Influence of cyclosporine A on contractile function, calcium handling, and energetics in isolated human and rabbit myocardium
Open accessAbstract
OBJECTIVE: The immunosuppressive drug Cyclosporine A (CsA) is a key substance in pharmacological therapy following solid organ transplantation and has been suggested to prevent cardiac hypertrophy. We investigated the direct effects of CsA on myocardial function, because these are largely unknown. METHODS: In multicellular cardiac muscle preparations from end-stage failing and non-failing human hearts as well as from non-failing rabbit hearts we investigated the effects of CsA on contractile performance, sarcoplasmic reticulum (SR) Ca2+-load, cytosolic calcium transients, calcium sensitivity of the myofilaments, and myocardial oxygen consumption. RESULTS: In failing human muscle preparations there was a concentration dependent decrease in contractile force; the maximal effect amounted to 55.6+/-6.4% of control while EC50 was reached at 1.0+/-0.3 nM (n=6). These concentrations are at and even below the therapeutic plasma levels. CsA decreased the aequorin light signal in human failing trabeculae to 71.5+/-5.9% (n=5), indicating decreased calcium transients. Estimation of the SR calcium load via measurement of rapid cooling contractures revealed a decrease to 84.4+/-6.5% in failing human preparations (n=6). Measurements of both decreased SR calcium load and force development in presence of CsA were also observed in four non-failing human muscle preparations. In rabbit muscle preparations (n=8), developed force decreased to 50.2+/-7.7% (n=8, EC50: 1.9+/-0.4 nM) and rapid cooling contractures to 74.0+/-7.4% of control at 100 nmol/l CsA. No direct effects were observed on myofilament calcium sensitivity nor on maximal force development of permeabilized preparations from the rabbit (n=7). Oxygen consumption measurements showed that CsA decreased the economy of contraction to 76.4+/-7.9% in rabbit preparations (n=8). CONCLUSIONS: CsA causes a direct cardio-depressive effect at clinically relevant concentrations, most likely due to altered handling of Ca2+ by the SR.
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In vitro contraction assessment in human cardiac tissue is a valuable tool for studying drugs or physiological processes.
“Still, despite these difficulties, in vitro assessment of contraction in human cardiac tissue can be an important tool to study drugs or physiological processes (Hermann, et al., 2002; Janssen, et al., 1999; Janssen, et al., 2000; Pieske, et al., 1995; Rossman, et al., 2004).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Janssen, et al., 2000
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- Authors
- Janssen, P.
- Affiliations
- University of Göttingen (DE)
- Corresponding author
- Janssen, P
- ORCID
- Janssen, P
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-07
- Volume
- 47
- Issue
- 1
- Pages
- 99-107
- ISSN
- 0008-6363 (ISSN-L)
- OpenAlex
- W2142527066
- Cited by
- 45
- References
- 34
- Citations by year
- 2024: 2 · 2021: 2 · 2019: 1 · 2017: 3 · 2015: 1 · 2014: 2 · 2013: 2
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- cyclosporine, cardiac contractility, sarcoplasmic reticulum calcium handling, calcium transients, myofilament calcium sensitivity, myocardial oxygen consumption, heart failure, immunosuppressants, cardiotoxicity
- MeSH terms
- Animals, Calcium, Cold Temperature, Depression, Chemical, Dose-Response Relationship, Drug, Heart Failure, Humans, Immunosuppressive Agents, Myocardial Contraction, Myocardium, Oxygen Consumption, Rabbits, Sarcoplasmic Reticulum, Cyclosporine, In Vitro Techniques
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