Background:
Diabetic cardiomyopathy (DCM) increases the risk of heart failure. As yet, no effective therapeutic strategies exist. Recent evidence indicates that intracellular Na
+
concentration ([Na
+
]
i
) is augmented in the myocytes from diabetic hearts, where it causes oxidative stress, augments the sarcoplasmic reticulum Ca
2+
leak and contributes to electrical, structural and functional remodeling. Ranolazine (RAN), inhibiting persistent or late inward Na
+
current has been proposed to be a therapeutic choice for DCM. However, the role and mechanism of chronic RAN in DCM are unclear. We assessed the hypothesis that RAN improves myocyte function, [Ca
2+
]
i
regulation, and β-adrenergic receptor (AR) signaling effectiveness, thus limiting DCM.
Methods:
We compared LV myocyte function, [Ca
2+
]
i
transient ([Ca
2+
]
iT
) and responses to the stimulation of β-AR in 3 groups wild-type (WT) female mice over 10 weeks (W):1)
DM
(n=8), 10 W after receiving streptozotocin (STZ, 200 mg/kg, ip); 2)
DM/RAN
(n=6), 6 W after STZ, RAN (10
-5
M/kg/day, mini-pump) was initiated and was given for 4 W; and 3)
Sham controls (C)
(n=8).
Results:
Versus control, STZ-treated WT mice had DM with significantly elevated blood glucose levels (410 vs 128mg/dl) followed by LV myocyte dysfunction with decreases in myocyte contractility (dL/dt
max
) (75.0 vs 140.1 μm/s), relengthening (dR/dt
max
) (62.5 vs 116.6 μm/s) and [Ca
2+
]
iT
(0.15 vs 0.22). In DM myocytes, the ability of β-AR agonist, isoproterenol (ISO, 10
-8
M) to increase cell contractility was blunted. Versus control, in DM myocytes, ISO-induced increases in dL/dt
max
(31% vs 60%), dR/dt
max
(23% vs 50%) and [Ca
2+
]
iT
(15% vs 30%) were significantly reduced. By contrary, versus DM alone, DM/RAN myocytes showed normal basal cell contraction (137.8 μm/s), relaxation (117.2 μm/s) and [Ca
2+
]
iT
(0.22) with preserved ISO-stimulated positive inotropic effect. Compared control, in DM/RAN, ISO caused similar increases in dL/dt
max
(62% vs 60%), dR/dt
max
(52% vs 50%) and [Ca
2+
]
iT
(32% vs 30%).
Conclusion:
Chronic ranolazine leads to the preservation of myocyte function, [Ca
2+
]
iT
and β-AR responsiveness in DCM. Thus, antagonizing myocyte [Na
+
]
i
dysregulation might provide a new therapeutic strategy for DM-related decline in myocardial function.