Diverse regulation of IP₃ and ryanodine receptors by pentazocine through σ₁-receptor in cardiomyocytes

Although pentazocine binds to σ₁-receptor (σ₁R) with high affinity, the physiological relevance of its binding remains unclear. We first confirmed that σ₁R stimulation with pentazocine rescues contractile dysfunction following pressure overload (PO)-induced cardiac hypertrophy ovariectomized (OVX) female rats. In in vivo studies, vehicle, pentazocine (0.5-1.0 mg/kg ip), and NE-100 (1.0 mg/kg po), a σ₁R antagonist, were administered for 4 wk (once daily) starting from the onset of aortic banding after OVX. We also examined antihypertrophic effects of pentazocine (0.5-1 μM) in cultured cardiomyocytes exposed to angiotensin II. Pentazocine administration significantly inhibited PO-induced cardiac hypertrophy and rescued hypertrophyinduced impairment of cardiac dysfunctions such as left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular contraction and relaxation (±dp/dt) rates. Coadministration of NE-100 with pentazocine eliminated pentazocine-induced amelioration of heart dysfunction. Interestingly, pentazocine administration inhibited PO-induced σ₁R reduction and inositol-1,4,5-trisphosphate (IP₃) receptor type 2 (IP₃R2) upregulation in heart. Therefore, the reduced mitochondrial ATP production following PO was restored by pentazocine administration. Furthermore, we found that σ₁R binds to the ryanodine receptor (RyR) in addition to IP₃ receptor (IP₃R) in cardiomyocytes. The σ₁ R/RyR complexes were decreased following OVX-PO and restored by pentazocine administration. We noticed that pentazocine inhibits the ryanodine-induced Ca²⁺ release from sarcoplasmic reticulum (SR) in cultured cardiomyocytes. Taken together, the stimulation of σ₁ R by pentazocine rescues cardiac dysfunction by restoring IP₃R-mediated mitochondrial ATP production and by suppressing RyR-mediated Ca²⁺ leak from SR in cardiomyocytes.