The novel compound liguzinediol exerts positive inotropic effects in isolated rat heart via sarcoplasmic reticulum Ca2+ ATPase-dependent mechanism.
OBJECTIVE
The present work investigated the underlying mechanism for the positive inotropic effect of liguzinediol (LZDO) in isolated rat hearts.


METHODS
Isolated rat heart perfusion, intracellular action potential recording, patch clamp and Ca2+ imaging were used to measure the isolated rat heart contractility, action potential duration, L-type Ca2+ current and sarcoplasmic reticulum (SR) Ca2+ transient in rat cardiomyocyte, respectively.


RESULTS
LZDO (1, 10, and 100μM) significantly enhanced the inotropy of isolated rat hearts, but not heart rates. Nimodipine (1μM, an L-type Ca2+ channel antagonist), ruthenium red (5μM, a ryanodine receptor inhibitor) and thapsigargin (2μM, an irreversible SR Ca2+ ATPase inhibitor) completely blocked the positive inotropic effect of LZDO. LZDO significantly enhanced the intracellular Ca2+ transient in rat cardiomyocyte. However, LZDO (100μM) did not increase L-type Ca2+ channel current. Moreover, LZDO (100μM) restored the depletion effect of caffeine on Ca2+ transient. The following compounds also failed to block the positive inotropic effect of LZDO (100μM): β-AR antagonist (propranolol 1μM), phosphodiesterase (PDE) inhibitor (IBMX 5μM), Na+-K+ ATPase inhibitor (ouabain 1μM), α(1)-AR antagonist (prazosin 1μM), dopamine D1 receptor antagonist (SCH23390 1μM) and Na+-Ca2+ exchange inhibitor (KB-R7943 1μM).


CONCLUSIONS
The positive inotropic effect of LZDO in isolated rat hearts was mediated through an elevation of SR Ca2+ transient, which may act on SR Ca2+ ATPase. LZDO has a unique biological mechanism that may prove effective in treating heart failure in clinic.
National Standard Laboratory of Pharmacology for Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China; Institute of Chinese Medicine of Taizhou China Medical City, Taizhou 225300, China. Electronic address: longchen@njutcm.edu.cn.
Long
L
Chen
National Standard Laboratory of Pharmacology for Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
Yi
Y
Xu
Department of Chemistry and Processing for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China. Electronic address: liweii@126.com.
Wei
W
Li
Department of Chemistry and Processing for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
Hao
H
Wu
National Standard Laboratory of Pharmacology for Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
Zhuoka
Z
Luo
National Standard Laboratory of Pharmacology for Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
Xuehua
X
Li
National Standard Laboratory of Pharmacology for Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
Feifei
F
Huang
Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, Canada BC V5G4W8.
Clint
C
Young
Department of Chemistry and Processing for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
Zheng
Z
Liu
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 10070, China.
Shuyuan
S
Zhou
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009553:Nimodipine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology
C572935:2,5-dihydroxymethyl-3,6-dimethylpyrazine; D002316:Cardiotonic Agents; D011719:Pyrazines; D012430:Ruthenium Red; D002110:Caffeine; D009553:Nimodipine; D010042:Ouabain; D019284:Thapsigargin; D011433:Propranolol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015056:1-Methyl-3-isobutylxanthine; D011224:Prazosin