Abstract

Effects of ranolazine on isosorbide dinitrate- and on sildenafil-induced changes in mean arterial pressure and heart rate were assessed in conscious dogs. Dogs (n = 7) were chronically instrumented for measurements of mean arterial pressure and heart rate. Bolus intravenous injections of either isosorbide dinitrate (0.2 mg/kg) or sildenafil (0.5 mg/kg) caused biphasic changes in mean arterial pressure and heart rate: a transient ( 20 s) decrease in mean arterial pressure and an increase in heart rate, followed by prolonged (10–15 min) decreases in mean arterial pressure by 11 ± 1.6 and 11 ± 2.2 mm Hg, respectively. Infusion of ranolazine alone (plasma concentrations = 4 or 8 μM) for 10 min did not significantly affect mean arterial pressure and heart rate. The transient hypotension and tachycardia caused by isosorbide dinitrate were not altered by ranolazine. The sildenafil-induced transient tachycardia (Δ change: 114 ± 10 beats/min) was significantly (P < 0.05) blunted by either 4 (Δ change: 71 ± 8 beats/min) or 8 (Δ change: 66 ± 9 beats/min) μM ranolazine. However, the sildenafil-induced transient decrease in mean arterial pressure was not altered by ranolazine. During ranolazine infusion (4–5 or 8–10 μM), isosorbide dinitrate and sildenafil caused prolonged decreases in mean arterial pressure. These results indicate that except for a blunting of the transient tachycardia caused by sildenafil, ranolazine at concentrations up to 10 μM does not alter changes in mean arterial pressure and heart rate induced by either isosorbide dinitrate or sildenafil in conscious dogs.

Keywords: Ranolazine; Long-acting nitrate; Sildenafil; Blood pressure; Heart rate; Conscious dog

Article Outline

1. Introduction

2. Materials and methods

2.1. Surgical procedures

2.2. Recording from chronically instrumented dogs

2.3. Experimental protocols

2.3.1. Effects of isosorbide dinitrate or sildenafil on mean arterial pressure and heart rate

2.3.2. Effects of isosorbide dinitrate or sildenafil on mean arterial pressure and heart rate during infusion of ranolazine at 4–5 or 8–10 μM

2.4. Determination of plasma concentration of ranolazine

2.5. Drugs

2.6. Data analysis

3. Results

3.1. Effects of isosorbide dinitrate or sildenafil on mean arterial pressure and heart rate

3.2. Plasma concentrations and effects of ranolazine

3.3. Effects of isosorbide dinitrate or sildenafil on mean arterial pressure and heart rate during an infusion of ranolazine

3.4. Unexpected hypotensive response to sildenafil in some conscious dogs

4. Discussion

Acknowledgements

References