Related Research Articles
Cardiac glycosides are a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by inhibiting the cellular sodium-potassium ATPase pump. Their beneficial medical uses are as treatments for congestive heart failure and cardiac arrhythmias; however, their relative toxicity prevents them from being widely used. Most commonly found as secondary metabolites in several plants such as foxglove plants, these compounds nevertheless have a diverse range of biochemical effects regarding cardiac cell function and have also been suggested for use in cancer treatment.
The sodium–potassium pump is an enzyme found in the membrane of all animal cells. It performs several functions in cell physiology.
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger). Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.
SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.
The cardiac action potential is a brief change in voltage across the cell membrane of heart cells. This is caused by the movement of charged atoms between the inside and outside of the cell, through proteins called ion channels. The cardiac action potential differs from action potentials found in other types of electrically excitable cells, such as nerves. Action potentials also vary within the heart; this is due to the presence of different ion channels in different cells.
Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding something heavy in the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.
Cerberin is a type of cardiac glycoside, a steroidal class found in the seeds of the dicotyledonous angiosperm genus Cerbera; including the suicide tree and the sea mango. This class includes digitalis-like agents, channel-blockers that as a group have found historic uses as cardiac treatments, but which at higher doses are extremely toxic; in the case of cerberin, consumption of the C. odollam results in poisoning with presenting nausea, vomiting, and abdominal pain, often leading to death. The natural product has been structurally characterized, its toxicity is clear—it is often used as an intentional human poison in third-world countries, and accidental poisonings with fatalities have resulted from individuals even indirectly consuming the agent—but its potentially therapeutic pharmacologic properties are very poorly described.
Phospholamban, also known as PLN or PLB, is a micropeptide protein that in humans is encoded by the PLN gene. Phospholamban is a 52-amino acid integral membrane protein that regulates the calcium (Ca2+) pump in cardiac muscle cells.
T-tubules are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. With membranes that contain large concentrations of ion channels, transporters, and pumps, T-tubules permit rapid transmission of the action potential into the cell, and also play an important role in regulating cellular calcium concentration.
Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of tissue, that is, between filaments of myosin (thick) and actin (thin) tissue. The degree of binding depends upon the concentration of calcium ions in the cell. Within an in vivo intact heart, the action/response of the sympathetic nervous system is driven by precisely timed releases of a catecholamine, which is a process that determines the concentration of calcium ions in the cytosol of cardiac muscle cells. The factors causing an increase in contractility work by causing an increase in intracellular calcium ions (Ca++) during contraction.
Cardioplegia is a solution given to the heart during cardiac surgery, to minimize the damage caused by myocardial ischemia while the heart is paused.
Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high-gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high-gain CICR, which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.
The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca2+). A single calcium ion is exported for the import of three sodium ions. The exchanger exists in many different cell types and animal species. The NCX is considered one of the most important cellular mechanisms for removing Ca2+.
Ca2+ ATPase is a form of P-ATPase that transfers calcium after a muscle has contracted. The two kinds of calcium ATPase are:
The Anrep effect is an autoregulation method in which myocardial contractility increases with afterload. It was experimentally determined that increasing afterload caused a proportional linear increase in ventricular inotropy. This effect is found in denervated heart preparations, such as the Starling Preparation, and represents an intrinsic autoregulation mechanism.
Lusitropy or Lucitropy is the rate of myocardial relaxation. The increase in cytosolic calcium of cardiomyocytes via increased uptake leads to increased myocardial contractility, but the myocardial relaxation, or lusitropy, decreases. This should not be confused, however, with catecholamine-induced calcium uptake into the sarcoplasmic reticulum, which increases lusitropy.
Mydicar is a genetically targeted enzyme replacement therapy being studied for use in patients with severe heart failure. It is designed to increase the level of SERCA2a, a sarcoplasmic endoplasmic reticulum calcium (Ca2+) ATPase found in the membrane of the sarcoplasmic reticulum (SR). The SERCA2a gene is delivered to the heart via an adeno-associated viral vector. Using the α-myosin heavy chain gene promoter in the cardiac muscle cells, also called cardiomyocytes, Mydicar is able to direct the gene expression only to the heart muscle. Mydicar is being tested in a phase 2 study, in which has been compared to a placebo in 39 advanced heart failure patients. Thus far, patients treated with Mydicar have shown a 52% reduction in the risk of worsening heart failure compared to patients treated with the placebo.
Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure
Calcium buffering describes the processes which help stabilise the concentration of free calcium ions within cells, in a similar manner to how pH buffers maintain a stable concentration of hydrogen ions. The majority of calcium ions within the cell are bound to intracellular proteins, leaving a minority freely dissociated. When calcium is added to or removed from the cytoplasm by transport across the cell membrane or sarcoplasmic reticulum, calcium buffers minimise the effect on changes in cytoplasmic free calcium concentration by binding calcium to or releasing calcium from intracellular proteins. As a result, 99% of the calcium added to the cytosol of a cardiomyocyte during each cardiac cycle becomes bound to calcium buffers, creating a relatively small change in free calcium.
Cardiac excitation-contraction coupling (CardiacEC coupling) describes the series of events, from the production of an electrical impulse (action potential) to the contraction of muscles in the heart. This process is of vital importance as it allows for the heart to beat in a controlled manner, without the need for conscious input. EC coupling results in the sequential contraction of the heart muscles that allows blood to be pumped, first to the lungs (pulmonary circulation) and then around the rest of the body (systemic circulation) at a rate between 60 and 100 beats every minute, when the body is at rest. This rate can be altered, however, by nerves that work to either increase heart rate (sympathetic nerves) or decrease it (parasympathetic nerves), as the body's oxygen demands change. Ultimately, muscle contraction revolves around a charged atom (ion), calcium (Ca2+), which is responsible for converting the electrical energy of the action potential into mechanical energy (contraction) of the muscle. This is achieved in a region of the muscle cell, called the transverse tubule during a process known as calcium induced calcium release.
References
- ↑ "Chapter 12". droualb.faculty.mjc.edu. Modesto Junior College. Archived from the original on 2013-03-21. Retrieved 28 December 2020.
- ↑ Noble, M. I. (1988). An introduction to modern work on the Bowditch phenomenon. Cardiovascular Research, 22(8), 586-586. doi:10.1093/cvr/22.8.586
- 1 2 3 Physiology at a Glance, Second Edition (2008) — Jeremy Ward & Roger Linden
- ↑ Boron, Walter; Boulpaep, Emile (2017). Medical Physiology. Philadelphia: Elsevier. p. 528. ISBN 978-0-323-42796-8.
- 1 2 3 Usman, Abira; Gupta, Gunjan (2020), "Physiology, Bowditch Effect", StatPearls, StatPearls Publishing, PMID 30725706 , retrieved 2020-02-20
- ↑ Balcazar, Darío; Regge, Victoria; Santalla, Manuela; Meyer, Heiko; Paululat, Achim; Mattiazzi, Alicia; Ferrero, Paola (December 2018). "SERCA is critical to control the Bowditch effect in the heart". Scientific Reports. 8 (1): 12447. Bibcode:2018NatSR...812447B. doi:10.1038/s41598-018-30638-9. ISSN 2045-2322. PMC 6102201 . PMID 30127403.
- ↑ Ker, James (February 2009). "From Bowditch to beta-blockers: evolution of the understanding of the importance of heart rate and myocardial energetics in cardiomyopathy". Cardiovascular Journal of Africa. 20 (1): 37–38. ISSN 1995-1892. PMC 4200567 . PMID 19287814.