Open AccessRole of inositol 1,4,5‐trisphosphate receptors in α 1 ‐adrenergic receptor‐induced cardiomyocyte hypertrophy 1
Author(s) -
LUO Dali,
GAO Jian,
LAN Xiaomei,
WANG Gang,
WEI Sheng,
XIAO Ruiping,
HAN Qide
Publication year - 2006
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2006.00382.x
Subject(s) - receptor , inositol , adrenergic receptor , chemistry , endocrinology , medicine , alpha 1b adrenergic receptor , adrenergic , pharmacology , biology , microbiology and biotechnology , beta 3 adrenergic receptor
Aim: Intracellular Ca 2+ plays pivotal roles in diverse cellular functions, including gene transcription that underlies cardiac remodeling during stress responses. However, the role of inositol 1,4,5‐trisphosphate receptors (IP 3 Rs) in the mediation of cardiac intracellular Ca 2+ and hypertrophic growth remains elusive. Prior work with neonatal rat ventricular myocytes suggests that activation of IP 3 Rs may be linked to α 1 adrenergic receptor (α 1 AR) increased stereotyped Ca 2+ spark occurrence and global Ca 2+ oscillations. Thus, we hypothesized that Ca 2+ release through IP 3 Rs was necessary for α 1 AR‐stimulated cardiac hypertrophy. Methods : We used myoinositol 1,4,5‐trisphosphate hexakis (butyryloxymethyl) ester (IP 3 BM), a membrane‐permeant ester of IP 3 , to activate IP 3 Rs directly, and Fluo 4/AM to measure intracellular Ca 2+ signaling. Results : IP 3 BM (10 μmol‐L −1 ) mimicked the effects of phenylephrine, a selective agonist of α 1 AR, in increments in local Ca 2+ spark release (especially in the perinuclear area) and global Ca 2+ transient frequencies. More importantly, IP 3 R inhibitors, 2‐aminoethoxydiphenyl borate and Xestospongin C, abolished the IP 3 BM‐induced Ca 2+ responses, and significantly suppressed α 1 AR‐induced cardiomyocyte hypertrophy assayed by cell size, [ 3 H] leucine incorporation and atrial natriuretic factor gene expression, during sustained (48 h) phenylephrine stimulation. Conclusion : These results, therefore, provide cellular mechanisms that link IP 3 R signaling to α 1 AR‐stimulated gene expression and cardiomyocyte hypertrophy.