2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and Hydronephrosis

Twenty-four hours of complete unilateral ureteral obstruction (UUO) produces intense renal vasconstriction in the rat even after release of obstruction. In the ex vivo perfused hydronephrotic rabbit kidney, bradykinin stimulates increased production of the vasoconstrictor autocoid thromboxane. In the present study, we measured basal and bradykinin-stimulated thromboxane and prostaglandin E2 production by UUO and contralateral rat kidneys perfused ex vivo. Furthermore, we evaluated thromboxane synthetase inhibition by imidazole and by two of its substituted derivatives, UK 37248 and UK 38485, in vitro. We compared these in vitro findings with in vivo measurements of renal hemodynamics and excretory function before and after the intrarenal artery administration of thromboxane synthetase inhibitors. Both basal and bradykinin-stimulated thromboxane and prostaglandin E2 production were significantly increased in hydronephrotic kidneys. Imidazole and its substituted congeners were effective inhibitors of bradykinin-stimulated thromboxane B2 production in vitro. However, the substituted imidazoles were more potent, more efficacious, and more selective for thromboxane synthetase inhibition than the parent compound. In vivo, administration of imidazole into the renal artery of the UUO kidney improved function slightly, whereas administration of UK 37248 or UK 38485 doubled renal blood flow and excretory function but did not restore them to normal. We conclude that the hydronephrotic rat kidney produces increased amounts of the vasoconstrictor eicosanoid thromboxane and that thromboxane is an important mediator of vasoconstriction in this model of disease.

Topics: Animals; Dinoprostone; Dose-Response Relationship, Drug; Hydronephrosis; Imidazoles; Methacrylates; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Ureteral Obstruction

The development of hydronephrotic atrophy as measured by dry and wet weight in relation to wholebody weight, in rats after complete unilateral ureteral obstruction could be influenced by oral administration of OKY 1581, an inhibitor of thromboxane A2 synthesis. The data are consistent with the thesis that preglomerular thromboxane A2-mediated active vasoconstriction is involved, most likely by ischemia, in the development of hydronephrotic atrophy, at least in the renal cortex.

Topics: Animals; Atrophy; Female; Hydronephrosis; Kidney Cortex; Kidney Medulla; Methacrylates; Rats; Thromboxane A2; Ureteral Obstruction

In conclusion, the evidence to date demonstrates that the enhanced arachidonate metabolism seen in hydronephrosis is responsible for the pathophysiological alterations observed in this model of renal injury. The balance between vasodilating prostaglandins and the vasoconstrictor thromboxane A2 may be critical in determining blood flow to the obstructed kidney. The alterations in arachidonate metabolism in this pathophysiologic state appear to result from the invasion of macrophages and the proliferation of fibroblasts in the cortical interstitium. Additionally, the macrophage appears to be necessary for the expression of the enhanced hormone-stimulated arachidonate metabolism. We envision the temporal sequence of events in this model to be as follows: ureter obstruction causes a mechanical disruption and/or immunologic stimulus in the cortex, which triggers a regional inflammatory response resulting in the proliferation of interstitial cells and the invasion of mononuclear cells. The macrophages, which are in direct contact with fibroblasts, are capable of releasing a factor that stimulates fibroblast proliferation, cortical microsomal cyclooxygenase activity, and prostaglandin E2 release (i.e., intrinsic arachidonate metabolism). The enhanced thromboxane synthetase levels and thromboxane A2 appear to come from the macrophage. The prostaglandin E2 and thromboxane A2 released modulate vascular tone. Prostaglandin E2 may also serve as an inhibitor of macrophage function. Two other models of renal damage also exhibit marked enhancement of renal prostaglandin synthesis and induction of thromboxane production: renal venous occlusion (32) and glycerol-induced acute renal failure (3). The finding that several models of renal damage have definite quantitative and qualitative alterations in the prostaglandin cascade reflects the importance of this pathway in renal pathophysiology.

Topics: Angiotensin II; Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Dinoprostone; Hydronephrosis; Kidney; Macrophages; Methacrylates; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Rabbits; Thromboxane-A Synthase; Ureteral Obstruction; Vasoconstriction

Thromboxane A2 is not produced in normal rabbit kidneys, but its synthesis is induced in numerous renal pathological states. The presence of this potent vasoconstrictor could readily compromise renal hemodynamics. We found that the thromboxane synthetase inhibitor, OKY-1581 (sodium-3-[4,3-pyridylmethyl)phenyl]-2-methylacrylate) is effective in the perfused hydronephrotic kidney in selectively inhibiting thromboxane production without altering prostaglandin E2 or prostacyclin release. The vasoactive peptides bradykinin and angiotensin cause the hydronephrotic kidney to produce thromboxane A2, which results in a profound renal vasoconstriction which is reversed by pretreatment with OKY-1581. Thus, OKY-1581 provides a powerful tool which can be used to assess the participation of thromboxane in pathophysiological states and to ascertain the therapeutic potential of thromboxane synthetase inhibitors in numerous disease states.

Topics: Animals; Bradykinin; Dinoprostone; Epoprostenol; Hydronephrosis; Methacrylates; Perfusion; Prostaglandins E; Rabbits; Renal Circulation; Thromboxane A2; Thromboxanes; Vascular Resistance