Abstract 3369: Impaired Contractile Response of Human Peripheral Arterioles to Endothelin-1 After Cardiopulmonary Bypass
Objectives: We investigated the effects of cardiopulmonary bypass (CPB) on contractile response of human peripheral microvasculature to S797endothelin-1 (ET-1) and examined the role of specific ET receptors and protein kinase C-alpha (PKC-α) in these responses.
Methods: Human skeletal muscle arterioles (90 to 180 micrometer in diameter) were dissected from tissue harvested pre- and post-CPB from 30 patients undergoing cardiac surgery. The in-vitro contractile response to ET-1 was assessed by videomicroscopy, with and without an endothelin-A (ET-A) receptor antagonist, an endothelin-B (ET-B) antagonist, or a PKC-α inhibitor. The expression and localization of ET-A and ET-B receptors were also examined using immunoblot and confocol immunofluorescence microscopy.
Results: The post-CPB contractile response of peripheral arterioles to ET-1 (10−7M) was significantly decreased compared with pre-CPB (46±5% vs. 25±4%, P<0.05). The response to ET-1 was significantly inhibited in the presence of the ET-A antagonist BQ123 (10−7 M) (46±5% vs. 8±1% of pre-CPB; 25±4% vs. 5±0.6% of post-CPB, P<0.05, respectively), but unchanged in the presence of the ET-B receptor antagonist BQ788 (10−7M) (46±5% vs. 42±3% of pre-CPB; 25±4% vs. 29±3% of post-CPB, P >0.05, respectively). Pretreatment with PKC-α inhibitor safingol (2.5×10−5M) reversed ET-1-induced response from contraction to relaxation (46±5% vs −15±2% of pre-CPB; 25±4% vs. −11±2.5% of post-CPB, P<0.05, respectively). The total protein levels of ET-A and ET-B receptors were not altered post-CPB by immunoblotting. Immunofluorescent staining displayed strong signals for ET-A receptors and relatively weak signals for ET-B receptors localized to the smooth muscle.
Conclusion: CPB decreases the myogenic contractile function of human peripheral microvessels in response to ET-1. The contractile response to ET-1 is via activation of ET-A receptors and PKC-α. ET-A receptors are predominately expressed in the smooth muscle of human peripheral arterioles, whereas ET-B appears less abundant. These results provide novel mechanisms of ET-1-induced contraction in the setting of vasomotor dysfunction after cardiac surgery.