Fropofol significantly reduced maximum Ca2+-activated force from 84.5 to 49.6 mN/mm2 in normal intact trabeculae and decreased twitch force by up to 35% in hypercontractile muscle.
Does fropofol reduce force development in normal and hypercontractile rat cardiac muscle?
Fropofol, a nonanesthetic propofol derivative, directly depresses cardiac myofilament contractility by targeting actomyosin interactions, suggesting potential utility for treating hypercontractile cardiac disorders like hypertrophic cardiomyopathy.
Tasa de eventos absoluta: 49.6% vs 84.5%
valor p: p=<0.01
Supranormal contractile properties are frequently associated with cardiac diseases. Anesthetic agents, including propofol, can depress myocardial contraction. We tested the hypothesis that fropofol, a propofol derivative, reduces force development in cardiac muscles via inhibition of cross‐bridge cycling and may therefore have therapeutic potential. Force and intracellular Ca 2+ concentration (Ca 2+ i ) transients of rat trabecular muscles were determined. Myofilament ATPase, actin‐activated myosin ATPase, and velocity of actin filaments propelled by myosin were also measured. Fropofol dose dependently decreased force without altering Ca 2+ i in normal and pressure‐induced hypertrophied‐hypercontractile muscles. Similarly, fropofol depressed maximum Ca 2+ ‐activated force (F max ) and increased the Ca 2+ i required for 50% of F max (Ca 50 ) at steady state without affecting the Hill coefficient in both intact and skinned cardiac fibers. The drug also depressed cardiac myofibrillar and actin‐activated myosin ATPase activity. In vitro actin sliding velocity was significantly reduced when fropofol was introduced during rigor binding of cross‐bridges. The data suggest that the depressing effects of fropofol on cardiac contractility are likely to be related to direct targeting of actomyosin interactions. From a clinical standpoint, these findings are particularly significant, given that fropofol is a nonanesthetic small molecule that decreases myocardial contractility specifically and thus may be useful in the treatment of hypercontractile cardiac disorders.—Ren, X., Schmidt, W., Huang, Y., Lu, H., Liu, W., Bu, W., Eckenhoff, R., Cammarato, A., Gao, W. D. Fropofol decreases force development in cardiac muscle. FASEB J . 32, 4203‐4213 (2018). www.fasebj.org
Ren et al. (Fri,) conducted a other in Cardiac hypercontractility. Fropofol vs. Baseline (no fropofol) was evaluated on Maximum Ca2+-activated force (Fmax) in normal intact trabeculae (mN/mm2) (p=<0.01). Fropofol significantly reduced maximum Ca2+-activated force from 84.5 to 49.6 mN/mm2 in normal intact trabeculae and decreased twitch force by up to 35% in hypercontractile muscle.