Key result
Ranolazine at plasma concentrations <10 μM had minimal antiadrenergic effects in conscious dogs with intact autonomic regulation, but attenuated phenylephrine- and isoproterenol-induced changes during autonomic blockade.
Ranolazine exhibits potential antiadrenergic effects that are masked by intact autonomic control mechanisms but become apparent during autonomic blockade.
Ranolazine's antiadrenergic effects appear masked by intact autonomic tone in dogs; leaves open translation to human therapy and requires clinical validation.
Effects of ranolazine alone and in the presence of phenylephrine (PE) or isoproterenol (ISO) on hemodynamics, coronary blood flow and heart rate (HR) in the absence and presence of hexamethonium (a ganglionic blocker) were studied in conscious dogs. Ranolazine (0.4, 1.2, 3.6, and 6 mg/kg, intravenous) alone caused transient (<1 minute) and reversible hemodynamic changes. PE (0.3-10 μg/kg) caused a dose-dependent increase in blood pressure and decrease in HR. ISO (0.01-0.3 μg/kg) caused a dose-dependent decrease in blood pressure and an increase in HR. Ranolazine at high (11-13 mM), but not at moderate (4-5 mM) concentrations partially attenuated changes in mean arterial blood pressure and HR caused by either PE or ISO in normal conscious dogs. However, in dogs treated with hexamethonium (20 mg/kg) to cause autonomic blockade, ranolazine (both 4-5 and 11-13 μM) significantly attenuated both the PE- and ISO-induced changes in mean arterial blood pressure. The results suggest that a potential antiadrenergic effect of ranolazine was masked by autonomic control mechanisms in conscious dogs but could be observed when these mechanisms were inhibited (eg, in the hexamethonium-treated dog). Ranolazine, at plasma concentrations <10 μM and in conscious dogs with intact autonomic regulation, had minimal antiadrenergic (α and β) effects.
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Zhao et al. (2011) studied Normal conscious dogs and dogs with autonomic blockade. Ranolazine was evaluated on Hemodynamics, coronary blood flow and heart rate. Ranolazine at plasma concentrations <10 μM had minimal antiadrenergic effects in conscious dogs with intact autonomic regulation, but attenuated phenylephrine- and isoproterenol-induced changes during autonomic blockade.
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