From Myogenic Mechanisms to Heart Rate Control: A Deep Dive into the Heart’s Regulatory Functions

BY RAINBOW ZHAO

1. Introduction 

The human body comprises various organs, including the stomach, liver, and lungs (Wakim and Grewal, 2018). However, none of these organs can function without energy, specifically adenosine triphosphate (ATP) produced during cell respiration (BBC Bitesize, 2018). Of the two types of cell respiration, aerobic respiration allows for the mass production of ATP (BBC Bitesize, 2024). During this process, O₂ acts as an essential electron acceptor (Babcock, 1999). In essence, O₂ serves an unwavering purpose for every organ. But which organ ensures that oxygen is delivered to all the others? The heart. 

2. Anatomy and the Cardiac Cycle 

The heart is located behind the sternum and in between the lungs (Cleveland Clinic, 2024; Texas Heart Institute, 2024). It is the main organ of the cardiovascular system, with the role of pumping blood throughout the body (Chaudhry et al., 2023). The heart consists of four chambers: left and right atria and ventricles (ibid). The right atrium and ventricle receives deoxygenated blood and pumps it through the pulmonary arteries to the lungs for oxygenation of the blood (Pollock and Makaryus, 2021). Afterwards, oxygenated blood comes back through the pulmonary veins into the left atrium, and the left ventricle pumps the oxygenated blood into the aorta, delivering oxygen to the rest of the body (ibid).

Figure 1: A labeled diagram of the heart demonstrating the cardiac cycle (adapted from: Learn How the Heart Beats 2010). 

3. Cardiomyocytes 

Cardiomyocytes constitute approximately 30% of the heart’s cells, while accounting for about 70-85% of the heart’s volume (Dewing et al., 2022). There are two main types of cardiomyocytes: pacemaker and contractile (Gopalan and Kirk, 2022). In reality, the heart pumps blood by contracting, and this is achieved through contractile cardiomyocytes. On the other hand, pacemaker cardiomyocytes, or cells, don’t contract (Jakoi, 2024). Instead, they serve a different purpose. 

The heart is often described as myogenic, meaning the signal of contraction, or action potential, originates in the heart itself (Encyclopedia Britannica, 2024). The pacemaker cells are the ones capable of intrinsically generating action potentials. There are five main locations of pacemaker cells: sinoatrial (SA) node, atrioventricular (AV) node, bundle of His, bundle branches, and Purkinje fibres (Metkus, 2022). 

Figure 2: A labeled diagram of the heart showing the main locations of pacemaker cells (adapted from: EKG, ECG Interpretation, 2024) 

4. The Intrinsic Conduction System and the Heart’s Myogenic Nature

4.1 Initiating the Action Potential 

The intrinsic conduction system establishes the base sinus rhythm of the heart (Bhattacharyya and Munshi, 2020). The SA node is located in the right atria (Kashou et al., 2022). It serves as the primary pacemaker-region of the heart, containing lots of pacemaker cells (ibid). These cells are abundant in hyperpolarization-activated cyclic nucleotide–gated (HCN) channels, specifically HCN4 channels (Hennis et al., 2022). These channels are voltage-gated, and they open upon hyperpolarization (Sartiani et al., 2017). This implies that they are ‘leaky’ during the resting membrane potential of -60 mV (Levick, 1991). Once the HCN channels open, Na⁺ can enter the cell, bringing the membrane potential from -60 mV to approximately -55 mV (Manoj et al., 2023). This causes the opening of another voltage-gated channel called T-type calcium channels (TTCC) (ibid). They allow the inflow of a limited amount of Ca²⁺to bring the membrane potential to -40 mV, enough to trigger the action potential (Ono and Iijima, 2005). At this point, a third type of voltage-gated channel called L-type calcium channel (LTCC) opens up, bringing the membrane potential to +40 mV with a significant influx of Ca²⁺(Satin and Schrode, 2009). 

