Page last updated: 2024-10-24

regulation of the force of heart contraction by chemical signal

Definition

Target type: biologicalprocess

The regulation of the force of heart muscle contraction mediated by chemical signaling, hormonal, autocrine or paracrine. [GOC:mtg_cardio, GOC:rl]

The force of heart contraction, or cardiac contractility, is meticulously regulated by a complex interplay of chemical signals. This intricate process involves a cascade of events that ultimately influence the interaction between the contractile proteins, actin and myosin, within cardiac muscle cells (cardiomyocytes). Here's a detailed breakdown:

**1. Calcium as the Key Player:**

- **Calcium influx:** The arrival of an action potential at the sarcolemma (cell membrane) of a cardiomyocyte triggers the opening of voltage-gated calcium channels. This allows a small influx of calcium ions from the extracellular space into the cell.
- **Calcium-induced calcium release:** This small influx of calcium binds to ryanodine receptors located on the sarcoplasmic reticulum (SR), a specialized intracellular calcium store. This binding initiates a cascade of events leading to the release of a much larger amount of calcium from the SR into the cytoplasm.

**2. The Role of Troponin and Tropomyosin:**

- **Troponin complex:** Calcium ions bind to the troponin complex, which comprises three subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT).
- **Tropomyosin shift:** The binding of calcium to TnC triggers a conformational change in the troponin complex, causing it to move tropomyosin away from the binding sites on actin filaments. This "unblocking" of the binding sites allows myosin to interact with actin.

**3. Cross-Bridge Cycling and Contraction:**

- **Myosin-actin interaction:** With tropomyosin out of the way, myosin heads can bind to actin filaments, forming cross-bridges.
- **Power stroke:** ATP hydrolysis by myosin provides the energy for the myosin head to swivel, pulling the actin filaments towards the center of the sarcomere, the basic contractile unit of the muscle.
- **Cross-bridge detachment:** The binding of another ATP molecule to the myosin head causes it to detach from the actin filament, completing the cross-bridge cycle. This cycle repeats, leading to the shortening of the sarcomere and ultimately the contraction of the cardiomyocyte.

**4. Regulation by Chemical Signals:**

- **Catecholamines (epinephrine and norepinephrine):** Released from the adrenal glands and sympathetic nerve endings, these hormones bind to beta-adrenergic receptors on cardiomyocytes. This activation leads to the production of cAMP, which activates protein kinase A (PKA). PKA phosphorylates several proteins, including:
- **L-type calcium channels:** This increases calcium influx into the cell, enhancing the force of contraction.
- **Phospholamban:** This protein inhibits the SR Ca2+-ATPase pump. When phosphorylated, its inhibitory action is reduced, leading to faster calcium reuptake into the SR, which allows for more rapid relaxation and a faster heart rate.
- **Acetylcholine:** Released from parasympathetic nerve endings, acetylcholine binds to muscarinic receptors on cardiomyocytes. This activates a signaling pathway that inhibits cAMP production and ultimately reduces the force of contraction.

**5. Other Factors Influencing Contractility:**

- **Intracellular calcium concentration:** The amount of calcium released from the SR directly influences the force of contraction. Factors that increase intracellular calcium concentration, such as increased sympathetic stimulation or higher heart rate, increase contractility.
- **Length-tension relationship:** The force of contraction is also dependent on the initial length of the sarcomere. Optimal force is generated at an intermediate length, reflecting the optimal overlap between actin and myosin filaments.
- **Muscle fatigue:** Prolonged and intense contractions can lead to depletion of ATP and accumulation of metabolic byproducts, ultimately reducing contractility.

**6. Clinical Relevance:**

- **Cardiac disease:** Many cardiovascular diseases involve alterations in the regulation of cardiac contractility. For instance, heart failure can result from weakened contractility, while hypertrophic cardiomyopathy can be caused by excessive contractility.
- **Pharmaceuticals:** Many drugs target the mechanisms of contractility regulation for therapeutic purposes. For example, beta-blockers are used to reduce heart rate and contractility in patients with hypertension, while calcium channel blockers are used to reduce calcium influx and treat conditions like angina.

