The role of endothelin during myocardial ischaemia and reperfusion : pathophysiological mechanisms and interactions with nitric oxide

Acute myocardial infarction followed by reperfusion results in accelerated necrosis of irreversibly injured myocytes as well as induction of lethal injury to reversibly injured cells. Polymorphonuclear leukocytes (PMNs) are major participants in the reperfusion-initiated inflammation. Myocardial ischaemia and reperfusion are associated with changes in synthesis, release and vascular actions of endothelial factors. The production of the endothelium-derived relaxing factor nitric oxide (NO) is impaired, and the production/release of the vasoconstrictor endothelin-1 (ET-1) is enhanced.

The aim of the studies was to investigate the pathophysiological mechanisms of ET-1 and its interactions with NO during ischaemia and reperfusion.

1. Administration of the selective ETA receptor antagonist LU 135252 to anaesthetized pigs limited the extent of myocardial necrosis by 50% and the increase in myocardial tissue levels of ET-like immunoreactivity (ET-LI) following 45 min of ischaemia and 4 h of reperfusion. The degree of cardioprotection achieved by systemic i.v. administration prior to ischaemia was the same as that obtained by local i.c. infusion into the area at risk during the last min of ischaemia and early reperfusion.

2. LU 135252 protected the isolated rat heart from contractile dysfunction following ischaemia and reperfusion in the presence, but not in absence of PMNs. The outflow of PMNs in the coronary effluent was 4 times higher in the group given LU 135252 than in the vehicle group. Administration of ET-1 together with PMNs resulted in complete loss of contractile function and no outflow of PMNs. The recovery of the outflow of PMNs in the coronary effluent correlated significantly with the recovery of myocardial function.

3. Myeloperoxidase (MPO) activity in the ischaemic/reperfused myocardium as an index of PMN accumulation in the pig was significantly lower following i.c. administration of LU 135252 in comparison to vehicle. There was a significant correlation between the infarct size and MPO activity.

4. Perfusion with the NO synthase inhibitor L-NNA reduced coronary flow in the isolated rat heart. Pre-treatment with the mixed ETA/ETB bosentan and the selective ETA receptor antagonist BQ-123, but not the selective ETB receptor antagonist BQ-788 attenuated the coronary vasoconstrictor response induced by NOS inhibition. Bosentan increased ET-LI in the coronary effluent two-fold, whereas L-NNA did not affect the release of ET-LI.

5. Cardioprotection by the selective ETA receptor antagonist LU 135252 was not affected by co-administration of L-arginine in the pig in vivo. Inhibition of NO synthase reversed the cardioprotective effect of LU 135252 as well as the attenuation of ET-LI levels in ischaemic/reperfused myocardium induced by the ETA receptor antagonist.

In conclusion, ET-1 contributes to myocardial ischaemia and reperfusion injury by activation of the ETA receptor. Selective blockade of the ETA receptor protects the heart from ischaemia and reperfusion injury. The cardioprotective effect seems to be related to inhibition of PMN-induced myocardial injury and preserved production of NO.

List of scientific papers

I. Gonon AT, Wang QD, Shimizu M, Pernow J (1998). The novel non-peptide selective endothelin A receptor antagonist LU 135,252 protects against myocardial ischaemic and reperfusion injury in the pig. Acta Physiol Scand. 163(2): 131-137.
https://pubmed.ncbi.nlm.nih.gov/98312450

II. Gonon AT, Wang QD, Pernow J (1998). The endothelin A receptor antagonist LU 135252 protects the myocardium from neutrophil injury during ischaemia/reperfusion. Cardiovasc Res. 39(3): 674-682.
https://pubmed.ncbi.nlm.nih.gov/99078304

III. Gonon AT, Gourine AV, Pernow J. limitation of infarct size and attenuation of myeloperoxidase activity by an endothelin A receptor antagonist following ischaemia and reperfusion. [Manuscript]

IV. Wang QD, Gonon A, Shimizu M, Sjoquist PO, Pernow J (1998). Contribution of endothelin to the coronary vasoconstriction in the isolated rat heart induced by nitric oxide synthase inhibition. Acta Physiol Scand. 163(4): 325-330.
https://pubmed.ncbi.nlm.nih.gov/99006004

V. Gonon AT, Gourine AV, Pernow J. Cardioprotection from ischaemia and reperfusion injury by an endothelin A receptor antagonist in relation to nitric oxide production. [Manuscript]