Search PubMed⌕ Search

Biomedical subjects

K F Badr

Publications and source records attributed to K F Badr.

At least 37 records · Page 2Linked to original sources
PubMed1995

Role for Doppler ultrasound in the assessment of renal circulation: effects of dopamine and dobutamine on renal hemodynamics in humans.

To examine the utility of Doppler ultrasound in assessing renal hemodynamics, we investigated the effects of dopamine and dobutamine on renal blood flow using Doppler ultrasound technique and conventional clearance tests in 7 healthy volunteers. After visualization of arterial blood flow in the right renal hilus by two-dimensional color flow mapping, the phasic blood flow velocity in the vessel was obtained by a pulsed Doppler method. Intravenous infusion of dopamine at a low dose increased the velocity and decreased the waveform pulsatility of renal artery blood flow without causing any significant changes in blood pressure, heart rate, or cardiac index. In contrast, dobutamine infusion increased the peak systolic velocity in a dose-dependent manner, but did not increase the mean velocity or decrease the waveform pulsatility. Percent changes of renal blood flow during infusions of both agents correlated well with those of the mean velocity. Furthermore, the degrees of changes of the waveform pulsatility were consistent with those of renal vascular resistance obtained from clearance tests and blood pressure. Our results suggest that mean velocity reflects renal blood flow and the pulsatility of blood flow waveform represents renal vascular resistance. We conclude that the effects of vasoactive agents on renal blood flow and renal vascular resistance can be estimated noninvasively, directly, and repeatedly using Doppler ultrasound.

Adult↗
PubMed1995

Tachyphylaxis of human forearm vascular responses does not occur rapidly after exposure to isoproterenol.

In vitro and limited in vivo data suggest that rapid desensitization of beta-adrenoceptor responses occurs after exposure to agonist. Tachyphylaxis to a beta-adrenoceptor agonist would represent a potentially important mechanism for the short-term regulation of vascular tone. The effects of a 4-hour infusion of 400 ng/min intra-arterial isoproterenol on forearm blood flow and presynaptic beta-adrenoceptor-mediated norepinephrine release were determined in eight healthy volunteers. Intra-arterial isoproterenol at 400 ng/min resulted in a significant increase in forearm blood flow in all eight subjects at all time points, with no evidence of tachyphylaxis. In fact, forearm blood flow after 4 hours of the isoproterenol infusion (22.8 +/- 3.3 mL/100 mL per minute) was significantly greater than after 7 minutes (14.6 +/- 2.8 mL/100 mL per minute), 15 minutes (15.4 +/- 2.4 mL/100 mL per minute), and 30 minutes (17.4 +/- 3.0 mL/100 mL per minute) of the infusion (P < .05). Similarly, presynaptic beta-adrenoceptor responses showed no evidence of tachyphylaxis, so forearm norepinephrine spillover values after 7 minutes (6.6 +/- 0.94 ng/min), 15 minutes (7.6 +/- 1.5 ng/min), and 4 hours (8.8 +/- 1.1 ng/min) of isoproterenol infusion were increased and similar. Minimal systemic effects were observed, and there was no evidence of tolerance, there being no difference in heart rate after 7 minutes (70.7 +/- 2.7 beats per minute) and 4 hours (72.2 +/- 3.6 beats per minute) of isoproterenol infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Role of leukotrienes and lipoxygenases in glomerular injury.

The 5-lipoxygenated metabolites of arachidonic acid, the leukotrienes, are increasingly recognized as major mediators of early glomerular hemodynamic and structural deterioration during experimental glomerulonephritis. Generation of these metabolites is largely by infiltrating leukocytes, but can also occur by intrinsic glomerular cells via transcellular metabolism of intermediates. In several animal models of glomerulonephritis and other renal pathologic states, leukotrienes have been shown to exert adverse effects in the glomerulus. Leukotriene B4 augments neutrophil infiltration, and leukotrienes C4 and D4 mediate potent vasoconstrictor effects on the glomerular microcirculation. Selective blockade of the 5-lipoxygenase pathway in the course of glomerular injury is associated with a significant amelioration of the deterioration of renal hemodynamic and structural parameters. 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), the immediate product of arachidonate 15-lipoxygenase, and the lipoxins, which are produced by sequential 15- and 5- or 5- and 12-lipoxygenation of arachidonic acid are also generated in the course of glomerular injury. These eicosanoids have actions that contrast with those of leukotrienes. 15-S-HETE antagonizes leukotriene-induced neutrophil chemotaxis and lipoxin A4 antagonizes the effects of leukotrienes C4 and D4 on the glomerular microcirculation. The contrasting effects of 5- and 15-lipoxygenase products may represent endogenous pro- and anti-inflammatory influences that could ultimately regulate the extent and severity of glomerular inflammation. The recent availability of safe and effective 5-lipoxygenase inhibitors will be helpful to test the effect of blocking leukotriene production on the course of human glomerulonephritis and other disease states.

