Abstract
We investigated the contractile function in responses to endothelin-1 (ET-1) in the human coronary microvasculature as well as the roles of endothelin receptors and protein kinase C-alpha (PKC-alpha) in these responses. Human atrial tissue was harvested from patients who underwent cardiac surgery pre- and post-cardioplegia (CP)/cardiopulmanory bypass (CPB). Microvascular constriction was assessed in pre- and post-CP/CPB samples in responses to ET-1, in the presence and absence of an endothelin-A (ET-A) receptor antagonist, an endothelin-B (ET-B) receptor antagonist, or a PKC-alpha inhibitor, respectively. The expression and localization of the ET-A and ET-B receptors were also examined using immunoblot and immunofluorescence photomicroscopy. The post-CP/CPB contractile response of coronary arterioles to ET-1 was significantly decreased compared with the pre-CP/CPB responses. The response to ET-1 was significantly inhibited in the presence of the ET-A antagonist BQ123 (10(-7)mol/L), but these values remained unchanged with the ET-B receptor antagonist BQ788 (10(-7)mol/L). Pretreatment with the PKC-alpha inhibitor safingol (2.5 x 10(-5) mol/L) reversed the ET-1 responses from contraction into relaxation. The total polypeptide levels of ET-A and ET-B receptors were not altered post-CP/CPB. Immunoblot and immunofluorescent staining displayed strong signals for ET-A receptors and relatively weak signals for ET-B receptors localized on coronary microvasculature. CP/CPB decreases the contractile function of human coronary microvessels in responses to ET-1. ET-A receptors are predominantly localized in the human coronary microcirculation, whereas ET-B receptors seem to be less abundant. The contractile response to ET-1 is in part through the activation of ET-A receptors and PKC-alpha. These results suggest a role of ET-1-induced contraction in the vasomotor dysfunction after cardiac surgery.
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