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An inotrope^{[help 1]} is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.

The term inotropic state is most commonly used in reference to various drugs that affect the strength of contraction of heart muscle (myocardial contractility). However, it can also refer to pathological conditions. For example, enlarged heart muscle (ventricular hypertrophy) can increase inotropic state, whereas dead heart muscle (myocardial infarction) can decrease it.

Medical uses

Both positive and negative inotropes are used in the management of various cardiovascular conditions. The choice of agent depends largely on specific pharmacological effects of individual agents with respect to the condition. One of the most important factors affecting inotropic state is the level of calcium in the cytoplasm of the muscle cell. Positive inotropes usually increase this level, while negative inotropes decrease it. However, not all positive and negative drugs affect calcium release, and, among those that do, the mechanism for manipulating the calcium level can differ from drug to drug.

While it is often recommended that vasopressors are given through a central line due to the risk of local tissue injury if the medication enters the local tissue, they are likely safe when given for less than two hours in a good peripheral iv.^[6]

Positive inotropic agents

By increasing the concentration of intracellular calcium or increasing the sensitivity of receptor proteins to calcium, positive inotropic agents can increase myocardial contractility.^[7] Concentrations of intracellular calcium can be increased by increasing influx into the cell or stimulating release from the sarcoplasmic reticulum.^[8]

Once in the cell, calcium can pass through one of two channels: the L-type calcium channel (long-lasting) and the T-type calcium channel (transient). These channels respond to voltage changes across the membrane differently: L-type channels respond to higher membrane potentials, open more slowly, and remain open longer than T-type channels.

Because of these properties, L-type channels are important in sustaining an action potential, while T-type channels are important in initiating them.^[9]

By increasing intracellular calcium, via the action of the L-type channels, the action potential can be sustained for longer and therefore, contractility increases.

Positive inotropes are used to support cardiac function in conditions such as decompensated congestive heart failure, cardiogenic shock, septic shock, myocardial infarction, cardiomyopathy, etc.

Examples of positive inotropic agents include:

Digoxin
Amiodarone
Berberine
Calcium
Calcium sensitisers
- Levosimendan
Cardiac myosin activators
- Omecamtiv
Catecholamines
- Dopamine
- Dobutamine
- Dopexamine
- Epinephrine (adrenaline)
- Isoprenaline (isoproterenol)
- Norepinephrine (noradrenaline)
Angiotensin II
Eicosanoids
- Prostaglandins^[10]
Phosphodiesterase inhibitors
- Enoximone
- Milrinone
- Amrinone
- Theophylline
Glucagon
Insulin

Negative inotropic agents

Negative inotropic agents decrease myocardial contractility, and are used to decrease cardiac workload in conditions such as angina. While negative inotropism may precipitate or exacerbate heart failure, certain beta blockers (e.g. carvedilol, bisoprolol and metoprolol) have been believed to reduce morbidity and mortality in congestive heart failure. Quite recently, however, the effectiveness of beta blockers has come under renewed critical scientific scrutiny.^{[citation needed]}

Examples of negative inotropic agents include:

Beta blockers
Calcium channel blockers
- Diltiazem
- Verapamil
- Clevidipine

Class IA antiarrhythmics such as

Quinidine
Procainamide
Disopyramide

Class IC antiarrhythmics such as

Flecainide

Notes

^ The word inotrope is ISV via New Latin, from Greek in-, fibre or sinew, plus -trope, turning or moving. The prevalent pronunciations are /ˈaɪnəˌtroʊp, -noʊ-/^[1]^[2] and /ˈɪnəˌtroʊp, -noʊ-/,^[3]^[4] with /ˈiːnəˌtroʊp, -noʊ-/^[2]^[5] being less common.

References

^ Merriam-Webster, Merriam-Webster's Collegiate Dictionary, Merriam-Webster.
^ ^a ^b Houghton Mifflin Harcourt, The American Heritage Dictionary of the English Language, Houghton Mifflin Harcourt.
^ Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier.
^ Wolters Kluwer, Stedman's Medical Dictionary, Wolters Kluwer.
^ Merriam-Webster, Merriam-Webster's Medical Dictionary, Merriam-Webster.
^ Loubani, OM; Green, RS (June 2015). "A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters.". Journal of critical care. 30 (3): 653.e9–17. PMID 25669592. doi:10.1016/j.jcrc.2015.01.014.
^ Gordon, DVM, DVSc, DACVIM (Cardiology), Sonya; Saunders, DVM, DACVIM (Cardiology), Ashley (November 2015). "Positive Inotropes". The Merck Veterinary Manual. Retrieved 2016-11-28.
^ Berry, William; McKenzie, Catherine (2010-01-01). "Use of inotropes in critical care". Clinical Pharmacist. 2: 395. Retrieved 2016-11-28.
^ Sherwood, L (2008). Human Physiology, From Cells to Systems (7 ed.). ISBN 9780495391845. |access-date= requires |url= (help)
^ Schrör K, Hohlfeld T (1992). "Inotropic actions of eicosanoids". Basic Res. Cardiol. 87 (1): 2–11. PMID 1314558. doi:10.1007/BF00795384.