Animals↗
PubMed1995

Leukotrienes and 15-lipoxygenase products in glomerulonephritis.

In Figure 2, a schematic summary of current evidence implicates products of the 15-lipoxygenase pathway of arachidonic acid metabolism, principally 15-(S)-HETE and LXA4, as endogenous antagonists for the proinflammatory actions of leukotrienes. In this review, we have presented evidence for the pathophysiologic relevance of leukotrienes in glomerular immune injury and the emerging data on the multifaceted, counter-inflammatory actions of 15-lipoxygenase products as they relate specifically to the renal glomerulus. Clearly, these concepts are of a broader nature and would be expected to pertain to inflammatory reactions in general, whether they be in the glomerulus, the renal interstitium, or in extrarenal sites. The extent to which these early observations can be exploited to design strategies for the control of self-destructive inflammatory reactions in the kidney and elsewhere will be determined by future studies. Imaginative design of molecular tools for the manipulation of these enzyme systems in vivo, however, represents a potentially fruitful area of research toward the attainment of a highly worthwhile goal--the cure of glomerulonephritis.

Animals↗
PubMed1995

Stimulatory effect of 8-Epi-PGF2 alpha, an F2-isoprostane, on endothelin-1 release.

8-Epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) is an F2-isoprostane produced in vivo by a cyclooxygenase-independent, free radical-catalyzed lipid peroxidation mechanism. It exhibits renal vasoconstrictor effects by binding to a receptor related to, but distinct from, that of thromboxane A2 (TxA2). In cultured bovine aortic endothelial cells (BAECs), competitive binding assays using [3H]-8-epi-PGF2 alpha indicated the existence of two distinct binding sites. The Kd values were similar to those of cultured rat aortic smooth-muscle cells, suggesting that the high- and the low-affinity binding sites represent isoprostane and TxA2 receptors, respectively. 8-Epi-PGF2 alpha dose-dependently stimulated endothelin-1 (ET-1) secretion from BAECs. These increases were partially inhibited by a TxA2 receptor antagonist, consistent with the premise that isoprostanes and TxA2 recognize closely related receptors. The presence of specific binding sites for F2-isoprostanes on endothelial cells widens the scope of the possible pathophysiologic significance of these eicosanoids, released during oxidant injury, to include alteration of endothelial cell biology. The release of ET-1 by 8-epi-PGF2 alpha may help to explain the large increases in plasma and urinary concentrations for both ET-1 and 8-epi-PGF2 alpha in patients with hepatorenal syndrome.

Animals↗
PubMed1994

Lipoxygenase products in normal and diseased glomeruli.

Figure 4 is a schematic summary of current evidence implicating products of the 15-lipoxygenase pathway of arachidonic acid metabolism, principally 15-S-HETE and LXA4, as endogenous antagonists for the proinflammatory actions of leukotrienes. Here, we have presented evidence for the pathophysiologic relevance of leukotrienes in glomerular immune injury and the emerging data on the multifaceted counterinflammatory actions of 15-lipoxygenase products as they relate specifically to the renal glomerulus. Clearly, these concepts are of a broader nature and would be expected to pertain to inflammatory reactions in general, be they in the glomerulus, the renal interstitium, or in extrarenal sites. The extent to which these early observations can be exploited to design strategies for the control of self-destructive inflammatory reactions in the kidney and elsewhere will be determined by future studies. Imaginative design of molecular tools for the manipulation of these enzyme systems in vivo, however, represents a potentially fruitful area of research towards the attainment of a highly worthwhile goal: the cure of glomerulonephritis.

Animals↗
PubMed1994

Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes.

