Ranolazine Improves Diastolic Function in the Stress-Tested Spontaneously Hypertensive Rat

Background Delayed left ventricular relaxation impairs diastolic function, mostly at high heart rates; thus, exercise or dobutamine stress tests are often used in clinical diagnosis. Ranolazine, a late I Na inhibitor, can reverse diastolic dysfunction in vitro and in vivo . However, mechanisms other than late I Na inhibition have been suggested. In this study, we tested the hypothesis that late I Na is elevated in spontaneously hypertensive rat hearts (SHR), a model of diastolic dysfunction, and that ranolazine can improve diastolic function in vivo when heart rate is increased. Methods SHR and Wistar Kyoto (WKY) rats aged 10 months were used for all experiments. Late I Na was measured from isolated SHR and WKY rat ventricular myocytes using a voltage-ramp protocol. Diastolic function was evaluated in vivo by echocardiography and left ventricular pressure–volume (LVPV) catheter techniques. Effects of ranolazine (R, 30 mg/kg) or saline (S) pretreatment on the response to dobutamine (β-agonist) were measured in SHR. In echo experiments (n = 5/group), the dose of dobutamine was titrated (∼40 μg/kg/min to achieve a heart rate of 450 bpm, whereas the dose response to 10, 20, and 40 μg/kg/min (n = 2/group) was measured by PV loop analysis. Results Baseline echo and LVPV loop analysis confirmed diastolic dysfunction in SHR. Late I Na current density was larger in SHR ventricular myocytes (–0.69 pA/pF, n=7) compared with WKY (0.32 pA/pF, n=9, P P P >.05). Ranolazine pretreatment also prevented the dose-dependent increase in end-diastolic pressure in response to dobutamine in SHR, although the heart rate increased dose-dependently in both groups. At 40 μg/kg/min, the change (Δ) from baseline was (S) 8 ± 3 mm Hg vs (R) –1 ± 1 mm Hg ( P Conclusions Our data indicate that ranolazine may protect against heart rate-dependent worsening of diastolic dysfunction. Inhibition of late I Na , which is enhanced in this model, may underlie this effect.