Cardioprotective effects of the novel selective endothelin-A receptor antagonist BSF 461314 in ischemia-reperfusion injury.
OBJECTIVE
The aims of the study were to visualize the dynamics of ischemia-reperfusion injury by real-time myocardial contrast echocardiography and to investigate the cardioprotective effects of the novel endothelin-A receptor antagonist BSF 461314. BSF 461314 reduced infarct size by 47% and preserved microvascular integrity. Real-time myocardial contrast echocardiography allowed visualization of postischemic microvascular dysfunction and quantification of cardioprotective effects of selective endothelin antagonism. Blood flow index A x beta was reduced in anterior segments during ischemia compared with baseline (0.06 +/- 0.01 vs 0.98 +/- 0.2 dB/s) but was higher in the BSF 461314 group after 120 minutes of reperfusion (0.7 +/- 0.08 vs 0.3 +/- 0.05 dB/s, P = .015). Therefore, selective endothelin-A receptor antagonism improved microvascular integrity during postischemic reperfusion. Real-time myocardial contrast echocardiography accurately detected changes in microvascular reflow.


BACKGROUND
Endothelin-1 is a potent vasoconstrictor and elevated in myocardial ischemia. The aims of the study were to examine cardioprotective effects of the novel selective endothelin-A receptor antagonist BSF 461314 and to visualize changes in the microvasculature by real-time myocardial contrast echocardiography (MCE).


METHODS
A total of 16 open-chest pigs underwent 45 minutes of left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. A total of 1 mg/kg BSF 461314 or vehicle was given intravenously before reperfusion. Serial MCE was performed to assess changes in myocardial blood flow A x beta and perfusion defect size. Myocardial blood flow was measured by fluorescent microspheres and infarct size was measured by triphenyltetrazolium chloride tissue staining.


RESULTS
Dynamics of infarct size expansion and tissue perfusion were correctly assessed by MCE. A x beta Was reduced in anterior segments during left anterior descending coronary artery occlusion (0.06 +/- 0.01 dB/s) compared with baseline (0.98 +/- 0.2 dB/s), approached higher levels postrecanalization (1.2 +/- 0.1 dB/s), but gradually decreased during reperfusion (0.3 +/- 0.05 dB/s, P < .01). After 120 minutes of reperfusion A (2.1 +/- 0.5 vs 1.0 +/- 0.6 dB, P < .03), beta (0.36 +/- 0.09/s vs 0.21 +/- 0.09/s, P = .01), and A x beta (0.7 +/- 0.08 vs 0.3 +/- 0.05 dB/s, P = .015) in the risk area were higher in the BSF 461314-treated group compared with vehicle indicating preserved myocardial perfusion. Triphenyltetrazolium chloride staining confirmed a 47% reduction in infarct size by BSF 461314.


CONCLUSIONS
Selective endothelin-A receptor antagonism improved microvascular integrity during postischemic reperfusion. Real-time MCE allows visual and quantitative evaluation of dynamics of myocardial ischemia-reperfusion injury and monitoring of cardioprotective effects during pharmacologic interventions.
Hansen
Alexander
A
Department of Cardiology, University of Heidelberg, Heidelberg, Germany. alexander_hansen@med.uni-heidelberg.de
Bekeredjian
Raffi
R
Filusch
Arthur
A
Wolf
David
D
Gross
Marie-Luise
ML
Mueller
Sebastian
S
Korosoglou
Grigorios
G
Kuecherer
Helmut F
HF
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D003326:Coronary Circulation / Q000187:drug effects; D008833:Microcirculation / Q000000981:diagnostic imaging* / Q000187:drug effects*; D044022:Receptor, Endothelin A / Q000008:administration & dosage*; D015427:Reperfusion Injury / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D013552:Swine; D016896:Treatment Outcome; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging* / Q000209:etiology / Q000517:prevention & control*
D002316:Cardiotonic Agents; D044022:Receptor, Endothelin A