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Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice
06:22

Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice

Published on: September 17, 2015

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Adenylyl cyclase-mediated effects contribute to increased Isoprenaline-induced cardiac contractility in

Sebastian Uhl1, Ilka Mathar2, Rudi Vennekens3

  • 1Pharmakologisches Institut, Universität Heidelberg, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany.

Journal of Molecular and Cellular Cardiology
|June 28, 2014
PubMed

Insights

TRPM4 deficiency enhances heart muscle contraction, particularly under ATP-depleting conditions like ischemia. Inactivating TRPM4 may boost cardiac contractility in heart failure and related conditions.

Area of Science:

  • Cardiovascular Physiology
  • Ion Channel Function
  • Molecular Cardiology

Background:

  • TRPM4 and TRPM5 are Transient Receptor Potential (TRP) ion channels forming Ca(2+)-activated nonselective cation channels.
  • TRPM4 deficiency (Trpm4(-/-)) previously showed increased Isoprenaline-induced inotropy due to faster action potential repolarization.
  • The role of TRPM4 and TRPM5 in cardiac contractility, especially under stress, requires further investigation.

Purpose of the Study:

  • To investigate the contribution of the β-adrenergic signaling cascade to augmented inotropy in TRPM4-deficient mice.
  • To determine if TRPM5 additively affects cardiac contractility using double-deficient (Trpm4/Trpm5((-/-)2)) mice.
  • To explore TRPM4's role in cardiac contractility under ATP-depleting conditions.

Main Methods:

  • Contractility measurements on isolated papillary muscles from wild type, Trpm4(-/-), and Trpm4/Trpm5((-/-)2) mice.
  • Stimulation with Isoprenaline, Forskolin (adenylyl cyclase activator), and IBMX (phosphodiesterase inhibitor).
  • Assessment of cardiac function under simulated ischemic conditions.

Main Results:

  • Isoprenaline-induced inotropy was significantly increased in Trpm4(-/-) and Trpm4/Trpm5((-/-)2) mice compared to wild type.
  • Forskolin also increased twitch force in Trpm4(-/-) preparations, but cAMP levels were comparable to wild type.
  • TRPM4 deficiency improved contractile function under simulated ischemic conditions, suggesting a role in ATP-depleting states.

Conclusions:

  • TRPM4 deficiency enhances cardiac contractility, particularly during conditions of increased catecholamine levels and ATP depletion.
  • The augmented inotropic response in TRPM4-deficient hearts is not solely due to altered cAMP accumulation but is linked to ATP hydrolysis.
  • TRPM4 inactivation presents a potential therapeutic strategy for increasing cardiac contractility in conditions like heart failure and ischemia.
Keywords:
ATPCalciumCardiac contractilityIschemic conditionsTRPM4β-Adrenergic signalling

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