UpToDate Contents

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1. 昇圧剤および強心剤の使用 use of vasopressors and inotropes
2. 駆出率低下を伴う心不全における強心剤 inotropic agents in heart failure with reduced ejection fraction
3. Inhalation anesthetic agents
4. 心臓手術施行患者の術後合併症 postoperative complications among patients undergoing cardiac surgery
5. カルシウム拮抗剤中毒 calcium channel blocker poisoning

English Journal

Alpha-2 adrenoceptors and imidazoline receptors in cardiomyocytes mediate counterbalancing effect of agmatine on NO synthesis and intracellular calcium handling.

Maltsev AV1, Kokoz YM2, Evdokimovskii EV3, Pimenov OY4, Reyes S5, Alekseev AE6.Author information 1Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: goicr@rambler.ru.2Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: malat_88@mail.ru.3Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: onletaet@gmail.com.4Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Institutskaya 3, Pushchino, Moscow Region 142290, Russia. Electronic address: poleg237@rambler.ru.5Division of Cardiovascular Diseases, Department of Molecular Pharmacology and Experimental Therapeutics, Stabile 5, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA. Electronic address: reyesramirez.santiago@mayo.edu.6Division of Cardiovascular Diseases, Department of Molecular Pharmacology and Experimental Therapeutics, Stabile 5, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA. Electronic address: alekseev.alexey@mayo.edu.AbstractEvidence suggests that intracellular Ca(2+) levels and contractility of cardiomyocytes can be modulated by targeting receptors other than already identified adrenergic or non-adrenergic sarcolemmal receptors. This study uncovers the presence in myocardial cells of adrenergic α2 (α2-AR) and imidazoline I1 (I1R) receptors. In isolated left ventricular myocytes generating stationary spontaneous Ca(2+) transients in the absence of triggered action potentials, the prototypic agonist of both receptors agmatine can activate corresponding signaling cascades with opposing outcomes on nitric oxide (NO) synthesis and intracellular Ca(2+) handling. Specifically, activation of α2-AR signaling through PI3 kinase and Akt/protein kinase B stimulates NO production and abolishes Ca(2+) transients, while targeting of I1R signaling via phosphatidylcholine-specific phospholipase C (PC-PLC) and protein kinase C (PKC) suppresses NO synthesis and elevates averaged intracellular Ca(2+). We identified that endothelial NO synthase (eNOS) is a major effector for both signaling cascades. According to the established eNOS transitions between active (Akt-dependent) and inactive (PKC-dependent) conformations, we suggest that balance between α2-AR and I1R signaling pathways sets eNOS activity, which by defining operational states of myocellular sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) can adjust Ca(2+) re-uptake and thereby cardiac inotropy. These results indicate that the conventional catalog of cardiomyocyte sarcolemmal receptors should be expanded by the α2-AR and I1R populations, unveiling previously unrecognized targets for endogenous ligands as well as for existing and potential pharmacological agents in cardiovascular medicine.
Journal of molecular and cellular cardiology.J Mol Cell Cardiol.2014 Mar;68:66-74. doi: 10.1016/j.yjmcc.2013.12.030. Epub 2014 Jan 9.
Evidence suggests that intracellular Ca(2+) levels and contractility of cardiomyocytes can be modulated by targeting receptors other than already identified adrenergic or non-adrenergic sarcolemmal receptors. This study uncovers the presence in myocardial cells of adrenergic α2 (α2-AR) and imidazo
PMID 24412533

PDE3-inhibition by levosimendan is sufficient to account for its inotropic effect in failing human heart.

