Role of inositol 1,4,5-trisphosphate receptors in α₁-adrenergic receptor-induced cardiomyocyte hypertrophy

Aim: Intracellular Ca²⁺ 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 (IP₃Rs) in the mediation of cardiac intracellular Ca²⁺ and hypertrophic growth remains elusive. Prior work with neonatal rat ventricular myocytes suggests that activation of IP₃Rs may be linked to α₁ adrenergic receptor (α₁ AR) increased stereotyped Ca²⁺ spark occurrence and global Ca²⁺ oscillations. Thus, we hypothesized that Ca²⁺ release through IP₃Rs was necessary for α₁ AR-stimulated cardiac hypertrophy.
Methods: We used myoinositol 1,4,5-trisphosphate hexakis (butyryloxymethyl) ester (IP₃BM), a membrane-permeant ester of IP₃, to activate IP₃Rs directly, and Fluo 4/AM to measure intracellular Ca²⁺ signaling.
Results: IP₃BM (10 μmol-L^-1) mimicked the effects of phenylephrine, a selective agonist of α₁AR, in increments in local Ca²⁺ spark release (especially in the perinuclear area) and global Ca²⁺ transient frequencies. More importantly, IP₃R inhibitors, 2-aminoethoxydiphenyl borate and Xestospongin C, abolished the IP₃BM-induced Ca²⁺ responses, and significantly suppressed α₁AR-induced cardiomyocyte hypertrophy assayed by cell size, [³H] leucine incorporation and atrial natriuretic factor gene expression, during sustained (48 h) phenylephrine stimulation.
Conclusion: These results, therefore, provide cellular mechanisms that link IP₃R signaling to α₁ AR-stimulated gene expression and cardiomyocyte hypertrophy.