Dynamin-independent CaV1.2 and KCa1.1 channels regulation and vascular tone modulation by the mitochondrial fission inhibitors dynasore and dyngo-4a

by Selleckchem | Jul 15 2023

A role for mitochondrial fission in vascular contraction has been proposed based on the vasorelaxant activity of the dynamin (and mitochondrial fission) inhibitors mdivi-1 and dynasore. However, mdivi-1 is capable to inhibit Ba2+ currents through CaV1.2 channels (IBa1.2), stimulate KCa1.1 channel currents (IKCa1.1), and modulate pathways key to the maintenance of vessel active tone in a dynamin-independent manner. Using a multidisciplinary approach, the present study demonstrates that dynasore, like mdivi-1, is a bi-functional vasodilator, blocking IBa1.2 and stimulating IKCa1.1 in rat tail artery myocytes, as well as promoting relaxation of rat aorta rings pre-contracted by either high K+ or phenylephrine. Conversely, its analogue dyngo-4a, though inhibiting mitochondrial fission triggered by phenylephrine and stimulating IKCa1.1, did not affect IBa1.2 but potentiated both high K+- and phenylephrine-induced contractions. Docking and molecular dynamics simulations identified the molecular basis supporting the different activity of dynasore and dyngo-4a at CaV1.2 and KCa1.1 channels. Mito-tempol only partially counteracted the effects of dynasore and dyngo-4a on phenylephrine-induced tone. In conclusion, the present data, along with previous observations (Ahmed et al., 2022) rise caution for the use of dynasore, mdivi-1, and dyngo-4a as tools to investigate the role of mitochondrial fission in vascular contraction: to this end, a selective dynamin inhibitor and/or a different experimental approach are needed.

Comments:

The passage you provided describes a study that investigates the effects of certain compounds on vascular contraction and their potential role in mitochondrial fission. The compounds studied include mdivi-1, dynasore, and dyngo-4a, which are inhibitors of dynamin and mitochondrial fission. The study employs a multidisciplinary approach to examine the effects of these compounds on various channels and pathways involved in vascular tone regulation.

The results of the study show that both mdivi-1 and dynasore have dual effects on vascular contraction. They inhibit the IBa1.2 currents through CaV1.2 channels and stimulate IKCa1.1 channel currents, which are both involved in maintaining vessel tone. Additionally, both compounds promote relaxation of pre-contracted blood vessel rings. On the other hand, dyngo-4a, an analogue of dynasore, inhibits mitochondrial fission triggered by phenylephrine and stimulates IKCa1.1 but does not affect IBa1.2 currents. Interestingly, dyngo-4a potentiated contractions induced by high potassium and phenylephrine.

Further investigations using docking and molecular dynamics simulations were performed to understand the molecular basis for the differential activity of dynasore and dyngo-4a on CaV1.2 and KCa1.1 channels. The simulations provided insights into the interactions between these compounds and the channels.

The study also tested the effects of mito-tempol, a mitochondrial-targeted antioxidant, on the compounds' actions. Mito-tempol only partially counteracted the effects of dynasore and dyngo-4a on phenylephrine-induced vascular tone.

In conclusion, the study highlights the need for caution in using dynasore, mdivi-1, and dyngo-4a as tools to investigate the role of mitochondrial fission in vascular contraction. The compounds exhibit effects on multiple channels and pathways involved in vascular tone regulation, and their selectivity for mitochondrial fission inhibition is not well-defined. The study suggests that a selective dynamin inhibitor and/or a different experimental approach may be necessary to better understand the specific role of mitochondrial fission in vascular contraction.