15-Lipoxygenase (15-LO) catalyzes hydroperoxidation of fatty acids, a reaction of potential relevance to inflammation, membrane remodeling, and atherosclerosis. In human leukocytes, 15-lipoxygenation of arachidonic acid produces 15-(S)-hydroxyeicosatetraenoic acid and lipoxin A4, which suppress white cell chemotaxis, adherence, and activation, and antagonize proinflammatory leukotrienes. Interleukin (IL)-13, produced by T-helper subset 2 (TH-2) lymphocytes, specifically and potently induced 15-LO gene expression and enzyme activity in human monocytes. Among other TH-2 lymphokines, this induction of 15-LO is shared by IL-4 but not by IL-10. Interferon-gamma, a product of TH-1 lymphocytes, blocked IL-13-mediated induction of 15-LO. The induction of the anti-inflammatory 15-LO pathway by IL-13 reveals a new facet of IL-13 biology that supports its role as a cytokine with potential to down-regulate inflammatory pathways. The contrasting effects of interferon-gamma and IL-13 on 15-LO induction demonstrate mechanisms by which T-lymphocyte subsets may modulate macrophage/monocyte function in inflammation or atherosclerosis.

Arachidonate 15-Lipoxygenase↗
PubMed1994

Free radical-induced generation of isoprostanes in vivo. Evidence for the formation of D-ring and E-ring isoprostanes.

We recently reported the discovery that a series of novel prostaglandin (PG)F2-like compounds (F2-isoprostanes) are produced in vivo independent of the cyclooxygenase as products of free radical-catalyzed lipid peroxidation. F2-isoprostanes are initially formed in situ from arachidonic acid esterified to phospholipids and then released preformed. We have now investigated whether PGD2/E2-like isoprostanes are also produced by rearrangement of the PGG2-like intermediates involved in isoprostane formation. Using a variety of approaches utilizing mass spectrometry, compelling evidence was obtained for the presence of D2/E2-isoprostane-containing phosphospholipids in the liver (85 +/- 33 ng/g of liver) and free D2/E2-isoprostanes in the circulation (215 +/- 90 pg/ml) of rats treated with CCl4 to induce lipid peroxidation. In untreated rats, levels of D2/E2-isoprostanes esterified in liver phospholipids were much lower (0.90 +/- 0.10 ng/g), and free compounds could not be detected in the circulation (< 5 pg/ml). Interestingly, one of the E2-isoprostanes that would be expected to be formed in abundance, 8-epi-PGE2, was found to be a potent renal vasoconstrictor, and these effects could be abrogated by SQ29548, a thromboxane receptor antagonist. Further understanding of the biological consequences of the formation of these novel compounds and factors that influence their formation may provide valuable insights into the pathophysiology of oxidant injury.

Animals↗
PubMed1994

Evidence that the F2-isoprostane, 8-epi-prostaglandin F2 alpha, is formed in vivo.

F2-isoprostanes are prostaglandin (PG)F2-like compounds that are produced in vivo as non-enzymatic products of free radical catalyzed peroxidation of arachidonic acid. One F2-isoprostane whose formation should be favored is 8-epi-PGF2 alpha. 8-Epi-PGF2 alpha has been shown to exert potent bioactivity but proof that it is formed in vivo is lacking. Evidence is now presented suggesting that 8-epi-PGF2 alpha is, in fact, formed in vivo by demonstrating that an endogenous F2-isoprostane with a retention time on capillary GC identical with that of 8-epi-PGF2 alpha co-chromatographs through four high resolving HPLC purification procedures with authentic radiolabelled 8-epi-PGF2 alpha.

Animals↗
PubMed1994

Co-regulated expression of glomerular 12/15-lipoxygenase and interleukin-4 mRNAs in rat nephrotoxic nephritis.

