Glomerular actions of a free radical-generated novel prostaglandin, 8-epi-prostaglandin F2 alpha, in the rat. Evidence for interaction with thromboxane A2 receptors.

8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) and related compounds are novel prostanoid produced by a noncyclooxygenase mechanism involving lipid peroxidation. Renal ischemia-reperfusion injury increased urinary excretion of these compounds by 300% over baseline level. Intrarenal arterial infusion at 0.5, 1, and 2 micrograms/kg per min induced dose-dependent reductions in glomerular filtration rate (GFR) and renal plasma flow, with renal function ceasing at the highest dose. Micropuncture measurements (0.5 microgram/kg per min) revealed a predominant increase in afferent resistance, resulting in a decrease in transcapillary hydraulic pressure difference, and leading to reductions in single nephron GFR and plasma flow. These changes were completely abolished or reversed by a TxA2 receptor antagonist, SQ 29,548. Competitive radioligand binding studies demonstrated that 8-epi-PGF2 alpha is a potent competitor for [3H]SQ 29,548 binding to rat renal arterial smooth muscle cells (RASM) in culture. Furthermore, addition of 8-epi-PGF2 alpha to RASM or isolated glomeruli was not associated with stimulation of arachidonate cyclooxygenase products. Therefore, 8-epi-PGF2 alpha is a potent preglomerular vasoconstrictor acting principally through TxA2 receptor activation. These findings may explain, in part, the beneficial effects of antioxidant therapy and TxA2 antagonism observed in numerous models of renal injury induced by lipid peroxidation.

Differential effects of alpha and beta adrenergic blockade on glucose and lactate metabolism during acute stress.

In this study we examined the role of alpha and beta blockade on glucose and lactate metabolism during the acute stress of insulin-induced hypoglycemia. Three groups of conscious dogs with chronically fitted catheters in the femoral artery and in the femoral, portal, and hepatic veins were studied after an 18-hr fast. After a 1-hr basal period, hypoglycemia was induced with insulin infusion at 5 mU/kg.min for 3 hr. Group 1 received no other treatment. Groups 2 and 3 received, respectively, phentolamine (8 micrograms/kg.min) and propranolol (4 micrograms/kg.min) beginning 30 minutes before and throughout the experimental period. Despite similar hyperinsulinemia, plasma glucose dropped in Group 1 (from 115 +/- 10 to 40 +/- 3 mg/dl) and in Group 2 (from 110 +/- 4 to 60 +/- 3 mg/dl) but in Group 3 it was maintained at 45 +/- 4 mg/dl by exogenous glucose infusion at a rate of 2.2 +/- 0.4 mg/kg.min. Hepatic glucose production increased 50 +/- 13%, 127 +/- 30%, and 55 +/- 30% in Groups 1, 2, and 3, respectively, within 60 minutes and was 56 +/- 19%, 55 +/- 17%, and -0.04 +/- 12% during the last hour of the experiment. Glucose utilization did not change in Groups 1 and 2 but it increased in Group 3. Plasma lactate increased in Group 1 (from 850 +/- 190 to 1,980 +/- 450 mumol/L) and in Group 2 (985 +/- 180 to 4,785 +/- 500 mumol/L), while in Group 3 there was an early rise (to 695 +/- 120 mumol/L) within 30 minutes that gradually dropped to near basal.(ABSTRACT TRUNCATED AT 250 WORDS)

The amino acid-induced alteration in renal hemodynamics is glucagon independent.

The amino acid-induced alteration in renal hemodynamics is glucagon independent. An oral protein load or i.v. administration of an amino acid solution results in an increase in glomerular filtration rate and renal plasma flow in both humans and animals. The change in renal hemodynamics has been attributed to the simultaneous induced rise in glucagon. Whether glucagon is necessary for the change in renal hemodynamics after an amino acid infusion was investigated. Two groups of dogs were used, and the experimental protocol was divided into four different periods (P1 through P4). Group I animals received an amino acid solution, and group II dogs received an equiosmolar solution of mannitol. In P1, the animals in both groups were hydrated with normal saline, whereas, in P2, the pancreatic clamp technique was used to fix the plasma glucagon levels. P2 served as a basal period in which measurements of glomerular filtration rate, renal plasma flow, and plasma glucagon were obtained. IN P3, group I animals received amino acid solution, and group II received mannitol and served as controls. In this period, an increase of 32 and 27% in glomerular filtration rate and renal plasma flow, respectively, in group I dogs was observed, whereas there were no significant changes in these parameters in group II. During this period, plasma glucagon remained still at basal level in both groups. In P4, an infusion of glucagon at a rate of 5 ng/kg/min was added to both groups. This maneuver resulted in a fourfold increase in plasma glucagon levels in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism.

Increasing attention has focused on the role of free radicals derived from oxygen in the pathophysiology of a wide variety of disorders. One of the well-recognized targets of free radical-induced injury is peroxidation of lipids. Using a variety of approaches, we have found that a series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase mechanism involving free radical-catalyzed peroxidation of arachidonic acid. Levels of these compounds in normal human plasma and urine range from 5 to 40 pg/ml and 500 to 4000 pg/mg of creatinine, respectively. In rats, their formation was found to increase as much as 200-fold in association with marked free radical-catalyzed lipid peroxidation induced by administration of CCl4 and diquat. To explore whether these prostanoids can exert biological activity, the effects of one of the compounds formed by this mechanism, 8-epi-prostaglandin F2 alpha, was examined in the kidney in the rat. Infusion of 8-epi-prostaglandin F2 alpha into a peripheral vein (5 micrograms/kg per min) or intrarenally (0.5-2.0 micrograms/kg per min) resulted in marked parallel reductions in renal blood flow and glomerular filtration rate. That the formation of these prostanoids is catalyzed by free radicals and that they can exert potent biological activity suggest that these prostanoids may participate as pathophysiological mediators in oxidant injury. Quantification of these compounds may also provide a noninvasive approach to assess oxidant status in humans. That the formation of these prostanoids occurs independent of the catalytic activity of the cyclooxygenase enzyme suggests that there may be limitations at times regarding the reliability of the use of cyclooxygenase inhibitors to assess the role of prostaglandins in certain pathophysiological processes.