Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure
Autor: | Sakthivel Sadayappan, Kristin Wilson, Anuradha Guggilam, Pamela A. Lucchesi, Xiaojin Zhang, Mary J. Cismowski, Pieter P. de Tombe, Aaron J. Trask, T. Aaron West |
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Rok vydání: | 2014 |
Předmět: |
Male
Sarcomeres Myofilament medicine.medical_specialty Cardiotonic Agents Physiology Volume overload Hemodynamics Ventricular Function Left Calcium sensitizer Rats Sprague-Dawley Ventricular Dysfunction Left Myofibrils Arterio-Arterial Fistula Physiology (medical) Internal medicine Troponin I medicine Animals Myocytes Cardiac Calcium Signaling Simendan Ultrasonography Heart Failure business.industry Hydrazones Levosimendan medicine.disease Myocardial Contraction Rats Pyridazines Heart failure Cardiology Cardiology and Cardiovascular Medicine business Muscle Mechanics and Ventricular Function medicine.drug |
Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 307:H1605-H1617 |
ISSN: | 1522-1539 0363-6135 |
Popis: | Aortocaval fistula (ACF)-induced volume overload (VO) heart failure (HF) results in progressive left ventricular (LV) dysfunction. Hemodynamic load reversal during pre-HF (4 wk post-ACF; REV) results in rapid structural but delayed functional recovery. This study investigated myocyte and myofilament function in ACF and REV and tested the hypothesis that a myofilament Ca2+ sensitizer would improve VO-induced myofilament dysfunction in ACF and REV. Following the initial sham or ACF surgery in male Sprague-Dawley rats (200–240 g) at week 0, REV surgery and experiments were performed at weeks 4 and 8, respectively. In ACF, decreased LV function is accompanied by impaired sarcomeric shortening and force generation and decreased Ca2+ sensitivity, whereas, in REV, impaired LV function is accompanied by decreased Ca2+ sensitivity. Intravenous levosimendan (Levo) elicited the best inotropic and lusitropic responses and was selected for chronic oral studies. Subsets of ACF and REV rats were given vehicle (water) or Levo (1 mg/kg) in drinking water from weeks 4–8. Levo improved systolic (% fractional shortening, end-systolic elastance, and preload-recruitable stroke work) and diastolic (τ, dP/d tmin) function in ACF and REV. Levo improved Ca2+ sensitivity without altering the amplitude and kinetics of the intracellular Ca2+ transient. In ACF-Levo, increased cMyBP-C Ser-273 and Ser-302 and cardiac troponin I Ser-23/24 phosphorylation correlated with improved diastolic relaxation, whereas, in REV-Levo, increased cMyBP-C Ser-273 phosphorylation and increased α-to-β-myosin heavy chain correlated with improved diastolic relaxation. We concluded that Levo improves LV function, and myofilament composition and regulatory protein phosphorylation likely play a key role in improving function. |
Databáze: | OpenAIRE |
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