by Violet Wallerstein
On Wednesday, March 29, the RISE program hosted a guest lecturer as part of their regular lecture series, this one featuring a more biological spin. Dr. Maria Luisa Garcia came to talk about her work developing a new hypertensive drug in her presentation “Targeting the Inward-rectifier Potassium Channel ROMK in Cardiovascular Disease.” She completed her bachelor’s and doctoral degrees at the Universidad Autónoma de Madrid and did her post-doctoral training at the Roche Institute of Molecular Biology. She worked at Merck research laboratories where she retired as a distinguished senior investigator.
Hypertension, defined as having blood pressure over 140/90 mmHg, is a huge issue in the US. It also affects 25% of the adult population in industrialized countries. High blood pressure is a risk factor for a lot of other conditions such as stroke and renal disease.
There are many antihypertensives, but 15 to 20 percent of people still do not get the lower blood pressure they want to achieve. Most antihypertensives act on the kidney, as it plays a significant role in the control of blood pressure. Thiazide diuretics are the first line therapy for hypertension by blocking the renal Na+/Cl- cotransporter, which in turn lowers blood pressure, but an issue with these drugs are that they can alter the K balance.
Garcia’s work focused on targeting the renal outer medullary potassium channel (ROMK). This channel did not have any selective small molecule inhibitors known for anything in the same family in 2004 until this work was started.
The research began by studying the channel’s reaction with a radioactively labeled protein called tertiapin. The initial studies with this molecule showed that in rats that got infusions of this protein, after eight hours there was increased excretion of Na+ and increased overall urine output, which were positive results for the effectiveness of tertiapin. Further assays and experiments were conducted to test this drug, which will not be discussed here, but when the scientists were sure that this compound had the antihypertensive properties they were looking for, tests were conducted to determine the purity of their compound.
The tertiapin was determined to be 99 percent pure when it was synthesized, but it did not have the effects of the previously isolated compound. This was because the other one percent was actually responsible for the antihypertensive properties. When this one percent was enhanced and purified, it turned out it had negative effects when tested in dogs, so tertiapin was abandoned, and a new compound working on the same ROMK, MK-7145 was found.
Tests with MK-7145 were successful and moved into clinical trials and assays. For more information about the results, go to clinicaltrials.gov.
Overall, this work is important to determine a more effective antihypertensive drug in order to help those who are currently unresponsive to current treatments.