Some drugs for hypertension, such as so-called ACE inhibitors, block specific receptor proteins on the cell. But researchers at Jefferson Medical College instead have looked to a certain molecular pathway called the Gq signaling pathway, showing that it plays an important role in developing various models of hypertension. The work might lead to new insights into the roots of hypertension, and eventually, the scientists believe, novel therapies.
Andrea Eckhart, Ph.D., associate professor of medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia and her co-workers focused on drugs known as alpha-adrenergic receptor blockers and angiotensin II receptor blockers (including ACE inhibitors), which block angiotensin over-production, and which can lead to high blood pressure. Both of these receptors normally bind to a class of receptors called Gq, which ultimately leads to hypertension.
"We thought that if we could somehow block all of the receptors bound to this Gq coupled protein, then instead of hitting each receptor individually, we could knock them all out with a specific inhibitor," explains Dr. Eckhart, who presented her team's results this week at the American Heart Association's Scientific Sessions 2004 in New Orleans.
Dr. Eckhart, who is director of the Eugene Feiner Laboratory in the Center for Translational Medicine in the Department of Medicine at Jefferson Medical College, and her team subsequently developed a Gq inhibitor and tested it in various mouse models of hypertension. They looked at two particular receptor proteins called GRK2 and GRK5, which are both linked to high blood pressure in human and animal models. They overexpressed the genes for GRK2 and GRK5, causing hypertension in mice.
When they mated the GRK2 mouse with a mouse with a genetic inhibition of Gq, the resulting offspring had lower blood pressure. But when the researchers mated the GRK5 mouse with a mouse with a Gq inhibition, the offspring's blood pressure didn't change.
"This finding suggests that the overexpression of both proteins leads to different pathways causing high blood pressure," she says. According to Dr. Eckhart, finding the right kind of drug for patients is difficult without knowing the underlying causes of the high blood pressure. Because potential contributing factors can include obesity, genetics, and other lifestyle factors such as smoking and diet, patients often are taking several drugs at once.
"The Gq pathway is a good molecular tool that allows us to start looking in the laboratory at discerning different pathways underlying high blood pressure," she says. "It also might provide insights on developing potential therapeutic strategies especially relevant for individuals taking more than one drug at a time."