Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to investigate the possible roles of selective inhibition of cyclic nucleotide phosphodiesterase (PDE) isozymes, adenylate cyclase activation, and tissue cyclic 3',5'-adenosine monophosphate (cyclic AMP) elevation in the positive inotropic action of five new cardiotonic drugs. Three PDE isozymes (PDE I, II and III), homogenates, and slices of guinea pig ventricles were used. The inotropics amrinone, milrinone, AR-L 115BS, MDL 17,043, and RMI 82,249 all inhibited cyclic AMP hydrolysis by PDE III in a concentration-dependent manner, as did the PDE inhibitors aminophylline and 1-methyl-3-isobutylxanthine (MIX). All drugs except for AR-L 115BS inhibited PDE III at concentrations lower than those producing a standard inotropic response. A significant correlation (r = 0.80, P less than 0.05) was observed between PDE III inhibition and inotropic activity for six of the drugs. Only aminophylline and MIX, but none of the cardiotonic drugs, inhibited cyclic AMP hydrolysis by PDE I and II and cyclic 3',5'-guanosine monophosphate (cyclic GMP) hydrolysis (amrinone not tested) by PDE I. Further, none of the cardiotonic drugs inhibited the calmodulin-stimulated cyclic AMP hydrolysis by PDE I, indicating their lack of calmodulin antagonist activity. These drugs also did not stimulate adenylate cyclase activity but all increased net cyclic AMP formation from ATP in guinea pig ventricular homogenates through inhibition of cyclic AMP breakdown. Amrinone, milrinone, MDL 17,043 and RMI 82,249, but not AR-L 115BS, raised cyclic AMP levels significantly (P less than 0.05) in guinea pig ventricular slices. Also, amrinone, MDL 17,043 and RMI 82,249, but not AR-L 115BS, potentiated forskolin-induced cyclic AMP increase. These data taken together suggest that the specific inhibition of cyclic AMP PDE III isozyme and the consequent elevation of tissue cyclic AMP levels in cardiac tissue are an important mechanism of action of amrinone, milrinone, MDL 17,043 and RMI 82,249. Because AR-L 115BS did not increase cyclic AMP levels, it is likely that another mechanism may participate in the inotropic response to AR-L 115BS.
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PMID:Effects of several newer cardiotonic drugs on cardiac cyclic AMP metabolism. 242 28

On isolated electrically stimulated left and spontaneously beating right guinea-pig atria the interaction between PDE-inhibitors and the positive inotropic and chronotropic action of orciprenaline, forskolin and histamine in dose-response curve was examined. The experiments led to the following results: triamterene (20-120 mumol/l) and papaverine (10-100 mumol/l) inhibit the positive inotropic and chronotropic action of orciprenaline, whereas theophylline (10-100 mumol/l) and isobutyl-methyl-xanthine (0.1-10 mumol/l) only inhibit the inotropic action of orciprenaline. Amrinone (100-316 mumol/l) increases the positive inotropic and chronotropic action of orciprenaline; the positive inotropic and chronotropic action of forskolin is inhibited by triamterene but not by theophylline and IBMX. The positive chronotropic action of forskolin and histamine is inhibited by triamterene, whereas the positive inotropic action of histamine is not influenced; our experimental results suggest that triamterene and papaverine antagonize orciprenaline action by inhibition of adenylate cyclase. For this there is further evidence in the antagonism between triamterene and the inotropic action of forskolin and the tachycardic action of histamine. As theophylline and IBMX inhibit only the inotropic action of orciprenaline, there might be a different mechanism for their interaction regarding the chronotropic action of orciprenaline compared to triamterene and papaverine. The amrinone mechanism differs from that of the other PDE-inhibitors as it increases the positive inotropic and chronotropic action of orciprenaline.
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PMID:Interaction of phosphodiesterase inhibitors triamterene, papaverine, theophylline, IBMX and amrinone with other positive inotropic acting substances on isolated guinea-pig atria. 244 95