Treatment with polyamine synthesis inhibitors reduces the positive inotropic effect of ouabain, noradrenaline and calcium.
Polyamines (putrescine, spermidine and spermine) are considered to act as intracellular second messengers by increasing Ca++ influx and mobilizing intracellular calcium. On the other hand, intracellular Ca++ increase is the common final step of the mechanism of action of many inotropic agents. To discover whether the functional integrity of the cardiac ornithine decarboxylase (ODC)/polyamine system is necessary to cope with a stimulated inotropism, we studied the effect of ouabain, noradrenaline, and calcium on ventricle strips obtained from rats treated with polyamine synthesis inhibitors. The combined administration of methylglioxal bis (guanylhydrazone) (MGBG) (single i.p. injection of 50 mgkg-1) and of alpha-di fluoromethylornithine (DFMO) (100 mgkg-1 every 12 h for 7 consecutive days) caused a 62.5% inhibition of ventricular ODC activity, and a significant decrease of the ventricular content of putrescine and spermidine (-59.5%, and -40.1%, respectively). While the basal isometric tension developed by ventricle strips obtained from rats treated with MGBG+DFMO was similar to that developed by ventricle strips from controls, the response to ouabain (1 microM), noradrenaline (10 microM), or Ca++ (3.6 mM) was significantly reduced. It cannot be excluded that effects of MGBG unrelated to the inhibition of polyamine synthesis may have also concurred in part to influence the effect of ouabain, Ca++ and noradrenaline adversely. However, the present results seem to indicate that the heart response to inotropic agents requires an efficient ODC/polyamine system, polyamines probably being involved in calcium ion movements or affecting the Ca++ sensitivity of contractile proteins.
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000518:Eflornithine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D010042:Ouabain / Q000037:antagonists & inhibitors*; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000096:biosynthesis; D011765:Pyruvaldehyde / Q000494:pharmacology; D051381:Rats; D013095:Spermidine / Q000096:biosynthesis; D013096:Spermine / Q000096:biosynthesis
D002316:Cardiotonic Agents; D011073:Polyamines; D013096:Spermine; D010042:Ouabain; D011765:Pyruvaldehyde; D002118:Calcium; D013095:Spermidine; D011700:Putrescine; D009638:Norepinephrine; D000518:Eflornithine