istaroxime and Myocardial-Ischemia

Synchronized release of Ca²⁺ into the cytosol during each cardiac cycle determines cardiomyocyte contraction.. We investigated synchrony of cytosolic [Ca²⁺] decay during diastole and the impact of cardiac remodeling.. Local cytosolic [Ca²⁺] transients (1-µm intervals) were recorded in murine, porcine, and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca²⁺] decay based on the local time constants of decay (TAUlocal). The SD of TAUlocal as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca²⁺ release. Stimulation of sarcoplasmic reticulum Ca²⁺ ATPase with forskolin or istaroxime accelerated and its inhibition with cyclopiazonic acid slowed TAUlocal significantly more in slowCaR, thus altering the relationship between SD of TAUlocal and global [Ca²⁺] decay (TAUglobal). Na⁺/Ca²⁺ exchanger inhibitor SEA0400 prolonged TAUlocal similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca²⁺ uniporter blocker Ru360. Variation in TAUlocal was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAUlocal correlated with local sarcomere relengthening. In mice with myocardial hypertrophy after transverse aortic constriction, in pigs with chronic myocardial ischemia, and in end-stage human heart failure, variation in TAUlocal was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density.. In cardiomyocytes, cytosolic [Ca²⁺] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca²⁺] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.

Topics: Aniline Compounds; Animals; Calcium Signaling; Calcium-Transporting ATPases; Colforsin; Cytosol; Diastole; Electric Stimulation; Etiocholanolone; Heart Failure; Heart Ventricles; Humans; Hypertrophy; Hypertrophy, Left Ventricular; Indoles; Mice; Mitochondria, Heart; Myocardial Ischemia; Myocytes, Cardiac; Phenyl Ethers; Ruthenium Compounds; Sarcomeres; Sarcoplasmic Reticulum; Sodium-Calcium Exchanger; Sus scrofa; Swine; Ventricular Remodeling

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.. 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).. 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.. ISTA may represent a novel strategy for enhancing left ventricular performance even in the context of acute MI and/or concomitant beta-adrenergic blockade.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Cardiotonic Agents; Dobutamine; Dogs; Etiocholanolone; Male; Milrinone; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Sodium-Potassium-Exchanging ATPase; Sympathomimetics; Time Factors; Treatment Failure; Ventricular Dysfunction, Left