Administration of Omecamtiv Mecarbil leads to hypotension and diastolic dysfunction in WKY rat model
Authors: Fulop Gabor Aron , Nagy Laszlo , Csipo Tamas , Kovacs Arpad , Juhasz Bela , Priksz Daniel , Helgadottir Solveig Lind , Porszasz Robert , Papp Zoltan , Toth Attila 
Published: November 2023

Direct miosin activators represent a new direction in the treatment of heart failure. In our experiments we tested the in vivo and in vitro effects of the miosin activator omecamtiv mecarbil (OM) on Wistar Kyoto rats.Ca2+‐dependent active force (Factive), Ca2+‐sensitivity (pCa50) Ca2+‐independent passive force (Fpassive) and the kinetics of contraction and relaxation of isolated left ventricular myocytes were measured after OM pretreatment. We measured the effects of OM on aortic flow, aortic pressure and coronary flow on isolated working heart system. We performed in vivo blood pressure expreiments, where we recorded the changes of blood pressure through carotid artery canule, in response to different doses of OM. In other part of in vivo experiments we performed echocardiographic examination after OM treatment. In the in vivo experiments we administered the OM in 3 different doses: 200, 400 and 600 μg/kg.600 μg/kg dose of OM decreased both the systolic and diastolic blood pressure (given in the precentage of the baseline) significantly (systolic: decreased to 41,47±8,5 %; diastolic decreased to 37,13±11,17%). OM elevated both the ejection fraction (baseline: 70±1,56; 200 μg/kg OM: 72±3,5; 400 μg/kg OM: 77,75±5,2; 600 μg/kg: 82,833±8,32), and the fractional shortening (baseline: 35±1,46; 200 μg/kg OM: 35,375±1,46 ; 400 μg/kg OM: 42,25±2,63; 600 μg/kg: 47,66±5,39) in a dose dependent pattern. Diastolic parameters were also changed, E/A ratio was decreased (baseline: 2,01; OM 200 μg/kg: 1,7464; OM 400 μg/kg: 1,4464; OM 600 μg/kg: non measurable), isovolumetric relaxation time (IVRT) (baseline: 22,25 ± 1,96; OM 200 μg/kg: 31,66 ± 0,80; OM 400 μg/kg: 35,07 ± 1,801; OM 600 μg/kg:50,66 ± 2,60 in ms) and deceleration time (DT) (baseline:46,07±3,33; OM 200 μg/kg: 46,38±2,46 ; OM 400 μg/kg: 55,23±5,741; OM 600 μg/kg:58,66±1,66 in ms) were prolonged. On isolated working heart OM decreased aortic pressure (baseline:102,6±1,07; OM 200 μg/kg: 93,6±0,74; OM 400 μg/kg: 54,622±6,22; OM 600 μg/kg:34,6±5,76 in Hgmm), aortic flow (baseline:58,6±3,29; OM 200 μg/kg: 57,6±5,53; OM 400 μg/kg: non measurable;OM 600 μg/kg:non measurable in ml/min), and coronary flow (baseline:23,4±1,77; OM 200 μg/kg: 24,6±2,24; OM 400 μg/kg: 13,4±2,29;OM 600 μg/kg:5,6±1,6 in ml/min) concentration dependently. On isolated cardiomyocytes OM increased Ca2+‐sensitivity, and passive force, and slowed down the kinetics of the activation of the cells. In our experiments we found that high dose of norepinephrine (NE) (5μg/kg) reverts the effects of OM on blood pressure, and systolic function, but not on diastolic function.Our data suggest that OM might be a good positive inotropic agent, but the terapeutic index of the drug is narrow, and can easily lead to serious hypotension. If overdose occurs, norepinephrine can revert most of the negative effects of the drug in vivo.Support or Funding InformationHungarian Scientific Research Fund: K116940; K109083