A szívelégtelenség kialakulásának és új kezelési lehetőségeinek experimentális vizsgálata(K
134939) Funder: NRDIO
Új perspektívák a renin-angiotenzin-aldoszteron rendszerben(K 116940) Funder: NRDIO
Kezelés-specifikus diagnosztikus módszerek fejlesztése a személyre szabott kardiovaszkuláris
terá...(K 132623)
Subjects:
Basic pharmacology
Biological sciences
MEDICAL AND HEALTH SCIENCES
Organ physiology and pathophysiology
Cardiac and Cardiovascular systems
Omecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility.
We tested the therapeutic range of OM and identified previously unrecognized side
effects. The Ca2+ sensitivity of isometric force production (pCa50) and force at low
Ca2+ levels increased with OM concentration in human permeabilized cardiomyocytes.
OM (1 µM) slowed the kinetics of contractions and relaxations and evoked an oscillation
between normal and reduced intracellular Ca2+ transients, action potential lengths
and contractions in isolated canine cardiomyocytes. Echocardiographic studies and
left ventricular pressure–volume analyses demonstrated concentration-dependent improvements
in cardiac systolic function at OM concentrations of 600–1200 µg/kg in rats. Administration
of OM at a concentration of 1200 µg/kg was associated with hypotension, while doses
of 600–1200 µg/kg were associated with the following aspects of diastolic dysfunction:
decreases in E/A ratio and the maximal rate of diastolic pressure decrement (dP/dtmin)
and increases in isovolumic relaxation time, left atrial diameter, the isovolumic
relaxation constant Tau, left ventricular end-diastolic pressure and the slope of
the end-diastolic pressure–volume relationship. Moreover, OM 1200 µg/kg frequently
evoked transient electromechanical alternans in the rat in vivo in which normal systoles
were followed by smaller contractions (and T-wave amplitudes) without major differences
on the QRS complexes. Besides improving systolic function, OM evoked diastolic dysfunction
and pulsus alternans. The narrow therapeutic window for OM may necessitate the monitoring
of additional clinical safety parameters in clinical application.
