How one of the oldest drugs for high blood pressure and a standard treatment for preeclampsia works at molecular level was unknown till now. It's not a surprise or uncommon as about 10% - 20% of drugs have unknown mechanism of action.
This finding not only unravelled how it works but also they made another surprising discovery of another possible use of the drug.
“Hydralazine is one of the earliest vasodilators ever developed, and it’s still a first-line treatment for preeclampsia—a hypertensive disorder that accounts for 5-15% of maternal deaths worldwide,” says Kyosuke Shishikura, a physician-scientist at the University of Pennsylvania. “It came from a ‘pre-target’ era of drug discovery, when researchers relied on what they saw in patients first and only later tried to explain the biology behind it.”
Shishikura, his postdoctoral adviser at Penn, Megan Matthews, and their collaborators have now resolved this long-standing mystery.
The team discovered that hydralazine inhibits an oxygen-sensing enzyme called 2-aminoethanethiol dioxygenase (ADO), which acts as a molecular switch that signals blood vessels when to constrict.
“ADO is like an alarm bell that rings the moment oxygen starts to fall,” Matthews says. “Most systems in the body take time; they have to copy DNA, make RNA, and build new proteins. ADO skips all that. It flips a biochemical switch in seconds.”
Hydralazine works by binding to ADO and blocking its activity, effectively “muting” this oxygen alarm. With the enzyme shut down, the signaling proteins it normally breaks down—known as regulators of G-protein signaling (RGS)—remain stable.
The buildup of RGS proteins, says Shishikura, tells the blood vessels to stop constricting, effectively overriding the “squeeze” signal. This reduces intracellular calcium levels, which he calls the “master regulator of vascular tension.” As calcium levels fall, the smooth muscles in blood vessel walls relax, causing vasodilation and a drop in blood pressure.
To see if hydralazine was a contender, Shishikura worked closely with structural biochemists at the University of Texas, who used X-ray crystallography, a high-resolution imaging technique, to visualize hydralazine bound to ADO’s metal center, and with neuroscientists at the University of Florida, who tested the drug’s effects in brain cancer cells.
They found that the ADO pathway that regulates vascular contraction also helps tumor cells survive in low-oxygen environments. Unlike chemotherapy, which aims to kill all cells outright, hydralazine disrupted that oxygen-sensing loop, triggering cellular “senescence,” or a dormant, non-dividing state in glioblastoma cells, effectively pausing growth without triggering further inflammation or resistance.
This finding not only unravelled how it works but also they made another surprising discovery of another possible use of the drug.
“Hydralazine is one of the earliest vasodilators ever developed, and it’s still a first-line treatment for preeclampsia—a hypertensive disorder that accounts for 5-15% of maternal deaths worldwide,” says Kyosuke Shishikura, a physician-scientist at the University of Pennsylvania. “It came from a ‘pre-target’ era of drug discovery, when researchers relied on what they saw in patients first and only later tried to explain the biology behind it.”
Shishikura, his postdoctoral adviser at Penn, Megan Matthews, and their collaborators have now resolved this long-standing mystery.
The team discovered that hydralazine inhibits an oxygen-sensing enzyme called 2-aminoethanethiol dioxygenase (ADO), which acts as a molecular switch that signals blood vessels when to constrict.
“ADO is like an alarm bell that rings the moment oxygen starts to fall,” Matthews says. “Most systems in the body take time; they have to copy DNA, make RNA, and build new proteins. ADO skips all that. It flips a biochemical switch in seconds.”
Hydralazine works by binding to ADO and blocking its activity, effectively “muting” this oxygen alarm. With the enzyme shut down, the signaling proteins it normally breaks down—known as regulators of G-protein signaling (RGS)—remain stable.
The buildup of RGS proteins, says Shishikura, tells the blood vessels to stop constricting, effectively overriding the “squeeze” signal. This reduces intracellular calcium levels, which he calls the “master regulator of vascular tension.” As calcium levels fall, the smooth muscles in blood vessel walls relax, causing vasodilation and a drop in blood pressure.
From preeclampsia to brain cancer: A common target
Prior to this study, cancer researchers and clinicians had begun to suspect that ADO was important in glioblastoma, where tumors often have to survive in pockets of very low oxygen, Shishikura explains. Elevated levels of ADO and its metabolic products had been linked with more aggressive disease, suggesting that shutting this enzyme down could be a powerful strategy, but no one had a good inhibitor to test that idea.To see if hydralazine was a contender, Shishikura worked closely with structural biochemists at the University of Texas, who used X-ray crystallography, a high-resolution imaging technique, to visualize hydralazine bound to ADO’s metal center, and with neuroscientists at the University of Florida, who tested the drug’s effects in brain cancer cells.
They found that the ADO pathway that regulates vascular contraction also helps tumor cells survive in low-oxygen environments. Unlike chemotherapy, which aims to kill all cells outright, hydralazine disrupted that oxygen-sensing loop, triggering cellular “senescence,” or a dormant, non-dividing state in glioblastoma cells, effectively pausing growth without triggering further inflammation or resistance.
