Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs

J Cardiovasc Pharmacol. 2011 Jun;57(6):639-47. doi: 10.1097/FJC.0b013e31821458e8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / administration & dosage
  • Acetanilides / blood
  • Acetanilides / metabolism
  • Acetanilides / therapeutic use*
  • Adrenergic Antagonists / administration & dosage
  • Adrenergic Antagonists / blood
  • Adrenergic Antagonists / metabolism
  • Adrenergic Antagonists / therapeutic use*
  • Animals
  • Autonomic Agents / administration & dosage
  • Autonomic Agents / therapeutic use
  • Coronary Circulation / drug effects
  • Dogs
  • Dose-Response Relationship, Drug
  • Ganglionic Blockers / pharmacology
  • Guinea Pigs
  • Heart Rate / drug effects
  • Hemodynamics / drug effects*
  • Hexamethonium / pharmacology
  • Hypertension / chemically induced
  • Hypertension / drug therapy*
  • Hypotension / chemically induced
  • Hypotension / drug therapy*
  • Isoproterenol / administration & dosage
  • Isoproterenol / toxicity
  • Kinetics
  • Phenylephrine / administration & dosage
  • Phenylephrine / toxicity
  • Piperazines / administration & dosage
  • Piperazines / blood
  • Piperazines / metabolism
  • Piperazines / therapeutic use*
  • Ranolazine
  • Rats
  • Receptors, Adrenergic, alpha / chemistry
  • Receptors, Adrenergic, alpha / metabolism*
  • Receptors, Adrenergic, beta / chemistry
  • Receptors, Adrenergic, beta / metabolism*
  • Vasoconstrictor Agents / administration & dosage
  • Vasoconstrictor Agents / toxicity
  • Vasodilator Agents / administration & dosage
  • Vasodilator Agents / toxicity

Substances

  • Acetanilides
  • Adrenergic Antagonists
  • Autonomic Agents
  • Ganglionic Blockers
  • Piperazines
  • Receptors, Adrenergic, alpha
  • Receptors, Adrenergic, beta
  • Vasoconstrictor Agents
  • Vasodilator Agents
  • Phenylephrine
  • Hexamethonium
  • Ranolazine
  • Isoproterenol