Cardioprotective effects of the novel selective endothelin-A receptor antagonist BSF 461314 in ischemia-reperfusion injury.

Abstract

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.

• Authors: Alexander Hansen, Raffi Bekeredjian, Arthur Filusch, David Wolf, Marie-Luise Gross, Sebastian Mueller, Grigorios Korosoglou, Helmut F Kuecherer
• Journal: Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography (J Am Soc Echocardiogr) Vol. 18 Issue 11 Pg. 1213-20 (Nov 2005) ISSN: 1097-6795 [Electronic] United States
• PMID: 16275532 (Publication Type: Journal Article)

Chemical References

• Cardiotonic Agents
• Receptor, Endothelin A

Topics

• Animals
• Cardiotonic Agents (administration & dosage)
• Coronary Circulation (drug effects)
• Microcirculation (diagnostic imaging, drug effects)
• Receptor, Endothelin A (administration & dosage)
• Reperfusion Injury (complications, diagnostic imaging, drug therapy)
• Swine
• Treatment Outcome
• Ultrasonography
• Ventricular Dysfunction, Left (diagnostic imaging, etiology, prevention & control)