The heart receives nerve input from several nerves. Some of these inputs come from the branches of the autonomic nervous system. If that sounds cryptic, just think of the word “automatic.” In other words, the things your body does without you consciously thinking about it are largely directed by the autonomic nervous system: digestion, breathing, the beating of your heart, and so on are all things that our body does without us consciously thinking about it.
The autonomic nervous system consists of two branches, the sympathetic and the parasympathetic branches of the autonomic nervous system. With respect to the heart, the sympathetic nerve inputs to the heart accelerate the heart beat and the force of the heart’s contractions. The parasympathetic inputs to the heart slow the heartbeat, but do not have any direct effect on the force of the heart’s contractions.
The sympathetic nerves that connect to the heart release the neurotransmitters epinephrine and norepinephrine. These neurotransmitters bind to receptors on the surface of heart muscle cells in order to elicit their stimulatory responses. The receptors that bind epinephrine and norepinephrine are called “adrenergic” receptors because they bind epinephrine, which used to be called “adrenaline.” When pharmacists talk about “adrenergic” stimulation, they mean receptors that bind to epinephrine and norepinephrine (for the sake of brevity, I am going to abbreviate these two molecules as Epi/NE).
Now if all this seems confusing, I am sorry, but it is going to get worse. You see there are different flavors of adrenergic receptors. There are alpha and beta adrenergic receptors. Both alpha and beta adrenergic receptors bind Ep/NE, but the specific responses they elicit can differ, depending on the cell and the machinery it has to respond to the bound receptor. A quick example might help make this clear. If you get an asthma attack, you can breathe in a product called Primatene Mist, which is simply aerosolized epinephrine. Epi, in your lungs, causes the smooth muscles that surround your breathing passages to relax and your breathing passages dilate. This allows you to breath much more easily. However, that same molecule, Epi, will cause your heart to beat faster and harder. The same molecule – Epi – elicits two completely distinct responses from two tissues. This is due to the fact that the heart has one type of adrenergic receptor on the surfaces of its cells (so-called beta1 adrenergic receptors), and the bronchial smooth muscle has a distinct beta adrenergic receptor the on the surfaces of its cells (so-called beta2 adrenergic receptors).
I realize that this is a very long introduction, but it is necessary in order to talk about the paper that I found. In this paper, scientists in Mark Sussman’s laboratory at the San Diego Heart Research Institute have examined cardiac progenitor cells (CPCs) from male mice and their response to beta adrenergic stimulation. You see, once we are born, adrenergic stimulation causes the heart to grow and mature. However, once the heart muscle cells mature, this stimulation no longer causes the heart to enlarge in the same way that heart normally does shortly after birth, although the heart is still capable of remodeling in response to constant aerobic exercise. However, after a heart attack, the secretion of Epi/Ne tends to drive deterioration of the heart. Therefore, a common drug strategy to treat heart attack patients is to prescribe a class of drugs called “beta blockers,” which protect the heart from the deleterious effects of adrenergic stimulation after a heart attack. However, the effects of adrenergic stimulation on CPCs is unknown, and Sussman’s laboratory used cultured CPCs to determine the effects of adrenergic stimulation on CPCs.
CPCs are a stem cell population that resides in the heart. A respectable corpus of literature has shown that CPCs can differentiate into various heart-specific cell types and replace dying heart muscle. Our hearts do not recover properly after a heart attack because the CPCs healing capacities are overwhelmed after a heart attack (See Leri A, Kajstura J, and Anversa P, Circulation Research 109 (2011) 941-61 for an excellent summary of the physiological tasks performed by CPCs).
In the Sussman paper, cultured CPCs from mice and humans were cultured in the laboratory. It was quickly discovered that CPCs do NOT express beta1 adrenergic receptors on their surfaces, but beta2 adrenergic receptors. You might smirk and this and say “so what?” However this is significant for the following reason: Early in their lives, heart muscle cells expression beta2 adrenergic receptors, but they later switch to exclusive expression of beta1 adrenergic receptors. They express beta2 adrenergic receptors during that time when they can rapidly divide and respond to the needs of the heart. CPCs express beta 2 adrenergic receptors only when they are in their undifferentiated state. Once they differentiate, they switch to beta1 adrenergic receptors.
Secondly, Sussman and his crew discovered that stimulation of the beta2 adrenergic receptors on the surfaces of CPCs caused them to divide. Sussman and others used a molecule called fenoterol, which binds very tightly to beta2 adrenergic receptors and activates them.
Third, once the CPCs were differentiated into heart muscle cells, they no longer expressed beta2 adrenergic receptors, but expressed beta 1 adrenergic receptors. Did this change the response of the cells to adrenergic stimulation? YES. Instead of dividing in response to adrenergic stimulation, the cells were much more sensitive to dying. To make sure that this result was not a fluke, Sussman and others engineered CPCs to express beta1 adrenergic receptors, and, sure enough, those cells were also sensitized to cell death upon expression of beta1 adrenergic receptor.
This is all fine and dandy for a culture dish, but can this make a difference in a living animal? Sussman used a specific mouse strain called TOT. These mice have a special pathology in that their hearts enlarge and start to not work very well once they are exposed to large quantities of Epi/NE. Can beta blockers prevent this enlargement of the heart in TOT mice? It definitely can. However, Sussman wanted to know what happened to the CPCs. Therefore, they broke the mice into three groups. Two groups received metoprolol and the third did not. Then four weeks later, one TOT mouse group that had received metoprolol and another that had not received transplantations of marked CPCs into their hearts (the CPCs glowed). Then they examined the CPCs two weeks after the implantation. The CPCs in non-metoprolol-treated TOT mice took a beating. However, in the metoprolol-treated mice, the CPCs were three times more prevalent and showed overall lower levels of programmed cell death. There was less DNA synthesis in the hearts of metoprolol-treated animals, indicating that there was less of a need for replacement of dead cells.
These results indicate that beta blockers do more than protect the heart from excessive Epi/NE after a heart attack. They also protect the CPCs in the heart, and that could be an even more significant contribution to the life of the heart after a heart attack. It is might be possible to direct or even augment the activity of CPCs in the heart after a heart attack to accelerate cardiac healing. That would be a tremendous step in cardiac healing.