Cardioprotective effects of ranolazine (RS-43285) in the isolated perfused rabbit heart.
OBJECTIVE
The aim was to examine the putative cardioprotective effects of the novel antianginal agent, ranolazine, using an isolated rabbit heart model of ischaemia and reperfusion.


METHODS
Hearts from male New Zealand White rabbits were perfused in the Langendorff mode with a recirculating Krebs buffer at a constant flow of 20-25 ml.min-1. After equilibration, hearts were treated with ranolazine (10 or 20 microM) or vehicle control for 10 min before exposure to a 30 min period of global ischaemia and 60 min reperfusion; a normoxic control group was also studied. Haemodynamic variables (left ventricular pressure), myocardial creatine kinase, and potassium release were measured at baseline (preischaemic) and at selected points during reperfusion; tissue calcium and ATP content were also measured and electron microscopy was performed.


RESULTS
Left ventricular developed pressure during reperfusion was improved (p < 0.05) in a concentration dependent manner by 10 and 20 microM ranolazine (the baseline value was unaffected) with the latter dose resulting in a return to preischaemic values. The release of creatine kinase and potassium was reduced in the ranolazine groups (p < 0.05). A 2.5-fold increase in tissue calcium content in vehicle treated hearts at the end of reperfusion (compared to normoxic time control) was reduced by 10 microM ranolazine (p < 0.05) and completely prevented by 20 microM ranolazine. Similarly, the decrease in tissue ATP was largely inhibited by ranolazine in a concentration dependent manner. Electron microscopy showed that 20 microM ranolazine prevented the occurrence of many indications of reperfusion injury observed in vehicle treated control hearts, for example, blurring of myofibrillar Z bands, derangement of myofibrillar architecture, disruption of mitochondrial cristae and matrices, and the appearance of electron-dense bodies within them. The deposition of lanthanum chloride, a marker of blood vessel integrity, is also modified in the ranolazine treated hearts.


CONCLUSIONS
Ranolazine has impressive cardioprotective properties in an isolated rabbit heart model of ischaemia and reperfusion, suggesting that the drug warrants further research into its precise mechanism of action.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626.
M R
MR
Gralinski
S C
SC
Black
K S
KS
Kilgore
A Y
AY
Chou
J G
JG
McCormack
B R
BR
Lucchesi
D000083:Acetanilides; D000255:Adenosine Triphosphate / Q000378:metabolism; D000787:Angina Pectoris / Q000517:prevention & control*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D008854:Microscopy, Electron; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000648:ultrastructure; D010477:Perfusion; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D000069458:Ranolazine; D017725:Ventricular Pressure / Q000187:drug effects
D000083:Acetanilides; D010879:Piperazines; D000255:Adenosine Triphosphate; D000069458:Ranolazine; D003402:Creatine Kinase; D011188:Potassium; D002118:Calcium