In vivo interaction of AR-L 115BS (Vardax) with the adrenergic nervous system.
In vitro studies have demonstrated that AR-L 115BS (AR-L), a new orally active nonglycosidic inotropic agent with vasodilator properties, does not act via adrenergic receptors. However, because AR-L is a phosphodiesterase inhibitor and interaction with the adrenergic nervous system may exist in vivo, we compared the actions of intravenous AR-L, isoproterenol, and propranolol, alone and in combination, in normal dogs. In seven awake morphine-sedated dogs, AR-L (4 mg/kg i.v.) did not alter circulating catecholamines despite increasing maximum rate of change of left ventricular pressure (dP/dt) by 76%. In anesthetized dogs, peak inotropic effect of AR-L occurred at 6 mg/kg (dP/dt from 5,450 +/- 1,280 to 12,000 +/- 3,050 mm Hg/s). Propranolol (1 mg/kg) depressed dP/dt from 5,725 +/- 2,032 to 2,530 +/- 631 mm Hg/s, and this was completely reversed by increasing doses of AR-L (2-30 mg/kg) but the maximum dP/dt attained in these dogs (6,050 +/- 221 mm Hg/s) remained below the level achieved by AR-L in the absence of propranolol. To determine if that difference was due to an interaction of AR-L with the adrenergic nervous system, the effect of AR-L on isoproterenol activity was studied in groups of beta-blocked and unblocked animals. In either group, the dose-response curve of dP/dt to isoproterenol was shifted upward by AR-L, but the actions of the two drugs were additive without real synergism (e.g., after propranolol:isoproterenol 10 micrograms/min 73%; AR-L 6 mg/kg 81%; both 160%. In unblocked dogs, the results were: isoproterenol 2 micrograms/min 96%; AR-L 1 mg/min 39%; both 138%). Similarly, isoproterenol and AR-L were only additive in their effects on heart rate and systemic vascular resistance. Thus, although AR-L is a phosphodiesterase inhibitor, its predominant mechanism of action appears to be independent of the adrenergic nervous system.
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002395:Catecholamines / Q000097:blood*; D004285:Dogs; D004837:Epinephrine / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D009638:Norepinephrine / Q000097:blood; D011433:Propranolol / Q000494:pharmacology; D011941:Receptors, Adrenergic / Q000187:drug effects*
D002316:Cardiotonic Agents; D002395:Catecholamines; D007093:Imidazoles; D011941:Receptors, Adrenergic; D011433:Propranolol; C029758:sulmazole; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine