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K F Badr

Publications and source records attributed to K F Badr.

At least 55 records · Page 3Linked to original sources
PubMed1993

Studies on the glomerular microcirculatory actions of manidipine and its modulation of the systemic and renal effects of endothelin.

We examined the actions of intravenously administered manidipine on systemic and renal microcirculatory hemodynamics and its efficacy in antagonizing endothelin-1 (ET-1)-evoked responses. Manidipine was a potent vasodilator with preferential activity in the renal vasculature. Its administration in optimal doses resulted in decreases in systemic arterial pressures accompanied by increases in renal perfusion and filtration rates. Its primary sites of action in the kidney were at both pre- and postglomerular arteriolar sites. Manidipine was capable of near-total reversal of the sustained elevations in arterial pressure and the progressive reductions in renal blood flow and glomerular filtration rates induced by intravenously administered ET-1. In the presence of prolonged calcium channel blockade, subsequent administration of ET-1 led to paradoxic hypotensive responses, which could be profound and blocked by an inhibitor of nitric oxide synthesis. These unexpected vasorelaxant actions of ET-1 in the presence of manidipine were likely caused by the dual effects of antagonism of its own intrinsic vasoconstrictor action (through calcium channel blockade), as well as ET-1-evoked release of the endothelium-derived relaxing factor, nitric oxide.

Animals↗
PubMed1993

The effects of surgery and acute rejection on glomerular hemodynamics in the transplanted rat kidney.

The effects of surgery and acute rejection on glomerular hemodynamics in the transplanted rat kidney are examined. Kidneys were transplanted from Munich-Wistar (MW) rats to syngeneic controls and MHC-incompatible PVG strain recipients. We report on 4 groups of animals: (1) two-kidney control MW rats; (2) unilaterally nephrectomized MW rats (UNX); (3) renal transplantation from MHC-identical MW littermates and removal of native kidneys (SYN); and (4) transplantation from MW donors to MHC-incompatible PVG rats and removal of native kidneys (ALLO). Glomerular filtration rate (GFR), single-nephron (SN)GFR, and glomerular capillary pressure (PGC) in SYN kidneys were depressed as compared to those in UNX (GFR, 1.41 +/- 0.08 vs. 0.80 +/- 0.08 ml/min; SNGFR, 67.2 +/- 4.8 vs. 44.7 +/- 6.6 nl/min; and PGC, 67 +/- 2 vs. 48 +/- 4 mmHg, UNX vs. SYN, respectively, P < 0.05). GFR and SNGFR in ALLO kidneys, however, were depressed even further (GFR, 0.40 +/- 0.05 ml/min; SNGFR, 13.8 +/- 1.8 nl/min; P < 0.05 for UNX vs. ALLO and SYN vs. ALLO). Afferent arteriolar resistance (RA) was increased greater than 4-fold (UNX, 1.01 +/- 0.15 10(10) dyn.sec.cm-5; SYN, 1.37 +/- 0.36 10(10) dyn.sec.cm-5; ALLO, 4.76 +/- 0.74 10(10) dyn.sec.cm-5 [P < 0.05, UNX vs. ALLO and SYN vs. ALLO]). This led to a precipitous fall in initial capillary flow rate in ALLO rats. These studies reveal the presence of moderate reductions in SNGFR and PGC in the nonrejecting transplanted kidney, which may relate to as yet unidentified consequences of the transplant surgery. More significantly, the principal mechanism leading to the reduced GFR characteristic of acute allograft rejection is identified as severe preglomerular vasoconstriction.

Acute Disease↗
PubMed1993

Arachidonate and renal function.

Basic and clinical investigations into the roles of arachidonate-derived compounds in regulating renal function under normal and pathophysiological conditions continued to expand over the past year. Exciting new insights regarding the pathobiology of thromboxane A2 revealed new roles for this potent cyclooxygenase-derived vasoconstrictor in the glomerular dysfunction that accompanies inflammatory disorders and insulin-dependent diabetes. Major advances have extended our understanding of the proinflammatory actions of leukotriene B4 and other 5-lipoxygenase compounds in mediating glomerular injury during experimental glomerulonephritis. Intriguingly, emerging evidence suggests the presence of an anti-inflammatory arm in the lipoxygenase pathway, ie, 15-lipoxygenase, products of which may act as endogenous leukotriene antagonists. New information has also become available about the renal biology of cytochrome P-450 metabolites of arachidonic acid as well as about nonenzymatically generated biologically potent eicosanoids, the F2-isoprostanes.

Animals↗
PubMed1993

Evidence for the existence of F2-isoprostane receptors on rat vascular smooth muscle cells.

The isoprostanes are nonenzymatically generated prostanoids synthesized in vivo in humans and rats through reactions catalyzed by free oxygen radicals. 8-Epi-prostaglandin F2 alpha (8-epi-PGF2 alpha), an F2-isoprostane, is a potent smooth muscle constrictor. A thromboxane A2 (TxA2) receptor antagonist, SQ 29548, blocks renal vasoconstriction during 8-epi-PGF2 alpha administration in rats. With the use of cultured rat aortic smooth muscle cells, we found specific binding sites for [3H]SQ 29548 and for [125I]BOP, a TxA2 agonist. Both ligands were displaced from these binding sites by 8-epi-PGF2 alpha, although with significantly lesser potency than nonlabeled SQ 29548, I-BOP, or U-46619, a TxA2 agonist. In contrast, 8-epi-PGF2 alpha stimulated inositol 1,4,5-trisphosphate production and DNA synthesis in these cells with significantly greater potency than any TxA2 agonist, effects only partially inhibited by SQ 29548. In human TxA2 receptor cDNA-transfected cells, competition by 8-epi-PGF2 alpha for specific [3H]SQ 29548 binding was negligible. Thus 8-epi-PGF2 alpha probably exerts its biological actions in vascular smooth muscle through activation of receptor sites related to but distinct from TxA2 receptors. The existence of such binding sites suggests novel avenues for investigation into the biology of TxA2 and of free radical-mediated tissue injury.

Animals↗
PubMed1993

Maintenance of endothelin-induced renal arteriolar constriction in rats is cyclooxygenase dependent.

Influence of arachidonate cyclooxygenase (COX) products on endothelin (ET)-evoked renal vasoconstriction was assessed. In microperfused rat afferent (AA) and efferent arterioles (EA), indomethacin had no effects on the maximal contraction of both AA and EA by ET, but reduced the duration of ET-induced constriction in both arterioles. ET infusion to rats in vivo resulted in a selective increase in efferent but not afferent arteriolar resistance, leading to a dramatic increase in transcapillary hydraulic pressure difference. Glomerular filtration rate (GFR), which fell progressively during infusion of ET alone, was markedly preserved by COX inhibition, but not during selective thromboxane A2 antagonism. In isolated glomeruli, release of prostaglandin (PG) F2 alpha in response to 10(-6) mol/l ET exceeded that the PGE2 by a ratio of 3.2. Collectively, these data provide strong evidence that locally released COX products, possibly PGF2 alpha, play a key role in sustaining ET-induced renal arteriolar constriction. COX inhibition leads to acute vasorelaxation of AA despite continued ET administration, without affecting EA constriction in vivo, thereby resulting in a dramatic reversal of the effects of ET on GFR.

Animals↗
PubMed1993

Leukotriene D4 is a mediator of proteinuria and glomerular hemodynamic abnormalities in passive Heymann nephritis.

We assessed the role of leukotrienes (LTs) in Munich-Wistar rats with passive Heymann nephritis (PHN), an animal model of human membranous nephropathy. 10 d after injection of anti-Fx1A antibody, urinary protein excretion rate (Upr) in PHN was significantly higher than that of control. Micropuncture studies demonstrated reduced single nephron plasma flow and glomerular filtration rates, increased transcapillary hydraulic pressure difference, pre- and postglomerular resistances, and decreased ultrafiltration coefficient in PHN rats. Glomerular LTB4 generation from PHN rats was increased. Administration of the 5-LO activating protein inhibitor MK886 for 10 d markedly blunted proteinuria and normalized glomerular hemodynamic abnormalities in PHN rats. An LTD4 receptor antagonist SK&F 104353 led to an immediate reduction in Upr and to reversal of glomerular hemodynamic impairment. Ia(+) cells/glomerulus were increased in PHN rats. In x-irradiated PHN rats, which developed glomerular macrophage depletion, augmented glomerular LT synthesis was abolished. Thus, in the autologous phase of PHN, LTD4 mediates glomerular hemodynamic abnormalities and a hemodynamic component of the accompanying proteinuria. The synthesis of LTD4 likely occurs directly from macrophages or from macrophage-derived LTA4, through LTC4 synthase in glomerular cells.

Animals↗
PubMed1993

Induction of renal arachidonate cytochrome P-450 epoxygenase after uninephrectomy: counterregulation of hyperfiltration.

After unilateral nephrectomy (UNx) in the rat, cytochrome P-450 (cP-450)-linked arachidonate enzymatic activity was markedly and specifically induced in microsomal fractions from the remaining kidney. The enzymatic activity reached 200% at 1 wk and 285% at 2 wk post-UNx as compared with non-UNx controls. Mean baseline values for GFR and RPF rate in the remaining kidney 2 wk after UNx were 1.56 +/- 0.10 and 6.47 +/- 0.35 mL/min, respectively. In these rats, the administration of ketoconazole, a cP-450 inhibitor, led to 75% inhibition of renal cP-450 arachidonate metabolism and was associated with acute augmentations in both GFR and RPF to 1.82 +/- 0.18 (P < 0.05 versus baseline) and 7.54 +/- 0.37 mL/min (P < 0.05 versus baseline), respectively. Because vasoconstrictor arachidonate epoxygenase products are endogenously generated in the rat kidney, these findings suggest that the stimulation of renal cP-450-mediated oxygenation of arachidonic acid may subserve an important counterregulatory function in mitigating the renal hyperperfusion and hyperfiltration that follow reductions in renal mass.

Alkaline Phosphatase↗
PubMed1993

Lipoxygenase products as mediators in immune-mediated glomerular injury.

Figure 4 is a schematic summary of current evidence implicating products of the 15-LO pathway of arachidonic acid metabolism, principally 15-(S)-HETE and LXA4, as endogenous antagonists for the proinflammatory actions of LTs. In this article, we have presented evidence for the pathophysiological relevance of LTs in glomerular immune injury, and the emerging data on the multifaceted counter-inflammatory actions of 15-LO 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.

Animals↗
PubMed1992

Two distinct pathways in the down-regulation of type-1 angiotension II receptor gene in rat glomerular mesangial cells.

The mRNA level of the type-1 angiotensin II receptor (AT1) was down-regulated by angiotensin II in cultured rat glomerular mesangial cells. The effect was maximum with 1 microM AII at 6 h, sensitive to cycloheximide, and specific to AT1 since this phenomenon was blocked by DuP753, an AT1 antagonist, but not by type-2 antagonist PD123319. Dibutyryl cAMP, forskolin, and cholera toxin also caused AT1 down-regulation. These effects were not altered by either the protein kinase A inhibitor H-8 or cycloheximide. Calcium ionophore A23187, pertussis toxin, protein kinase C inhibitor staurosporine, or prolonged incubation with phorbol ester were without effect. These results suggest that there are at least two pathways to down-regulate AT1 mRNA; one way is an angiotensin II-induced, protein kinase C-independent, and cycloheximide-sensitive pathway and the other is an angiotensin II-independent, cAMP-induced, and cycloheximide-insensitive pathway.

Angiotensin II↗
PubMed1992

Molecular cloning and functional expression of rat leukotriene A4 hydrolase using the polymerase chain reaction.

We isolated a cDNA encoding rat leukotriene A4 (LTA4) hydrolase from mesangial cells by the polymerase chain reaction according to the human amino acid sequence. The deduced amino acid sequence shows that rat LTA4 hydrolase is a 609 amino acid protein with an Mr 69 kDa. Comparison of human LTA4 hydrolase revealed 93% homology, and include zinc-binding motifs of aminopeptidases. COS-7 cells transfected with the cDNA revealed substantial LTA4 hydrolase activity, and their activities were abolished by preincubation with captopril, representing the first reported cDNA expression of recombinant enzyme in mammalian cells. RNA blot analysis indicated that LTA4 hydrolase was expressed in glomerular endothelial, epithelial and mesangial cells.

Amino Acid Sequence↗
PubMed1992

Sepsis-associated renal vasoconstriction: potential targets for future therapy.

Systemic sepsis is associated with acute deterioration in renal function despite normal or increased cardiac output. The kidney is often structurally normal, but severe renal vasoconstriction underlies a marked decrease in the glomerular filtration rate (GFR). The mechanisms underlying renal vasoconstriction in sepsis include locally and systemically released vasoconstrictors. Novel peptide and lipid-derived mediators that have been implicated in experimental models of sepsis include endothelin (ET)-1, thromboxane A2 (TXA2), leukotrienes (LTs), and, most recently, noncyclooxygenase-derived prostaglandin F2 (PGF2) analogues. Plasma ET-1 levels are elevated in septic patients and following endotoxin administration in experimental animals; antagonism of the endogenous actions of ET-1 is associated with improvement in renal perfusion and function during experimental endotoxemia. Antagonists of the TXA2 receptor and/or TXA2 synthesis in vivo have been associated with selective improvement in renal vascular tone and preservation of GFR during experimental endotoxemia in several mammalian species. Furthermore, antagonism of the TXA2 receptor inhibits the actions of endogenously released free radical-generated PGF compounds. The latter are the most potent renal vasoconstrictors among the family of arachidonic acid derivatives. Sulfidopeptide LTs, in particular LTC4 and LTD4, are also implicated in the renal vasoconstriction that attends sepsis in rats and other experimental animals. LT hepatobiliary elimination is suppressed during sepsis and endogenous LT production is enhanced. Antagonism of LTD4 receptors is associated with amelioration of renal vasoconstriction. Taken together, these novel potential mediators of renal vasoconstriction during sepsis constitute specific molecular targets for future therapeutic interventions.

Animals↗
PubMed1992

Fifteen-S-hydroxyeicosatetraenoic acid (15-S-HETE) specifically antagonizes the chemotactic action and glomerular synthesis of leukotriene B4 in the rat.

In models of experimental glomerulonephritis, there is temporal concordance between the shift in the glomerular cellular infiltrate from neutrophils (PMN) to macrophages/monocytes and the suppression of glomerular leukotriene B4 (LTB4) generation. Since macrophages are a rich source of 15-lipoxygenase (15-LO) products, we investigated whether the principal product of arachidonate 15-lipoxygenation, 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), was capable of antagonizing the proinflammatory actions of LTB4 in the rat. PMN exhibited chemotaxis to LTB4 in a dose dependent manner with an LC50 of 10(-8) M. When rat neutrophils were pre-treated with 15-S-HETE, chemotaxis to LTB4 was inhibited in a dose dependent manner (maximal at 30 microM 15-S-HETE) but, the same concentration did not inhibit chemotaxis to n-formyl-1-methionyl-1-phenylalanine (FMP). 12-S-HETE (30 microM) did not inhibit chemotaxis to LTB4. Glomeruli from rats injected with nephrotoxic serum three hours earlier generated increased levels of LTB4; prior exposure of such glomeruli to 15-S-HETE totally normalized LTB4 production. The glomerular production of 15-S-HETE and LTB4 was also determined 3 hours, 72 hours and 2 weeks after administration of nephrotoxic serum. Whereas there was an early, short-lived, burst of LTB4 followed by a return to baseline levels, the production of 15-S-HETE increased steadily over the two week period and was present in amounts fivefold greater than LTB4. Thus, these studies assign a role for locally generated 15-LO derivatives in arresting LTB4-promoted PMN infiltration and suppressing LTB4 synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Essential fatty acid deficiency normalizes function and histology in rat nephrotoxic nephritis.

The central lipid abnormality in essential fatty acid deficiency (EFAD) is the lack of availability of arachidonic acid. To examine the role of total eicosanoid's biosyntheses in the pathology and pathophysiology of glomerulonephritis, EFAD was induced in weanling rats, which were then subjected to antiglomerular basement membrane antibody (NTS)-induced injury in adulthood. Glomerular dynamics (as assessed by micropuncture), quantitative histology, and eicosanoid generation rates were measured at two hours and two weeks post-NTS, and compared to those of standard diet-fed (STD) controls. Two hours post-NTS, and despite the occurrence of proteinuria in both EFAD and STD animals, glomerular dynamics were essentially normal in EFAD rats, whereas STD animals had reduced values for glomerular filtration rate (GFR) and renal plasma flow rate (RPF). At two weeks, severe histologic changes were observed in STD animals including mesangial and stalk hypercellularity, moderate sclerosis, and interstitial nephritis, coupled with heavy proteinuria and reduced GFR and RPF. In dramatic contrast, EFAD rats displayed totally normal glomerular structures and functions. In parallel, glomerular generation rates of prostaglandin E2 and thromboxane A2 were suppressed markedly in EFAD rats. Thus, EFAD confers complete protection against the histopathologic and functional sequelae of immune-initiated injury in the glomerulus. The data suggest that the initial wave of complement-induced neutrophil infiltration (with resultant proteinuria) is not sufficient to perpetuate injury into the more destructive chronic phases. The results provide strong impetus for the design of more specific interventional therapies targeting the various enzymes and products of arachidonic acid metabolism in the attempts to control glomerular inflammation.

Acute Disease↗
PubMed1992

Renal hemodynamic actions of lipoxins in rats: a comparative physiological study.

