title: Ranolazine, a novel anti-anginal agent, does not alter isosorbide dinitrate- or sildenafil-induced changes in blood pressure in conscious dogs.
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 (approximately 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 microM) 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 (Delta change: 114 +/- 10 beats/min) was significantly (P < 0.05) blunted by either 4 (Delta change: 71 +/- 8 beats/min) or 8 (Delta change: 66 +/- 9 beats/min) microM ranolazine. However, the sildenafil-induced transient decrease in mean arterial pressure was not altered by ranolazine. During ranolazine infusion (4-5 or 8-10 microM), 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 microM does not alter changes in mean arterial pressure and heart rate induced by either isosorbide dinitrate or sildenafil in conscious dogs.
authors.affiliation: CV Therapeutics, Inc., Palo Alto, CA 94304, USA. gong.zhao@cvt.com
authors.forename: Gong
authors.initials: G
authors.lastname: Zhao
authors.forename: Eric
authors.initials: E
authors.lastname: Messina
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Xu
authors.forename: Manuel
authors.initials: M
authors.lastname: Ochoa
authors.forename: Sobrina
authors.initials: S
authors.lastname: Serpillon
authors.forename: John
authors.initials: J
authors.lastname: Shryock
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
mesh_terms: D000083:Acetanilides; D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced; D007275:Injections, Intravenous; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*; D011687:Purines; D000069458:Ranolazine; D000068677:Sildenafil Citrate; D013268:Stimulation, Chemical; D013450:Sulfones; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000069458:Ranolazine; D000068677:Sildenafil Citrate; D007548:Isosorbide Dinitrate