Study Explains How Cardiac Drugs Lower Blood Pressure

Mice lacking the gene for production of RGS2 are hypertensive and prone to heart failure, and several rare human mutations that speed RGS2 degradation have been identified in hypertensive patients. Therefore, drugs that would increase RGS2 protein levels could be beneficial.

Investigators at the University of Michigan (Ann Arbor, USA) utilized a beta-galactosidase complementation method to screen several thousand compounds with known pharmacological function for those that increase RGS2 protein levels.

They reported in the June 13, 2012, online edition of the journal Molecular Pharmacology that several cardiotonic steroids (CTS), including ouabain and digoxin increased RGS2 but not RGS4 protein levels. CTS increased RGS2 protein levels through a posttranscriptional mechanism by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment while protein levels were increased two to three fold. In other words, the drugs prevented breakdown of RGS2, but did not stimulate increased RGS2 production. In vivo treatment with digoxin led to increased RGS2 protein levels in both heart and kidney.

“In addition to test tube studies, low dose digoxin, the active ingredient of digitalis, was able to increase RGS2 levels in the heart and kidney,” said senior author Dr. Rick Neubig, professor of pharmacology at the University of Michigan. “This new action of digoxin could help explain the fact that low doses seem to improve the survival of heart failure patients. It also suggests new uses for low dose digoxin or other drugs that can activate this protective mechanism.”

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