Arachidonate 12- and 15-lipoxygenase (LO) products are generated in experimental glomerulonephritis. 15-S-HETE (a 15-LO product) and lipoxins (interaction products between 5-LO and either 12-LO or 15-LO) counteract the proinflammatory actions of leukotrienes. IL-4 has been shown to up-regulate 15-LO gene expression in human leukocytes. Based on homology with human 15-LO, we cloned a 0.76 kbp fragment of a rat LO cDNA from leukocytes stimulated by interleukin-4 (IL-4). The deduced amino acid sequence shows 71.0% and 60.1% homology to human 15-LO and 12-LO, respectively, and 100% homology to a recently cloned "leukocyte type" rat 12-lipoxygenase enzyme, which possesses significant 15-lipoxygenase activity (heretofore referred to as "12/15-LO"). A deletion mutant was utilized to generate internal standard cRNA in quantitative PCR assays. Glomerular 12/15-LO mRNA increased significantly over controls 24 and 48 hours after NTS injection, then decreased at 72 hours. RNA from NTS glomeruli contained higher levels of 12/15-LO mRNA than that from unstimulated peripheral leukocytes, suggesting that 12/15-LO transcription is up-regulated locally in native and/or infiltrating glomerular cells. Glomerular IL-4 mRNA increased markedly 16 hours post-NTS, and was then reduced, suggesting a potential role for T cell-derived IL-4 in directing the expression of 12/15-LO during glomerulonephritis. This represents the first demonstration of tandem regulated in vivo gene expression for a lymphokine (IL-4) and a lipoxygenase, both of which promote counter-inflammatory influences in immune complex-mediated injury.

Amino Acid Sequence↗
PubMed1994

Endothelin in kidney disease.

The role of endothelin in renal physiology and pathophysiology continues to be the subject of intense current research. Further insight into the mechanisms of interaction of endothelin in the kidney has provided a better understanding of its effects on renal hemodynamics and tubular function. Of interest is the emerging role of endothelin as a potential physiologic osmotic regulator of sodium and water reabsorption in the renal medulla. Increasing evidence implicates endothelin in the pathophysiology of progressive glomerulosclerosis, postischemic renal failure, cyclosporine-induced nephrotoxicity, and radiocontrast-induced nephropathy. The recent finding of elevated plasma endothelin levels in patients with the hepatorenal syndrome is particularly exciting and implicates a potential role for endothelin in the pathophysiology of the renal failure that occurs in patients with this syndrome.

Animals↗
PubMed1994

Mechanical stretch/relaxation of cultured rat mesangial cells induces protooncogenes and cyclooxygenase.

In cultured rat glomerular mesangial cells, continuous cycles of stretching and relaxation (stretch/relaxation) stimulate cell proliferation, protein synthesis, and prostaglandin production. We examined regulation of gene expression that may underlie these alterations in cell functions. Stretch/relaxation caused time-dependent induction of the immediate early genes, c-fos and zif 268/egr-1, with maximal increases occurring between 15 and 30 min. The mitogen-inducible prostaglandin G2/H2 synthase (PGH2S-2) gene was also induced within 30 min of stretch/relaxation, with concomitant increases in the immunoreactive PGH2S-2 protein. These gene inductions were preceded by transient translocation of protein kinase C activity from cytosol to membrane as well as by increases in 45Ca2+ uptake and total cellular calcium content. The stretch/relaxation-induced expression was suppressed by protein kinase C inhibition, whereas less profound inhibition was observed with inhibition of calcium influx in low (100 nM) calcium buffer. These findings indicate that in mesangial cells mechanical stress induces expression of the protooncogenes and the mitogen-inducible cyclooxygenase primarily through protein kinase C-dependent mechanisms.

Animals↗
PubMed1994

Consequences of acute nitric oxide synthesis inhibition in experimental glomerulonephritis.

To assess the functional relevance of the enhanced glomerular nitric oxide (NO) synthesis during acute nephrotoxic serum (NTS) nephritis, a NO synthesis inhibitor (NOI) NG-monomethyl-L-arginine was administered to normal (N + NOI) and acutely nephritic (NTS + NOI) Munich-Wistar rats, and systemic and glomerular hemodynamic responses were contrasted with those observed in vehicle-treated normal and nephritic (NTS) controls. Urinary protein excretion rates were equal in normal and N + NOI rats but were markedly elevated in NTS animals and further increased in NTS+NOI. NO inhibition in normal animals (normal versus N + NOI) led to reductions in glomerular plasma flow rate and the glomerular capillary ultrafiltration coefficient (Kf) and elevations in afferent and efferent arteriolar resistances and net transcapillary hydraulic pressure difference (delta P), as well as an increase in systemic arterial pressure. The increase in delta P offset the falls in glomerular plasma flow rate and Kf, and GFR was preserved. Directionally similar responses in efferent resistance occurred in NTS + NOI compared with NTS, however, afferent resistance was not further affected by NOI. Additionally, although Kf was severely depressed in the NTS group (approximately 60% versus normal), it was not further depressed by NOI treatment. Polymorphonuclear cell (PMN) infiltration/glomerulus was mildly increased in N + NOI over normal. In contrast, PMN number in NTS + NOI rats was diminished as compared with NTS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Dietary supplementation with L-arginine ameliorates glomerular hypertension in rats with subtotal nephrectomy.

