Sympathomimetic inefficiency in restoring contractility in the acute or chronic beta-blocker-treated ischaemic heart: comparison with a new agent.
BACKGROUND
Adequate pharmacologic cardiac support in acute myocardial infarction (MI), as well as in chronic MI patients under beta-blocker therapy, is problematic due to the impaired cardiac response to beta-adrenergic agonists. New therapeutic approaches could resolve this problem. Istaroxime (ISTA) is a new Na(+),K(+)-ATPase inhibitor and SERCA(2) agonist.


OBJECTIVE
To evaluate: 1) the effects of dobutamine (DOB) on left ventricular function in early (48-72 h) and late (14 days) phases of a post-MI canine model, compared to ISTA, and 2) the efficacy of DOB in chronic left ventricular dysfunction (6 months post-MI) in dogs pre-treated or not with a beta-blocker, compared with ISTA and milrinone (MIL).


RESULTS
When compared to the effects in healthy animals, DOB increased contractility only slightly in the first 48-72 h post-MI, whereas its efficacy recovered partially by day 14 and fully by 6 months after MI. ISTA had a greater effect on contractility than DOB and improved relaxation, while DOB did not. Moreover, beta-adrenergic blockade inhibited the inotropic action of DOB, without altering the effect of ISTA. Surprisingly, beta-adrenergic blockade blunted the effects of MIL.


CONCLUSIONS
ISTA may represent a novel strategy for enhancing left ventricular performance even in the context of acute MI and/or concomitant beta-adrenergic blockade.
Mattera
Giovan Giuseppe
GG
Research and Development Sigma-Tau S.p.A. Pomezia, Italy. giovanni.mattera@sigma-tau.it
Vanoli
Emilio
E
Gagnol
Jean-Pierre
JP
Loi
Francesca Maria Paola
FM
Borsini
Franco
F
Carminati
Paolo
P
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use; D004280:Dobutamine / Q000627:therapeutic use; D004285:Dogs; D005043:Etiocholanolone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008297:Male; D020105:Milrinone / Q000627:therapeutic use; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013566:Sympathomimetics / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D017211:Treatment Failure; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D013566:Sympathomimetics; D004280:Dobutamine; D005043:Etiocholanolone; D000254:Sodium-Potassium-Exchanging ATPase; D020105:Milrinone; C468128:Istaroxime