Flenner, Frederik and Friedrich, Felix W. and Ungeheuer, Nele and Christ, Torsten and Geertz, Birgit and Reischmann, Silke and Wagner, Stefan and Stathopoulou, Konstantina and Soehren, Klaus-Dieter and Weinberger, Florian and Schwedhelm, Edzard and Cuello, Friederike and Maier, Lars S. and Eschenhagen, Thomas and Carrier, Lucie (2016) Ranolazine antagonizes catecholamine-induced dysfunction in isolated cardiomyocytes, but lacks long-term therapeutic effects in vivo in a mouse model of hypertrophic cardiomyopathy. CARDIOVASCULAR RESEARCH, 109 (1). pp. 90-102. ISSN 0008-6363, 1755-3245
Full text not available from this repository. (Request a copy)Abstract
Aims Hypertrophic cardiomyopathy (HCM) is often accompanied by increased myofilament Ca2+ sensitivity and diastolic dysfunction. Recent findings indicate increased late Na+ current density in human HCM cardiomyocytes. Since ranolazine has the potential to decrease myofilament Ca2+ sensitivity and late Na+ current, we investigated its effects in an Mybpc3-targeted knock-in (KI) mouse model of HCM. Methods and results Unloaded sarcomere shortening and Ca2+ transients were measured in KI and wild-type (WT) cardiomyocytes. Measurements were performed at baseline (1 Hz) and under increased workload (30 nM isoprenaline (ISO), 5 Hz) in the absence or presence of 10 mu M ranolazine. KI myocytes showed shorter diastolic sarcomere length at baseline, stronger inotropic response to ISO, and drastic drop of diastolic sarcomere length under increased workload. Ranolazine attenuated ISO responses in WT and KI cells and prevented workload-induced diastolic failure in KI. Late Na+ current density was diminished and insensitive to ranolazine in KI cardiomyocytes. Ca2+ sensitivity of skinned KI trabeculae was slightly decreased by ranolazine. Phosphorylation analysis of cAMP-dependent protein kinase A-target proteins and ISO concentration-response measurements on muscle strips indicated antagonism at beta-adrenoceptors with 10 mu M ranolazine shifting the ISO response by 0.6 log units. Six-month treatment with ranolazine (plasma level > 20 mu M) demonstrated a beta-blocking effect, but did not reverse cardiac hypertrophy or dysfunction in KI mice. Conclusion Ranolazine improved tolerance to high workload in mouse HCM cardiomyocytes, not by blocking late Na+ current, but by antagonizing beta-adrenergic stimulation and slightly desensitizing myofilaments to Ca2+. This effect did not translate in therapeutic efficacy in vivo.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BINDING-PROTEIN-C; LATE SODIUM CURRENT; RANDOMIZED CONTROLLED-TRIAL; CHRONIC HEART-FAILURE; SARCOMERIC CARDIOMYOPATHIES; DILATED CARDIOMYOPATHY; DIASTOLIC DYSFUNCTION; TROPONIN-T; PRACTICE GUIDELINES; CURRENT INHIBITION; Hypertrophic cardiomyopathy; Ranolazine; Ca2+ sensitivity; beta-Adrenergic signalling; Cardiac myosin-binding protein C |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Mar 2019 12:36 |
| Last Modified: | 07 Mar 2019 09:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2210 |
Actions (login required)
 |
View Item |
