Effects of endothelin-1 and endothelin-A receptor antagonist on recovery after hypothermic cardioplegic ischemia in neonatal lamb hearts.

Abstract

BACKGROUND:

Prior studies suggest an important role for coronary endothelium in ischemia/reperfusion (I/R) injury. Decreased endothelial release of the vasodilator nitric oxide occurs after I/R, but the role of the endothelium-derived vasoconstrictor endothelin-1 (ET-1) in I/R is unknown.

METHODS AND RESULTS:

We measured plasma ET-1 concentrations by radioimmunoassay in isolated blood-perfused neonatal lamb hearts before and after 2 hours of 10 degrees C cardioplegic ischemia and examined the effects of ET-1 and the endothelin-A (ET-A) receptor antagonist BE-18257B on the postischemic recovery of isolated hearts. ET-1 levels in coronary sinus blood before ischemia and at 0 and 30 minutes of reperfusion in 8 control hearts were constant (2.2 +/- 1.2 fmol/L, 2.2 +/- 1.3 fmol/L, and 2.5 +/- 1.0 fmol/L, respectively). In group 2 (n = 6), 10 mumol/L of BE-18257B was given just before reperfusion. In group 3 (n = 8), 10 pmol/L ET-1 was given just before the start of reperfusion. At 30 minutes of reperfusion, the ET-A antagonist hearts had significantly greater recovery of LV systolic (positive dP/dt and dP/dt at V10) and diastolic function (negative dP/dt), coronary blood flow (CBF), and MVo2 compared with controls (P < .05). The ET-1 hearts showed significantly reduced recovery of LV systolic (positive maximum and volume-normalized dP/dt) and diastolic (negative maximum dP/dt) function, CBF, and myocardial oxygen consumption compared with controls (P < .05).

CONCLUSIONS:

These results, combined with prior studies, suggest that I/R causes reduced production of endogenous vasodilators (eg, nitric oxide), leaving unopposed the vasoconstriction that is caused by the continued presence of ET-1. This imbalance may contribute to I/R injury. ET-A receptor antagonists may be useful therapeutic agents in reducing the injury that results from I/R.

• Authors: T Hiramatsu, J Forbess, T Miura, S J Roth, M A Cioffi, J E Mayer Jr
• Journal: Circulation (Circulation) Vol. 92 Issue 9 Suppl Pg. II400-4 (Nov 01 1995) ISSN: 0009-7322 [Print] United States
• PMID: 7586445 (Publication Type: Journal Article)

Chemical References

• Endothelin Receptor Antagonists
• Endothelins
• Peptides, Cyclic
• Receptor, Endothelin A
• cyclo(glutamyl-alanyl-isoleucyl-leucyl-tryptophyl)

Topics

• Animals
• Biological Assay
• Coronary Circulation
• Endothelin Receptor Antagonists
• Endothelins (blood, pharmacology)
• Heart (drug effects)
• Heart Arrest, Induced
• Hypothermia, Induced
• Myocardial Ischemia (physiopathology)
• Oxygen Consumption
• Peptides, Cyclic (pharmacology)
• Receptor, Endothelin A
• Reference Values
• Sheep
• Ventricular Function, Left