The role of thromboxane in the renal response to mild hemorrhage
Description
Although prostanoids are known to participate in regulating renal function and renal hemodynamics in both physiological and pathophysiological states, increased renal thromboxane production has been demonstrated in response to relatively few stimuli. Even then, it is uncertain whether the thromboxane arises from renal tissue or from invading blood components. In this study data was obtained suggesting that after mild hemorrhage, thromboxane plays a role which is apparently restricted to the control of GFR. After a 10 ml/kg hemorrhage, a vasoconstrictor component preceding the dilation appeared in the response to the AA injection, suggesting formation of a vasoconstrictor metabolite. Administration of the cyclooxygenase inhibitor ibuprofen (5 mg/kg iv) blocked the entire response, indicating that the response was mediated by products of the cyclooxygenase pathway. Since the most likely vasoconstrictor in this pathway is thromboxane A$\sb{2}$, the experiment was repeated and a specific thromboxane synthetase inhibitor was administered after hemorrhage. After administration of the thromboxane synthetase inhibitor OKY-046 or OKY-1581 (2 mg/kg iv) the vasoconstrictor component was blocked. To confirm these findings, the thromboxane receptor antagonist BM 13.177 was used in additional experiments. Removal of this amount of blood from well-hydrated anesthetized dogs reduced both cardiac output (21%) and GFR (25%) compared to pre-hemorrhage values, and increased total peripheral resistance approximately 30%. Renal function parameters that depend on GFR also decreased significantly. After administration of either OKY-046 or BM 13.177, GFR and its dependent parameters returned to pre-hemorrhage levels. Plasma levels of vasopressin, plasma renin activity, and arterial and renal venous norepinephrine levels increased after hemorrhage. Measurements of renal venous thromboxane levels indicated an increase in Tx production in the kidney after hemorrhage, which was returned to control levels or to below control levels by OKY-046, further supporting the conclusion that thromboxane mediated the observed changes in GFR after hemorrhage. Additionally, experiments were conducted in which ibuprofen was administered after hemorrhage and OKY-046 administration, and the effects on renal blood flow and GFR were measured. Both RBF and GFR were significantly reduced after administration of ibuprofen, suggesting that the renal prostaglandins play an important role in the maintenance of renal hemodynamics after hemorrhage. (Abstract shortened with permission of author.)