Bladder secretion of inhibitors of calcium oxalate crystal growth

Bladder secretion of inhibitors of calcium oxalate crystal growth.Differences in calcium oxalate crystal growth inhibition were studied in normally voided urine (bladder urine) and in urine collected directly from the kidney (kidney urine) in nine dogs. Urine samples were collected before and 10 days after bilateral ureterostomies. Calcium oxalate crystal growth inhibition was measured in a standard seeded crystal growth system. The alcian blue-precipitable material of the urine samples was determined. Significantly lower values were observed in kidney urine than in bladder urine for calcium oxalate crystal inhibition (mean difference, 0.07 ± 0.02 inhibitor units/mg creatinine; P < 0.01) and for the alcian blue-precipitable material (mean difference, 0.07 ± 0.02 mg/mg creatinine; P < 0.01). We conclude that the bladder adds calcium oxalate crystal growth inhibition to urine. Glycosaminoglycans from the bladder mucosa may be responsible; however, other acidic polymers such as RNA fragments or glycopeptides have been shown to be a constituent of the alcian blue-precipitable material. These are potent inhibitors of calcium oxalate crystal growth, and their participation in the increase of inhibition observed in bladder urine cannot be excluded. Total calcium oxalate crystal growth inhibition present in normally voided urine may be an overestimation of the actual inhibition present at the level of the kidney, where calculi usually form

Endothelin Receptor Antagonists: Effect of Serum Albumin on Potency and Comparison of Pharmacological Characteristics

ABSTRACT Endothelins (ETs) are 21-amino acid peptides that bind to membrane receptors to initiate pathophysiological effects. Two types of ET receptors, ET A and ET B , have been identified. Various ET receptor antagonists are being developed as therapeutic agents. This report examines the effects of bovine serum albumin (BSA) on the potency of ET receptor antagonists and compares five ET receptor antagonists. Competition studies show that in the absence of BSA, A-127722 and L-749329 inhibited ET-1 binding to ET A receptor with the same IC 50 value of 0.09 nM. Addition of increasing concentrations of BSA incrementally decreased the potency of the antagonists: in the presence of 5% BSA, the IC 50 values increased to 4.3 and 820 nM, respectively. Similarly, addition of BSA decreased the potency of antagonists in inhibiting ET-1-stimulated phosphatidylinositol hydrolysis. These results suggest that serum albumin has profound effects on the potencies of ET receptor antago- ET, originally isolated from cultured porcine aortic endothelial cells, is a highly potent vasoconstricting peptide with 21-amino acid residues Since endothelins were discovered in 1988 ABBREVIATIONS: ET, endothelin; PI, phosphatidylinositol; AA, arachidonic acid; BSA, bovine serum albumin

A novel endothelin antagonist, A-127722, attenuates ischemic lesion size in rats with temporary middle cerebral artery occlusion: a diffusion and perfusion MRI study

BACKGROUND AND PURPOSE: Endothelins (ETs) are potent vasoconstrictors. Plasma ET levels increase during acute brain ischemia and may worsen the ischemic damage. Diffusion-weighted MRI (DWI) and perfusion imaging (PI) are powerful tools for evaluation of acute cerebral ischemia. We studied the effects of A-127722, a novel ET(A)-selective ET antagonist, on cerebral ischemic lesion size using 2,3,5-triphenyltetrazolium chloride (TTC) staining postmortem, on acute ischemic lesion development with DWI, and on the cerebral circulation using PI. METHODS: Twenty male Sprague-Dawley rats received either 5 mg/kg of A-127722 or vehicle (n=10 per group) intravenously 30 minutes and subcutaneously 4 hours after middle cerebral artery occlusion (MCAO). Whole-brain DWI and single-slice PI were done before initiation of treatment and repeated frequently thereafter up to 4 hours after MCAO. The animals were reperfused in the MRI scanner 90 minutes after the onset of MCAO. At 24 hours the animals were killed, and the brains were cut into six 2-mm-thick slices and stained with 2% TTC. Percent hemispheric lesion volume (%HLV) was calculated for each animal. RESULTS: Physiological parameters, body weight, neurological scores, and premature mortality (2 versus 2) did not differ between the two groups. No hypotension, abnormal behavior, or other adverse effects were seen. TTC-derived %HLV was 25.3+/-5.6% for controls and 16.2+/-9.6% for treated animals (36% reduction, PCONCLUSIONS: A-127722 significantly reduced ischemic lesion size in rats without observable adverse effects. It is not clear whether the effect was due to vasodilatation of collateral arterioles not detectable by PI or whether A-127722 has neuroprotective properties that are independent of vascular effects