Interactions between either the arachidonate 5-lipoxygenase (5-LO) and 15-LO or 5-LO and 12-LO can lead to the formation of lipoxins. Although the functional significance of lipoxygenase products of arachidonic acid has been recognized increasingly in glomerular inflammation, less is known regarding the specific effects of lipoxins on renal hemodynamics. Here, we examine the renal actions of lipoxin (LX) A4, LXB4, and, the recently identified 7-cis-11-trans-LXA4, which were administered into the renal artery of the euvolemic male Munich-Wistar rat. LXA4 caused increases in renal plasma flow (RPF) and glomerular filtration rate (GFR) in a dose-dependent manner. These effects were reversed during cyclooxygenase inhibition. LXB4 decreased both RPF and GFR, and its mode of action was independent of cyclooxygenase activity. 7-cis-11-trans-LXA4 decreased RPF and GFR, which effects were abolished during systemic infusion of the leukotriene D4 receptor antagonist SKF 104353. Results indicate that each of these lipoxins displays distinct hemodynamic effects via a specific mode of action on the renal vasculature of rats. Moreover, they suggest mechanisms whereby lipoxins may participate in the changes of renal hemodynamics that occur during glomerular inflammatory processes.

Animals↗
PubMed1992

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.

Animals↗
PubMed1992

Formation of novel non-cyclooxygenase-derived prostanoids (F2-isoprostanes) in carbon tetrachloride hepatotoxicity. An animal model of lipid peroxidation.

These studies examine the in vivo formation of a unique series of PGF2-like compounds (F2-isoprostanes) derived from free radical-catalyzed nonenzymatic peroxidation of arachidonic acid. We have previously shown that levels of these compounds increase up to 50-fold in rats administered CCl4. To understand further the formation of these compounds in vivo, we carried out a series of experiments assessing factors influencing their generation. After CCl4 (2 ml/kg) was administered to rats, plasma F2-isoprostanes increased 55-fold by 4 h. Levels declined thereafter, but at 24 h, they were still elevated 21-fold, indicating continued lipid peroxidation. Pretreatment of rats with isonicotinic acid hydrazide and phenobarbital to induce cytochrome P-450 enhanced the production of F2-isoprostanes after CCl4 administration eightfold and fivefold, respectively, whereas inhibition of the cytochrome P-450 system with SKF-525A and 4-methylpyrazole decreased formation of F2-isoprostanes after CCl4 by 55 and 82%, respectively. Further, the glutathione-depleting agents buthionine sulfoximine and phorone augmented the F2-isoprostane response to CCl4 by 22- and 11-fold, respectively. F2-isoprostanes are formed in situ esterified to lipids and, in addition to increases in levels of free F2-isoprostanes in the circulation, levels of F2-isoprostanes esterified to lipids in various organs and plasma also increase sharply during CCl4 poisoning. The measurement of F2-isoprostanes may facilitate investigation of the role of lipid peroxidation in human diseases.

Acetaminophen↗
PubMed1992

Five-lipoxygenase products in glomerular immune injury.

Leukocyte infiltration, proliferation, and activation are central pathogenetic components of immune injury in the glomerulus. Initial cellular infiltration by polymorphonuclear leukocytes (PMN) is a consequence of the deposition of immune complexes at discreet sites in the glomerulus. This is often followed by macrophage/monocyte infiltration, as well as proliferation of resident mesangial macrophages. Activated leukocytes constitute a rich source of lipid-derived bioactive autacoids, in particular, oxygenated metabolites of arachidonic acid. Here, we assess the role of the five-lipoxygenase (5-LO) family of eicosanoids, in particular, leukotrienes D4 and B4 (LTD4 and LTB4) in mediating functional and structural deterioration during immune inflammatory reactions in the glomerulus. LTD4 and other peptidyl LT appear to play a central role in the reductions in GFR in the acute phases of injury by virtue of their potent vasoactive properties, in particular, their capacity to reduce the glomerular capillary ultrafiltration coefficient, likely through contraction of smooth muscle elements in glomerular mesangial cells. The latter cells possess specific receptors for LTD4 in both humans and rat and contract in vitro when exposed to LTD4 after receptor-mediated activation of phospholipase C. LTB4, a nonvasoconstrictor LT, is released in the early phases of immune injury, likely from leukocyte sources as well as from transcellular metabolism of its precursor, LTA4, by the enzyme LTA4-hydrolase in glomerular mesangial and endothelial cells. LTB4, a potent promoter of PMN attraction, adhesion, and activation exacerbates glomerular functional impairment and structural damage by amplifying PMN-dependent mechanisms of injury. In their totality, 5-LO products of arachidonic acid contribute to the impairment of the normal glomerular filtration and sieving functions that attend acute inflammatory injury in the renal glomerulus and to the subsequent progression of glomerular destruction. This is high-lighted by the significant degree of protection afforded by the selective inhibition of arachidonate 5-LO in vivo in acute and chronic models of experimental glomerulonephritis.

Animals↗