TRPC6 Calcium Channel Offers New Target in PH, Mouse Study Suggests
A calcium channel called TRPC6 may offer a new target for the development of treatments for pulmonary hypertension (PH), including pulmonary arterial hypertension (PAH), a mouse study suggests.
Researchers also found that a calcium channel blocker called BI-749327, given orally, reversed PH in a mouse model of the disease. BI-749327 is selective for TRPC6, meaning it acts on TRPC6 and not other calcium channels.
“BI-749327, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH and PH due to respiratory diseases or hypoxemia [low blood oxygen],” the researchers wrote.
The study, “TRPC6, a therapeutic target for pulmonary hypertension,” was published in the American Journal of Physiology — Lung Cellular and Molecular Physiology by a team of researchers in the U.S. and China.
In the body, blood travels from the right side of the heart to each of the lungs through the pulmonary artery, where pressure is normally low. This allows the right side of the heart to be smaller and less muscular than the left side.
However, when muscle cells around the pulmonary artery contract, causing it to tighten, blood pressure rises. For a muscle cell to contract, it needs calcium, and for the calcium to flow into the cell, it needs an open channel.
One such calcium channel, TRPC6, is present in the lungs and the heart, and is found at particularly high levels in the muscle cells around the pulmonary artery of patients with PAH.
“Despite evidence supporting a pathological [disease-causing] role of TRPC6, no selective and orally bioavailable TRPC6 antagonist [blocker] has yet been developed and tested for treatment of PAH or PH,” the researchers wrote.
A calcium channel blocker is a type of medication that prevents calcium from entering the muscle cells. This causes the blood vessels to relax and widen, and the blood pressure to decrease.
In the study, the researchers wanted to see what happens when 2-APB, a non-selective blocker that acts on calcium channels in general, or BI-749327, a selective TRPC6 blocker, are given daily to mice with established PH. To induce PH, the mice were kept for four weeks in a special chamber where oxygen level was low.
First, the researchers asked whether the calcium channel blockers could reverse the blood vessel tightening induced by the low oxygen level. To test this, they applied a continuous flow of a solution containing either 2-APB or BI-749327 over the outside of isolated lungs. They found that both 2-APB and BI-749327 were able to stop blood vessel tightening.
Then, they tested whether 2-APB or BI-749327 could reverse PH. While 2-APB was given intraperitoneally — into the area that contains the abdominal organs — at 1 mg/kg of body weight (mg/kg), BI-749327 (30 mg/kg) was given by oral gavage, a way of administration in which a medication is given through a small tube placed through the mouth into the stomach. Both calcium channel blockers were given once a day for two weeks after the mice had developed PH.
The investigators found that both 2-APB and BI-749327 were able to partially reverse PH by lessening pulmonary vascular remodeling, a hallmark feature of PH that involves the uncontrolled growth of muscle cells around the pulmonary artery. The calcium channel blockers also stopped an increase in the size of the right side of the heart, which occurs when it has to push blood against a higher-than-normal pressure.
To understand how the calcium channel blockers work, the researchers grew muscle cells from human pulmonary arteries in the lab, and treated them with either 2-APB or BI-749327. Both inhibited the action of platelet-derived growth factor, a protein that activates a series of chemical reactions in a cell to control how it multiplies and moves within a tissue.
“Oral administration of BI-794327, a newly developed specific blocker of TRPC6 channels, can effectively reverse, at least in part, established experimental PH in mice,” the researchers concluded, adding that “more clinical studies in patients with PH are needed to define the therapeutic potential of inhibition of TRPC6 channels or BI-749327 … on different subgroups of PH.”
About the Author
