Beneficial effects of transforming growth factor-beta and tissue plasminogen activator in splanchnic artery occlusion and reperfusion in cats

Abstract

We studied the effects of transforming growth factor-beta (TGF-beta), tissue plasminogen activator (tPA), and their combination in cats subjected to splanchnic artery occlusion (SAO) with reperfusion. Untreated anesthetized cats subjected to total occlusion of the celiac, superior, and inferior mesenteric arteries for 120 min, followed by reperfusion, uniformly died within 120 min after reperfusion. The mean survival time was 75 +/- 8 min. Plasma amino-nitrogen concentrations and cathepsin D and myocardial depressant factor (MDF) activities were markedly elevated following reperfusion. Superior mesenteric artery (SMA) rings isolated from cats subjected to SAO with reperfusion exhibited a significant loss of vasorelaxation to the endothelium-dependent dilators acetylcholine and A-23187. Administration of tPA (1 mg/kg) intravenously just before reperfusion did not prolong survival time (81 +/- 10 min) nor did it influence any biochemical or cardiovascular responses following reperfusion or ameliorate the depressed endothelium-dependent relaxation of SMA rings. In contrast, TGF-beta (50 micrograms/cat) ameliorated the SAO postreperfusion state in terms of survival rate and plasma MDF activity, and protected against depressed endothelium-dependent relaxation of SMA rings. TGF-beta alone slightly increased the survival time to 102 +/- 11 min. However, combined treatment with tPA (1 mg/kg) and TGF-beta (50 micrograms/cat) preserved endothelium-dependent relaxation and prevented increases in plasma amino-nitrogen more prominently than TGF-beta given alone and significantly increased the survival time to 118 +/- 3 min (p less than 0.01). These results indicate that TGF-beta exerts beneficial effects in SAO followed by reperfusion in cats, and tPA has an augmenting action on some of the beneficial effects of TGF-beta. These findings suggest that TGF-beta alone or in combination with tPA may be potentially useful therapeutic regimens in splanchnic ischemia shock by preserving splanchnic parenchymal and endothelial cells.