4.2 Propagation of the Action Potential 

The cell is now abundant in Ca²⁺. In reality, specialized junctions called intercalated discs link cardiomyocytes together (Bennett, 2018). One very important component of the intercalated disc is the gap junction (Sun et al., 2020). The gap junction is made up of channels called connexons (Mammano, 2013). With the presence of connexons, Ca²⁺in the pacemaker cell can diffuse into other nearby pacemaker cells, allowing the action potential to propagate to the other four pacemaker regions (ibid). Along the way, Ca²⁺ can also diffuse into nearby contractile cardiomyocytes to trigger contraction (ibid). The specific mechanism of this isn’t too dissimilar from that of skeletal muscles, however, it is not the main focus of this article. 

Figure 3: A labeled diagram of cardiomyocytes showing gap junctions within intercalated discs (adapted from: Cardiac Muscle Tissue, 2024). 

4.3 Alternative Pacemakers 

The SA node establishes a base sinus rhythm of 60-100 bpm (Kashou et al., 2022). When the SA node fails due to various reasons such as diseases, the AV node takes over as the secondary pacemaker (Hafeez and Grossman, 2020). The AV node, bundle of His, and bundle branches can establish a base rhythm of 40-60 bpm, whereas Purkinje fibres can establish a base rhythm of 20-40 bpm (sites.pitt.edu, 2024). Although not ideal, these pacemaker cells can serve as a temporary backup if the SA node were to fail, ensuring that blood circulation can still occur.

5. The Extrinsic Conduction System and the Regulation of Heart Rate

5.1 The Autonomic Nervous System (ANS) 

Although the heart is described as myogenic, regulation of the heart rate still relies on the extrinsic conduction system. There are two main regulators of heart rate, including the autonomic nervous system (ANS) and hormones such as epinephrine (Mano et al., 1991). The role of the ANS in regulating heart rate will be explained in greater detail. However, the hormonal regulation mechanism only differs primarily in that hormones act as ligands rather than neurotransmitters. 

The ANS is part of the peripheral nervous system in charge of regulating involuntary physiological processes (Waxenbaum et al., 2023). It is composed of three divisions, including the sympathetic nervous system (SNS), parasympathetic nervous system (PNS), and enteric nervous system (ENS) (ibid). SNS and PNS are the ones regulating heart rate (ibid). The SNS is mainly in charge of elevated activity, or ‘fight or flight’ response, whereas the PNS is in charge of relaxation, or ‘rest or digest’ processes (ibid). Therefore, it is evident that SNS helps increase the heart rate, while PNS helps decrease the heart rate. 

5.2 Sympathetic Nervous System (SNS) Increasing Heart Rate 

The SNS releases norepinephrine, which stimulates a type of G protein-coupled receptor (GPCR) called the beta-1 adrenergic receptors (β₁-AR) located on the plasma membrane of pacemaker cells along with epinephrine released from the adrenal medulla (Bylund, 2009; Cleveland Clinic, 2022; Vasudevan et al., 2011). β₁-AR then activates a stimulatory G protein (Gs) (Pandey et al., 2020). Gs has three subunits, including α, β, and γ (Purves et al., 2001). Normally, the α subunit is bound to GDP (ibid). However, when activated, the Gαs releases its guanosine diphosphate (GDP) and instead binds to guanosine triphosphate (GTP) (ibid). This results in the dissociation of the Gαs-GTP complex from the βγ dimer (ibid). 

The Gαs-GTP complex is now free to interact with and stimulate an effector enzyme called adenylyl cyclase (AC) located on the plasma membrane of the pacemaker cell (Purves et al., 2001). AC is capable of hydrolyzing ATP into cyclic adenosine monophosphate (cAMP), which in turn is capable of activating protein kinase A (PKA) (Kuszak and Sunahara, 2010). Finally, PKA phosphorylates, in other words, stimulate LTCC, resulting in the increased influx of Ca²⁺ into the pacemaker cell (Liu et al., 2021). This makes it easier for the cell to depolarize again even after hyperpolarization, and hence, result in more frequent action potentials. As a result, the rate of contraction of the cardiomyocyte increases, and ultimately, the heart rate increases. 