Understanding the intricate regulation of cardiac contractility is crucial for comprehending normal heart function and for developing effective treatments for heart disease.'
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Proteins (1)

ProteinDefinitionTaxonomy
Nitric oxide synthase, endothelialA nitric oxide synthase 3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P29474]Homo sapiens (human)

Compounds (21)

CompoundDefinitionClassesRoles
n-(3-(aminomethyl)benzyl)acetamidineN-(3-(aminomethyl)benzyl)acetamidine: structure in first source

N-[3-(aminomethyl)benzyl]acetamidine : An aralkylamine that is Nbenzylacetamidine substituted at position 3 on the benzene ring by an aminomethyl group. An inhibitor of nitric oxide synthase.
aralkylamine;
carboxamidine;
primary amino compound
angiogenesis inhibitor;
EC 1.14.13.39 (nitric oxide synthase) inhibitor;
geroprotector
2-amino-4-picoline2-amino-4-picoline: RN given refers to parent cpd
7-nitroindazole7-nitroindazole: an inhibitor of nitric oxide synthase; exhibits anti-nociceptive activity without increasing blood pressure
pimagedineaminoguanidine : A one-carbon compound whose unique structure renders it capable of acting as a derivative of hydrazine, guanidine or formamide.

pimagedine: diamine oxidase & nitric oxide synthase inhibitor; an advanced glycosylation end product inhibitor; used in the treatment of diabetic complications; structure
guanidines;
one-carbon compound
EC 1.14.13.39 (nitric oxide synthase) inhibitor;
EC 1.4.3.4 (monoamine oxidase) inhibitor
etironetiron: a nitric oxide synthase inhibitor; RN given refers to parent cpd; structure
s-methylisothiopseudouroniumS-methylisothiopseudouronium: inhibits nitric oxide synthase; structure in first source
alpha-aminopyridinealpha-aminopyridine: RN given refers to parent cpd; structure in Merck Index, 9th ed, #485

aminopyridine : Compounds containing a pyridine skeleton substituted by one or more amine groups.
2-amino-3-methylpyridine2-amino-3-methylpyridine: structure in first source
2-aminothiazoline2-aminothiazoline: RN given refers to parent cpd; structure in first source & in Negwer, 5th ed, #97

4,5-dihydro-1,3-thiazol-2-amine : A 1,3-thiazole that is 4,5-dihydro-1,3-thiazole substituted by an amino group at position 2.
1,3-thiazoles;
primary amino compound
ng-nitroarginine methyl esterNG-Nitroarginine Methyl Ester: A non-selective inhibitor of nitric oxide synthase. It has been used experimentally to induce hypertension.alpha-amino acid ester;
L-arginine derivative;
methyl ester;
N-nitro compound
EC 1.14.13.39 (nitric oxide synthase) inhibitor
1-aminoisoquinoline
s-methylthiocitrullineS-methyl-L-thiocitrulline : An L-arginine derivative in which the guanidino NH2 group of L-arginine is replaced by a methylsufanyl group.

S-methylthiocitrulline: a nitric oxide synthase inhibitor; structure in first source
imidothiocarbamic ester;
L-arginine derivative;
L-ornithine derivative;
non-proteinogenic L-alpha-amino acid
EC 1.14.13.39 (nitric oxide synthase) inhibitor;
neuroprotective agent
n(g)-iminoethylornithineL-alpha-amino acid
omega-n-methylarginineN(omega)-methyl-L-arginine : A L-arginine derivative with a N(omega)-methyl substituent.

omega-N-Methylarginine: A competitive inhibitor of nitric oxide synthetase.
amino acid zwitterion;
arginine derivative;
guanidines;
L-arginine derivative;
non-proteinogenic L-alpha-amino acid
ng-nitroarginine methyl esterN(gamma)-nitro-L-arginine methyl ester hydrochloride : A hydrochloride obtained by combining N(gamma)-nitro-L-arginine methyl ester with one equivalent of hydrochloric acid.hydrochlorideEC 1.14.13.39 (nitric oxide synthase) inhibitor
delta-n-methylarginineN(5)-methyl-L-arginine : A non-proteinogenic L-alpha-amino acid that is L-arginine substituted by a methyl group at N(5)-position.guanidines;
L-arginine derivative;
non-proteinogenic L-alpha-amino acid
2-amino-5,6-dihydro-4h-1,3-thiazine2-amino-5,6-dihydro-4H-1,3-thiazine: RN given refers to parent cpd
nitroarginineN(gamma)-nitro-L-arginine : An L-arginine derivative that is L-arginine in which the terminal nitrogen of the guanidyl group is replaced by a nitro group.

Nitroarginine: An inhibitor of nitric oxide synthetase which has been shown to prevent glutamate toxicity. Nitroarginine has been experimentally tested for its ability to prevent ammonia toxicity and ammonia-induced alterations in brain energy and ammonia metabolites. (Neurochem Res 1995:200(4):451-6)
guanidines;
L-arginine derivative;
N-nitro compound;
non-proteinogenic L-alpha-amino acid
arl 17477
n(6)-(1-iminoethyl)lysineN(6)-acetimidoyl-L-lysine : An L-lysine derivative that is L-lysine in which one of the hydrogens attached to N(6) is substituted by an acetimidoyl groupL-lysine derivative;
non-proteinogenic L-alpha-amino acid
gw 274150