Background and purpose
Endothelins act via two receptor subtypes, ETA and ETB . Under physiological conditions in coronary arteries, ETA receptors expressed in smooth muscle cells mediate vasoconstriction whereas ETB receptors mainly found in endothelial cells mediate vasorelaxation. However, under pathophysiological conditions, ETB receptors may also be expressed in vascular smooth muscle cells mediating vasoconstriction. Here, we have investigated whether vasoconstrictor ETB receptors are up-regulated in coronary arteries after experimental myocardial ischaemia in rats. Experimental approach: Male Sprague-Dawley rats were subjected to either heart ischaemia-reperfusion (15 min ischaemia and 22 h reperfusion), permanent ischaemia (22 h) by ligation of the left anterior descending coronary artery, or sham operation. Using wire myography, the endothelin receptor subtypes mediating vasoconstriction were examined in isolated segments of the left anterior descending and the non-ligated septal coronary arteries. Endothelin receptor-mediated vasoconstriction was examined with cumulative administration of sarafotoxin 6c (ETB receptor agonist) and endothelin-1 (with or without ETA or ETB receptor blockade). The distribution of ETB receptors was localized with immunohistochemistry and quantified by Western blot. Key
Purpose
Endothelins act via two receptor subtypes, ETA and ETB . Under physiological conditions in coronary arteries, ETA receptors expressed in smooth muscle cells mediate vasoconstriction whereas ETB receptors mainly found in endothelial cells mediate vasorelaxation. However, under pathophysiological conditions, ETB receptors may also be expressed in vascular smooth muscle cells mediating vasoconstriction. Here, we have investigated whether vasoconstrictor ETB receptors are up-regulated in coronary arteries after experimental myocardial ischaemia in rats. Experimental approach: Male Sprague-Dawley rats were subjected to either heart ischaemia-reperfusion (15 min ischaemia and 22 h reperfusion), permanent ischaemia (22 h) by ligation of the left anterior descending coronary artery, or sham operation. Using wire myography, the endothelin receptor subtypes mediating vasoconstriction were examined in isolated segments of the left anterior descending and the non-ligated septal coronary arteries. Endothelin receptor-mediated vasoconstriction was examined with cumulative administration of sarafotoxin 6c (ETB receptor agonist) and endothelin-1 (with or without ETA or ETB receptor blockade). The distribution of ETB receptors was localized with immunohistochemistry and quantified by Western blot. Key
Results
Endothelin ETB receptor-mediated vasoconstriction and receptor protein levels were significantly augmented in coronary arteries situated downstream of the occlusion after ischaemia-reperfusion compared with non-ischaemic arteries. In contrast, the ETA receptor-mediated vasoconstriction was unaltered in all groups. Conclusions and implications: Ischaemia-reperfusion induced local up-regulation of ETB receptors in the smooth muscle cells of coronary arteries in the post-ischaemic area. In contrast, in non-ischaemic areas, ETB receptor function was unaltered.