Ouabain worsens diastolic sarcomere length in myocytes from a cardiomyopathy mouse model
- Resource Type
- Authors
- Christoph Maack; Lucie Carrier; Felix W. Friedrich; Johannes Bay; Frederik Flenner; Michael Kohlhaas; Silke Düsener
- Source
- European Journal of Pharmacology. 904:174170
- Subject
- Sarcomeres
0301 basic medicine
medicine.medical_specialty
Systole
Diastole
Sarcomere
Ouabain
Contractility
Mice
03 medical and health sciences
0302 clinical medicine
Internal medicine
medicine
Animals
Myocyte
Myocytes, Cardiac
Gene Knock-In Techniques
Enzyme Inhibitors
Pharmacology
Chemistry
Hypertrophic cardiomyopathy
Cardiomyopathy, Hypertrophic
medicine.disease
Myocardial Contraction
Disease Models, Animal
030104 developmental biology
Ion homeostasis
Endocrinology
Calcium
Sodium-Potassium-Exchanging ATPase
Carrier Proteins
030217 neurology & neurosurgery
Intracellular
medicine.drug
- Language
- ISSN
- 0014-2999
Diastolic dysfunction is a major feature of hypertrophic cardiomyopathy (HCM). Data from patient tissue and animal models associate increased Ca2+ sensitivity of myofilaments with altered Na+ and Ca2+ ion homeostasis in cardiomyocytes with diastolic dysfunction. In this study, we tested the acute effects of ouabain on ventricular myocytes of an HCM mouse model. The effects of ouabain on contractility and Ca2+ transients were tested in intact adult mouse ventricular myocytes (AMVMs) of Mybpc3-targeted knock-in (KI) and wild-type (WT) mice. Concentration-response assessment of contractile function revealed low sensitivity of AMVMs to ouabain (10 μM) compared to literature data on human cardiomyocytes (100 nM). Three hundred μM ouabain increased contraction amplitude (WT ~1.8-fold; KI ~1.5-fold) and diastolic intracellular Ca2+ in both WT and KI (+12–18%), but further decreased diastolic sarcomere length in KI cardiomyocytes (−5%). Western Blot analysis of whole heart protein extracts revealed 50% lower amounts of Na+/K+ ATPase (NKA) in KI than in WT. Ouabain worsened the diastolic phenotype of KI cardiomyocytes at concentrations which did not impair WT diastolic function. Ouabain led to an elevation of intracellular Ca2+, which was poorly tolerated in KI showing already high cytosolic Ca2+ at baseline due to increased myofilament Ca2+ sensitivity. Lower amounts of NKA in KI could amplify the need to exchange excessive intracellular Na+ for Ca2+ and thereby explain the general tendency to higher diastolic Ca2+ in KI.