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) inhibitor y activity of diazepam on the arterial wall. To this purpose, we examined t he interaction of diazepam with 3',5'-cyclic adenosine monophosphate (cycli c AMP)-elevating agents on vasodilatation and cyclic AMP levels in rat aort ic rings precontracted with phenylephrine. The involvement of benzodiazepin e receptors was also studied. Diazepam. (5-100 muM) produced a relaxation o f this preparation which was neither mimicked by gamma -aminobutyric acid ( GABA), nor antagonized by flumazenil and 1-(2-chlorophenyl)-N-methyl-N-(1-m ethylpropyl)-3-isoquinolinecarboxamide(PK 11195), inhibitors of central or peripheral type benzodiazepine receptors, respectively. The diazepam-induce d relaxation was potentiated by the presence of isoprenaline (10 nM), forsk olin (50 nM) or milrinone (0.1 muM). Furthermore, diazepam increased the en hancement of cyclic AMP levels induced by these three agents in this tissue . Our results demonstrate a functional and biochemical synergistic interact ion of diazepam with cyclic AMP-elevating agents on rat aortic rings. (C) 2 001 Elsevier Science B.V. All rights reserved.