5.3 Parasympathetic Nervous System (PNS) Decreasing Heart Rate 

On the contrary, the PNS releases acetylcholine (Tindle and Tadi, 2022). Acetylcholine stimulates another type of GPCR called the M2 muscarinic receptors (M₂-R) located on the plasma membrane of pacemaker cells (ibid). This time, M₂-R activates an inhibitory G protein (Gi) with 3 subunits, including αi, β, and γ (Harvey and Calaghan, 2012; Villaseca et al., 2022). Identical to what happens with the stimulatory pathway, Gαi releases GDP in exchange for GTP, leading to the dissociation of the Gαi-GTP complex from the βγ dimer (Harvey and Calaghan, 2012). 

However, in the inhibitory pathway, the Gαi-GTP complex can interact with and inhibit AC (Harvey and Calaghan, 2012). This results in the decrease of intracellular Ca²⁺levels. Moreover, the βγ dimer also dissociates from the Gi (Ang et al., 2012). They can directly interact and open G protein-gated inwardly rectifying potassium (GIRK) channels located on the plasma membrane of pacemaker cells (ibid). When these channels open, K⁺ can exit the cells, causing the cell to hyperpolarize. When the cell hyperpolarizes, it becomes harder to depolarize again. Thus, action potentials will be generated less frequently, resulting in the decrease of the rate of cardiomyocyte contraction, decreasing the heart rate. 

Figure 4: A visual representation of the mechanism regulating the heart rate (adapted from: Cardiac Signal Transduction Mechanisms (G-Protein-Linked), 2024) 

It is also worth noting that although the βγ dimer also dissociates from Gs in the stimulatory pathway, it doesn’t typically interact with GIRK as that would be counter-intuitive (Tennakoon et al., 2021). Instead, it is involved in other important steps of the signaling process, such as membrane anchoring, ensuring all the essential components are at the correct location during the process (Koch et al., 1993). 

6. Importance of the Heart’s Regulatory Functions 

The regulatory functions of the heart serve a variety of purposes. The most obvious one is supplying the rest of the body with an appropriate amount of O₂ and nutrients under any given circumstances to maintain homeostasis, whether that is during sleep or exercise (Information, 2019). During exercise, the body, especially the skeletal muscles, is in demand of more nutrients such as glucose and O₂(Hargreaves et al., 2020). In order to meet this demand, the rate of gas exchange needs to increase, as well as the rate of blood flow (James, 2022). Therefore, the heart rate must also increase to meet this demand (ibid). Conversely, during sleep, the body demands less energy, therefore, there is no need to generate and expand excess energy (Cleveland Clinic, 2023). Hence, the heart rate decreases. 

Additionally, this also implies that waste products like CO₂from cell respiration are removed consistently (Patel et al., 2022). CO₂ dissolves in H₂O (which makes up nearly 90% of the blood plasma and 50% of the blood) to form HCO₃^– and H⁺, especially with the help of carbonic anhydrase in erythrocytes (Boron, 2020; National Cancer Institute, 2020). If CO₂is not excreted from the body consistently at a sufficient level, blood pH can drop to a considerable extent with the presence of H⁺(Patel et al., 2022). This can lead to hypercarbia, with symptoms such as headache, depression, and confusion (Cleveland Clinic, 2023). 

Another very important reason to regulate heart rate is to control the blood pressure (Reule and Drawz, 2012). When the heart rate is too high, this can generally lead to elevated blood pressure (ibid). The opposite leads to low blood pressure (American Heart Association, 2023). If the heart rate isn’t regulated properly, conditions such as hypertension and hypotension may result (British Heart Foundation, 2024; Reule and Drawz, 2012). 

7. Conclusion 

The heart plays a crucial role in the body, controlling blood flow and thereby ensuring the proper delivery of nutrients and O₂to all other organs, as well as maintaining homeostasis. This is accomplished by pacemaker cells setting a base sinus rhythm, with the ANS regulating it by releasing neurotransmitters such as acetylcholine and norepinephrine, thereby triggering a cascade of regulatory mechanisms. After a deep dive into the detailed mechanism behind the heart’s incredible myogenic nature, it is evident that any disruptions in these complex mechanisms can lead to a variety of health conditions, whether that has to do with the heart itself or all the other parts of the body that the heart serves. Therefore, understanding these processes offers a powerful reminder to prioritize heart health, as it is essential to our overall well-being. 

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