title: Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs.
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.
authors.affiliation: Department of Biology, Gilead Sciences Palo Alto, Palo Alto, CA, USA. gong.zhao@gilead.com
authors.forename: Gong
authors.initials: G
authors.lastname: Zhao
authors.forename: Erin
authors.initials: E
authors.lastname: Walsh
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
authors.forename: Eric
authors.initials: E
authors.lastname: Messina
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Wu
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Xu
authors.forename: Manuel
authors.initials: M
authors.lastname: Ochoa
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Baker
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D018674:Adrenergic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D001337:Autonomic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005730:Ganglionic Blockers / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D018738:Hexamethonium / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy*; D007545:Isoproterenol / Q000008:administration & dosage / Q000633:toxicity; D007700:Kinetics; D010656:Phenylephrine / Q000008:administration & dosage / Q000633:toxicity; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D000069458:Ranolazine; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000737:chemistry / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000633:toxicity; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D000083:Acetanilides; D018674:Adrenergic Antagonists; D001337:Autonomic Agents; D005730:Ganglionic Blockers; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D018738:Hexamethonium; D000069458:Ranolazine; D007545:Isoproterenol