In vivo interaction of ar-l 115bs (vardax®) with the adrenergic nervous system

Marc Petein, Gordon L. Pierpont, Gary S. Francis, Jay N. Cohn, Arthur H.L. From

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2 Scopus citations

Abstract

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 -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 g/min 73%; AR-L 6 mg/kg 81%; both 160%. In unblocked dogs, the results were: isoproterenol 2 g/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.

Original languageEnglish (US)
Pages (from-to)1020-1026
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume6
Issue number6
DOIs
StatePublished - Jan 1 1984

Keywords

  • Adrenergic nervous system
  • Ar-l 115bs
  • Sulmazol
  • Vardax®

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