The development of drugs to force blood vessels into greater dilation, thereby lowering blood pressure, remains a popular ongoing concern despite the large number of such drugs already in use. Raised blood pressure causes significant downstream harm to the vasculature and surrounding delicate tissues in the body, enough that reductions in mortality can be achieved by forcing blood pressure reductions even without addressing the underlying mechanisms of aging that cause vascular stiffness. The materials here are a good example of the way in which early stage drug discovery takes place these days. Researchers start with a protein or protein interaction, then look for small molecules that (a) stimulate or interfere in that interaction in some way and (b) manage to do so with minimal side-effects and few to no other interactions.
The TRPV2 ion channel is formed by proteins in the membrane of some cells. When activated, they allow the entry of positive ions from the extracellular environment, changing the state of the cell and temporarily modifying aspects such as its ability to replicate, contract (in the case of a muscle cell) or even causing its death.
In a first study, the mechanisms involved in the contraction and relaxation of blood vessels by TRPV2 activation were analyzed in male mice. The researchers saw that TRPV2 produces multiple effects in different layers of the blood vessel, resulting in vasodilation. "This is important because it is the first time that the processes triggered by the activation of TRPV2 in blood vessels have been identified and have been described as leading to their dilation. This study represents a very important starting point for using this TRPV2 activation as a therapeutic strategy against diseases that cause excessive vasoconstriction, such as hypertension."
In a second study, the research group used computational techniques to identify a set of 270 molecules that, due to their physical and chemical characteristics, could interact with TRPV2, and grouped them by families according to how each of these molecules would bind to TRPV2. Then, by expressing the TRPV2 protein in yeast, a screening system was designed to test its effects. This made it possible to find a molecule (4-piperidin-1-sulfonyl-benzoic acid) capable of activating this protein more powerfully than the only drug known so far to do so: probenecid. "The activation of TRPV2 produced by the new molecule identified in this study has a very interesting vasodilator effect that could be used in the future as an antihypertensive therapy."
Link: https://www.uab.cat/...d=1345911637048
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