Changes in plasma levels of ET-1 and its precursor, big ET-1, in the arterial and venous circulation following double myocardial ischemia-reperfusioninjury in dogs

Upregulation of the endothelin (ET) system, following coronary ischemia-rep erfusion injury, may contribute to coronary vasospasm acid congestive heart failure. Because endothelin-1 (ET-1) is rapidly cleared from the circulati on, the levels of its inactive precursor big ET-1 and the ET-1/big ET-1 rat io may constitute better ways to assess the activation of the ET system in both venous and arterial beds. Anesthetized dogs (n = 6-12) were subjected to two successive coronary artery occlusions (with intervening 60 min reper fusion) over 6 h. Cardiac hemodynamics and electrocardiogram (ECG) were rec orded and blood samples were drawn simultaneously from the internal thoraci c artery and coronary sinus (venous blood). Under basal conditions at t = - 20 min, arterial plasma levels of ET-1 and big ET-1 were 2.05 +/- 0.21 and 2.00 +/- 0.51 pg/ml (ratio: 1.00: n = 12); venous values were 2.29 +/- 0.25 and 3.14 +/- 0.77, respectively (ratio: 0.73, n = 12). Both arterial and v enous plasma levels of ET-1 increased (by 46 and 56%) after 5 and 15 min of reperfusion, respectively, following the initial 120 min ischemic period c ompared to baseline values, and returned to near baseline values after 60 m in reperfusion. Both arterial and venous values for big ET-1 increased stea dily by 2.2 and 2.3 times maximum, respectively, during the initial 60 min reperfusion period; these values increased by 3.4 and 3.2 times, respective ly by the end of the second 120 min reperfusion period. ET-1/big ET-1 ratio s dropped to 0.39, in arterial, and 0.21, in venous plasma, at the end of t he second reperfusion period. In conclusion, plasma ET-1 levels increase si gnificantly but transiently after the first ischemic injury; the increased plasma big ET-1 levels were more pronounced in both the arterial and venous circulation along with ischemia-reperfusion injuries. These results sugges t an upregulation of the ET system that was easily monitored by increased p roduction of big ET-1. During ischemia-reperfusion injuries, the conversion to the active mature peptide ET-1 is either impaired, or ET-1 is more rapi dly degraded.