Studies with Human Cell Lines Show that Activation of the H3-Receptor Limits the Release of Arrhythmia-Causing Noradrenaline

Dec 20, 2001

When a heart attack strikes, the nerve endings in the heart release excessive amounts of the neurotransmitter noradrenaline, leading to arrhythmias, or disturbances of the heartbeat, with sometimes fatal consequences. In a just-published article in Proceedings of the National Academy of Sciences, two scientists at Weill Cornell Medical College—Drs. Roberto Levi and Randi Silver—report on studies showing how the activation of a histamine receptor, the H3-receptor, limits this release of noradrenaline via two independent systems, based on the intracellular concentrations of calcium and sodium. The research suggests a novel, potential therapeutic approach to heart attack, or to myocardial ischemia in general.

Dr. Levi, a Professor of Pharmacology, has been studying the role of the H3-receptor in myocardial ischemia (decreased blood supply to the heart) for several years. He says that while the receptor limits the release of noradrenaline in both normal states and ischemia, the receptor in normal states is "not terribly important." It is in ischemia that the receptor plays a critical role, which he and Dr. Silver, an Associate Professor of Physiology and Biophysics, have examined in two recent articles.

Role of Histamine and H3-Receptor

Histamine is a chemical found in many tissues in the body, and the H3-receptor is the third important receptor to have been discovered for it. The H1-receptor produces allergies, and blocking this receptor is how the common drugs known as antihistamines work. The H2-receptor is involved in the secretion of acid in the stomach, and its discovery has led to some common remedies for upset stomach. The H3-receptor may prove to be as important as the first two if Dr. Levi's and Dr. Silver's research leads to the fullest possible practical results.

The authors report on two main sets of experiments: with guinea pigs and with lines of human tumor cells—namely, neuroblastoma cells—which can reliably be used to stand for the heart's nerve cells. Each of these sets of experiments provides a model for the relationship between H3-receptors and noradrenaline release, and for the involvement in this relationship of intracellular sodium and calcium. With both the guinea pigs and the human cell lines, the study confirms the role of the H3-receptor in limiting the release of noradrenaline.

In addition to Drs. Levi and Silver, there is a third senior author of the latest two articles, Dr. Timothy W. Lovenberg of the R.W. Johnson Pharmaceutical Research Institute, in San Diego. Two years ago, Dr. Lovenberg cloned the H3-receptor. For the latest study, he transfected the cDNA of the H3-receptor into one subset of the neuroblastoma cells. The remaining neuroblastoma cells did not express the receptor. As Dr. Silver says, "The nice thing about this study is that you can compare exactly what the receptor is responsible for and what it's not, because you have one line of cells that doesn't express the receptor and another line of cells that does."

Key Findings and Implications

The authors observed the results of exposing the lines of neuroblastoma cells to an H3-receptor agonist (a chemical that activates the receptor) and to an H3-receptor antagonist (a chemical that blocks the receptor). The presence of the receptor proved to be necessary for the limiting of both noradrenaline release from the cells and calcium intake to the cells. The activated receptor performs its function by inhibiting the entry of sodium and calcium into the cells.

Thus, to limit the release of noradrenaline and the consequent risk of arrhythmia in the event of ischemia, the research suggests a potential strategy of stimulating the H3-receptor. Dr. Levi says, "The idea is to come up with a drug that stimulates the H3-receptor exclusively in the heart and peripheral nervous system, but not in the brain."

Of course, there already exist a number of drugs that can be taken at the time of a heart attack. Dr. Levi has previously written that stimulants of the H3-receptor do not have some of the problematical side effects of these other drugs.

Dr. Levi adds that it is important to put the relationship between arrhythmia and histamine in perspective. Severe arrhythmias can also result from the release of large amounts of histamine that occurs when there is a massive allergic reaction, such as anaphylaxis. This is because too much histamine stimulates the heart's H2-receptors, which tends to cause arrhythmia. In most myocardial ischemia, only a small amount of histamine is released in the heart, and its effect on the H3-receptors is favorable, tending to reduce the release of noradrenaline. The H3-receptor needs only a little histamine to be stimulated, whereas the H2-receptor needs much more, and the H1-receptor still more.

Besides Drs. Levi, Silver, and Lovenberg, the other authors of the article are Kumar S. Poonwasi and Nahid Seyedi of Weill Cornell's Department of Pharmacology, and Sandy J. Wilson of the R.W. Johnson Pharmaceutical Research Institute. The research was supported by the National Institutes of Health and the Underhill and Wild Wings Foundation.