of icilin on SOCE in PA and PASMCs of CHPH rats were significantly augmented due to enhanced SOCE activity in PH. Our results, therefore, demonstrated a novel mechanism of TRPM8-mediated inhibition of SOCE in pulmonary vasculature. Because SOCE is important for vascular remodeling and enhanced vasoconstriction, down-regulation of TRPM8 in PASMCs of CHPH rats may minimize its inhibitory influence to allow unimpeded SOCE activity for PH development.
AuthorsYun-Ping Mu, Da-Cen Lin, Si-Yi Zheng, Hai-Xia Jiao, James S K Sham, Mo-Jun Lin
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 365 Issue 3 Pg. 544-555 (06 2018) ISSN: 1521-0103 [Electronic] United States
PMID29622593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
Chemical References
  • Endothelin-1
  • Pyrimidinones
  • TRPC Cation Channels
  • TRPM Cation Channels
  • Trpm8 protein, rat
  • transient receptor potential cation channel, subfamily C, member 1
  • icilin
  • Calcium
Topics
  • Animals
  • Biological Transport (drug effects)
  • Calcium (metabolism)
  • Cell Hypoxia (drug effects)
  • Endothelin-1 (pharmacology)
  • Gene Expression Regulation (drug effects)
  • Hypertension, Pulmonary (metabolism, pathology, physiopathology)
  • Male
  • Myocytes, Smooth Muscle (drug effects, metabolism)
  • Pulmonary Artery (drug effects, physiopathology)
  • Pyrimidinones (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • TRPC Cation Channels (metabolism)
  • TRPM Cation Channels (metabolism)
  • Vasoconstriction (drug effects)
  • Vasodilation (drug effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: