Synergistic interaction of diazepam with 3',5'-cyclic adenosine monophosphate-elevating agents on rat aortic rings

We investigated the effect of the phosphodiesterase type 4 (PDE4) inhibitory activity of diazepam on the arterial wall. To this purpose, we examined the interaction of diazepam with 3',5'-cyclic adenosine monophosphate (cyclic AMP)-elevating agents on vasodilatation and cyclic AMP levels in rat aortic rings precontracted with phenylephrine. The involvement of benzodiazepine receptors was also studied. Diazepam (5-100 microM) produced a relaxation of this preparation which was neither mimicked by gamma-aminobutyric acid (GABA), nor antagonized by flumazenil and 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195), inhibitors of central or peripheral type benzodiazepine receptors, respectively. The diazepam-induced relaxation was potentiated by the presence of isoprenaline (10 nM), forskolin (50 nM) or milrinone (0.1 microM). Furthermore, diazepam increased the enhancement of cyclic AMP levels induced by these three agents in this tissue. Our results demonstrate a functional and biochemical synergistic interaction of diazepam with cyclic AMP-elevating agents on rat aortic rings.