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

Abstract

<h3>Background</h3> 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 <i>in vitro</i> and <i>in vivo</i>. 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 <i>in vivo</i> when heart rate is increased. <h3>Methods</h3> 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 <i>in vivo</i> 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. <h3>Results</h3> 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, <i>P</i> <.05). Whereas ranolazine alone did not alter isovolumic relaxation time (IVRT) (S: 13 ± 8% vs R: –4 ± 7% change from baseline, NS), pretreatment with ranolazine prevented an increase in IVRT during dobutamine infusion in SHR (S: 89 ± 27% vs R: 8 ± 14% change from baseline, <i>P</i> <.05), despite the matched increase in heart rate (<i>P</i> >.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 (<i>P</i> <.01). <h3>Conclusions</h3> 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.