Orstavik O1, Ata SH, Riise J, Dahl CP, Andersen GO, Levy FO, Skomedal T, Osnes JB, Qvigstad E.Author information 1Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway; K.G. Jebsen Cardiac Research Centre, Faculty of Medicine, University of Oslo, Oslo, Norway; Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway.AbstractBACKGROUND AND PURPOSE: Levosimendan is known as a calcium-sensitiser, although it is also known to inhibit phosphodiesterase (PDE) 3. We aimed to isolate each component and estimate their contribution to increased contractility.
British journal of pharmacology.Br J Pharmacol.2014 Feb 18. doi: 10.1111/bph.12647. [Epub ahead of print]
BACKGROUND AND PURPOSE: Levosimendan is known as a calcium-sensitiser, although it is also known to inhibit phosphodiesterase (PDE) 3. We aimed to isolate each component and estimate their contribution to increased contractility.EXPERIMENTAL APPROACH: Contractile force was measured in electrically s
PMID 24547784

Resuscitation with Lipid Emulsion: Dose-dependent Recovery from Cardiac Pharmacotoxicity Requires a Cardiotonic Effect.

Fettiplace MR1, Akpa BS, Ripper R, Zider B, Lang J, Rubinstein I, Weinberg G.Author information 1From the Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois (M.R.F., R.R., and G.W.); Research and Development Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois (M.R.F., R.R., I.R., and G.W.); University of Illinois College of Medicine, Chicago, Illinois (M.R.F. and B.Z.); Department of Chemical Engineering, University of Illinois at Chicago, Chicago, Illinois (B.S.A.); University of Illinois College of Medicine, Peoria, Illinois (J.L.); and Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois (I.R.).AbstractBACKGROUND:: Recent publications have questioned the validity of the "lipid sink" theory of lipid resuscitation while others have identified sink-independent effects and posed alternative mechanisms such as hemodilution. To address these issues, the authors tested the dose-dependent response to intravenous lipid emulsion during reversal of bupivacaine-induced cardiovascular toxicity in vivo. Subsequently, the authors modeled the relative contribution of volume resuscitation, drug sequestration, inotropy and combined drug sequestration, and inotropy to this response with the use of an in silico model.
Anesthesiology.Anesthesiology.2014 Feb 3. [Epub ahead of print]
BACKGROUND:: Recent publications have questioned the validity of the "lipid sink" theory of lipid resuscitation while others have identified sink-independent effects and posed alternative mechanisms such as hemodilution. To address these issues, the authors tested the dose-dependent response to intr
PMID 24496123

Japanese Journal

Advance in the management of acute human poisonings: new treatment modalities

YANG Chen-Chang
日本毒性学会学術年会 39.2(0), AS1-1, 2012
… Timely and effective treatment is important in minimizing the mortalities associated with acute poisonings.Methods: A Medline search of literature reports relating to insulin euglycemic therapy, intravenous lipid emulsion (ILE), and extracorporeal life support (ECLS) was conducted and summarized.Results: Insulin euglycemic therapy was mainly used in the management of beta-blocker and calcium channel blocker poisonings and the mechanisms underlying the therapy include increased inotropy, increased intracellular glucose transport, and vascular dilatation. …
NAID 130005009265

H2 Receptor-Mediated Positive Inotropic Effect of Histamine in Neonatal Guinea-Pig Left Atria

Agata Naoki,Kato Yoshimitsu,Namekata Iyuki [他],Takahara Akira,Tanaka Hikaru,Chino Daisuke,Koike Katsuo,Tanaka Yoshio
Biological and Pharmaceutical Bulletin 33(12), 2033-2035, 2010
The receptor type mediating the positive inotropic effect of histamine was examined in left atria from neonatal guinea pigs. The positive inotropic effect of histamine, as well as its action potential …
NAID 130000402340

Involvement of the Na^+/Ca^<2+> Exchanger in Ouabain-Induced Inotropy and Arrhythmogenesis in Guinea-Pig Myocardium as Revealed by SEA0400

Tanaka Hikaru,Shimada Hideaki,Namekata Iyuki [他],KAWANISHI Toru,IIDA TANAKA Naoko,SHIGENOBU Koki
Journal of pharmacological sciences 103(2), 241-246, 2007-02-20
… Involvement of the Na+/Ca2+ exchanger in ouabain-induced inotropy and arrhythmogenesis was examined with a specific inhibitor, SEA0400. … In right ventricular papillary muscle isolated from guinea-pig ventricle, 1 μM SEA0400, which specifically inhibits the Na+/Ca2+ exchanger by 80%, reduced the ouabain (1 μM)-induced positive inotropy by 40%, but had no effect on the inotropy induced by 100 μM isobutyl methylxantine. …
NAID 10024312778

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