This study was designed to examine the potential effect(s) of dietary supplementation with L-arginine on the renal microcirculation of female Munich-Wistar rats with ablation of 60 to 70% of total renal mass. All rats were fed a standard rat chow containing 22.8% protein (1.42% L-arginine). Groups 1 (N = 6) and 3 (N = 7) drank tap water and had micropuncture studies after 5 to 6 or 15 to 16 wk, respectively, of subtotal renal ablation. Groups 2 (N = 5) and 4 (N = 7) drank tap water supplemented with L-arginine (1%) and had micropuncture studies after 5 to 6 or 15 to 16 wk, respectively, of subtotal renal ablation. Glomerular micropuncture studies revealed no differences in any of the parameters of glomerular hemodynamics measured 5 to 6 wk after renal ablation (Groups 1 versus 2). However, by 15 to 16 wk postnephrectomy, values of glomerular capillary pressure and efferent arteriolar resistance were significantly greater and the glomerular capillary ultrafiltration coefficient was significantly lower in rats drinking tap water than in rats drinking tap water supplemented with L-arginine. Single-nephron GFR, single-nephron plasma flow rate, and afferent arteriolar resistance were not different between these two groups. The data suggest that the long-term administration of L-arginine prevents the progression of glomerular sclerosis in rats with subtotal nephrectomy, at least in part, by ameliorating glomerular capillary hypertension.

Animals↗
PubMed1993

Vascular smooth muscle actions and receptor interactions of 8-iso-prostaglandin E2, an E2-isoprostane.

8-iso-PGE2, an E2-isoprostane, decreased GFR and RPF dose-dependently in rats, but with lesser potency than 8-epi-PGF2 alpha, an F2-isoprostane. This effect was abolished by SQ29,548. 8-iso-PGE2 displaced [3H]SQ29,548 or [125I]BOP binding in aortic smooth muscle cells with the affinity rank order of SQ29,548 > = I-BOP > U46,619 > 8-iso-PGE2 > PGF2 alpha, while it activated phospholipase C with a potency greater than those of I-BOP or U46,619 and lesser than that of 8-epi-PGF2 alpha. We concluded that 8-iso-PGE2 is a renal vasoconstrictor linked to phosphoinositide metabolism. Its vascular smooth muscle contractile actions are likely mediated through activation of putative thromboxane A2 receptor-like "isoprostane receptors."

Animals↗
PubMed1993

Endothelins 1 and 3: potent cholestatic agents secreted and excreted by the liver that interact with cyclosporine.

Autoradiographic studies have shown that the liver accumulates endothelin. High-affinity binding sites for endothelin have been identified on rat liver plasma membranes. We investigated the role of endothelin isopeptides as mediators of cholestasis with isolated rat liver perfused by a recirculating solution of buffer and blood. These studies demonstrated that endothelin-1, as measured by means of radioimmunoassay, was cleared from the perfusate by the liver and that the liver concentrated both endothelin-1 and endothelin-3 in bile. Addition of endothelin-1 to the liver perfusate solution increased the concentration of endothelin-3 measured in the perfusate, suggesting that endothelin-1 caused release or secretion of endothelin-3. Both endothelin-1 and endothelin-3 at 5 nmol/L caused almost complete cessation of bile flow, but this effect was more prolonged after endothelin-1 than after endothelin-3 administration. Because it has been reported that cyclosporine increases endothelin levels, we studied the interaction of these two compounds. Cyclosporine (100 mumol/L) also produced cholestasis. Endothelin-3 secretion in bile, however, was decreased in livers perfused with cyclosporine compared with secretion in controls. Simultaneous addition of endothelin-1 and cyclosporine that on their own were not significantly cholestatic produced cholestasis. In conclusion, endothelin is a potent cholestatic agent secreted and excreted by the liver. It may potentiate the cholestatic action of cyclosporine.

Animals↗