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William J Welch

Publications and source records attributed to William J Welch.

18 recordsLinked to original sources
PubMed2003

Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression.

Oxidative stress accompanies angiotensin (ANG) II infusion, but the role of ANG type 1 vs. type 2 receptors (AT1-R and AT2-R, respectively) is unknown. We infused ANG II subcutaneously in rats for 1 wk. Excretion of 8-isoprostaglandin F2alpha (8-Iso) and malonyldialdehyde (MDA) were related to renal cortical mRNA abundance for subunits of NADPH oxidase and superoxide dismutases (SODs) using real-time PCR. Subsets of ANG II-infused rats were given the AT1-R antagonist candesartan cilexetil (Cand) or the AT2-R antagonist PD-123,319 (PD). Compared to vehicle (Veh), ANG II increased 8-Iso excretion by 41% (Veh, 5.4 +/- 0.8 vs. ANG II, 7.6 +/- 0.5 pg/24 h; P < 0.05). This was prevented by Cand (5.6 +/- 0.5 pg/24 h; P < 0.05) and increased by PD (15.8 +/- 2.0 pg/24 h; P < 0.005). There were similar changes in MDA excretion. Compared to Veh, ANG II significantly (P < 0.005) increased the renal cortical mRNA expression of p22phox (twofold), Nox-1 (2.6-fold), and Mn-SOD (1.5-fold) and decreased expression of Nox-4 (2.1-fold) and extracellular (EC)-SOD (2.1-fold). Cand prevented all of these changes except for the increase in Mn-SOD. PD accentuated changes in p22phox and Nox-1 and increased p67phox. We conclude that ANG II infusion stimulates oxidative stress via AT1-R, which increases the renal cortical mRNA expression of p22phox and Nox-1 and reduces abundance of Nox-4 and EC-SOD. This is offset by strong protective effects of AT2-R, which are accompanied by decreased expression of p22phox, Nox-1, and p67phox.

Angiotensin II↗
PubMed2003

Roles of oxidative stress and AT1 receptors in renal hemodynamics and oxygenation in the postclipped 2K,1C kidney.

The spontaneously hypertensive rat (SHR) exhibits angiotensin II (Ang II)-dependent oxidative stress and reduced efficiency of renal oxygen usage (QO2) for tubular sodium transport (TNa). We tested the hypothesis that oxidative stress determines the reduced TNa:QO2 ratio in the clipped kidney of the early 2-kidney, 1-clip (2K,1C) Ang II-dependent model. One week after sham operation (Sham) or clip placement, 2K,1C rats received for 2 weeks either a vehicle, the superoxide dismutase mimetic tempol (Temp), or candesartan (Cand). Oxidative stress was assessed from excretion of 8-isoprostaglandin F2alpha (PGF2alpha) and malondialdehyde (MDA) and renal oxygenation from pO2 in the renal cortex and from the ratio of calculated TNa and QO2 values. The mean arterial pressure (MAP) of Sham (113+/-6 mm Hg) was increased in 2K,1C vehicle-treated rats (148+/-4 mm Hg), but both Temp and Cand restored MAP to Sham levels. The excretions of 8-iso-PGF2alpha and MDA were higher in 2K,1C vehicle-treated rats compared with Sham and were normalized by Temp. The pO2 of Sham (42+/-2 mm Hg) was lower in 2K,1C vehicle-treated animals (28+/-2 mm Hg). This was restored to Sham values by Temp (36+/-3 mm Hg) but not by Cand (28+/-2 mm Hg). The TNa:QO2 of Sham (12.9+/-1.6) was reduced in 2K,1C vehicle-treated rats (9.7+/-2.8) and was restored to Sham values by Temp (13.7+/-2.5) but not by Cand (7.5+/-1.6). We conclude that the correction of oxidative stress in the 2K,1C model partially corrects renal cortical hypoxia and inefficient utilization of O2 for Na+ transport, independent of the fall in blood pressure.

Angiotensin Receptor Antagonists↗
PubMed2003

Thromboxane synthase and TP receptor mRNA in rat kidney and brain: effects of salt intake and ANG II.

A TP receptor (TP-R) mimetic causes salt-sensitive hypertension and renal afferent arteriolar vasoconstriction. TP-Rs mediate effects of ANG II on renal vascular resistance and drinking. Therefore, we investigated the hypothesis that thromboxane A(2) synthase (TxA(2)-S) and/or TP-R expression is regulated by salt and/or ANG II. Rats (n = 6) received high-salt (HS) or low-salt (LS) diets. Additional HS-diet rats received ANG II while other HS- and LS-diet rats received the AT(1) receptor (AT(1)-R) antagonist losartan. Excretion of thromboxane B(2) by conscious rats was increased with the HS diet compared with the LS diet (126 +/- 10 vs. 48 +/- 5 pmol/24 h, respectively; P < 0.01). The mRNA abundance for TP-Rs (relative to beta-actin) in the kidney cortex was enhanced 30% by the HS diet (P < 0.001) and was reduced 50% by the addition of ANG II (P < 0.001). However, during losartan administration, the effects of salt were reversed; mRNA more than doubled during the LS diet (P < 0.001). Similarly, the mRNA abundance for TP-Rs in the brain stem was reduced by 50% with the addition of ANG II (P < 0.001) and during losartan administration was almost doubled by the LS diet (P < 0.001). The mRNA abundance for TxA(2)-S in the kidney cortex also was increased many times with the HS diet (P < 0.001). In contrast, the mRNA for TxA(2)-S in the brain was unaffected by salt. ANG II did not affect TxA(2)-S at either site. During losartan administration, TxA(2)-S increased modestly in the brain stem with the LS diet. mRNA abundance for TP-Rs in the kidney cortex and brain stem is suppressed by ANG II acting on AT(1)-Rs. In the absence of AT(1)-Rs, expression of TP-Rs at both sites is enhanced by LS intake. In contrast, ANG II does not affect the mRNA abundance for TxA(2)-S. Expression of TxA(2)-S is enhanced by HS intake in the kidney cortex but by LS intake in the brain stem only during losartan administration. Thus TP-Rs are strongly dependent on ANG II acting on AT(1)-Rs, whereas TxA(2)-S is regulated differentially in the kidney cortex and brain stem by salt intake.

Angiotensin II↗
PubMed2003

Renal oxygenation defects in the spontaneously hypertensive rat: role of AT1 receptors.

BACKGROUND: The spontaneously hypertensive rat (SHR) has oxidative stress and enhanced O2 usage (Q(O2)) relative to tubular sodium transport (TNa). Angiotensin II (Ang II) acting on Type I receptors (AT1-R) causes renal oxidative stress and functional nitric oxide (NO) deficiency that could enhance O2 usage. Therefore, we investigated the hypothesis that AT1-Rs mediate the inefficient renal oxygenation in the SHR. METHODS: Groups of SHR and WKY received vehicle (Veh), candesartan (Cand) or hydralazine + hydrochlorothiazide + reserpine (HHR) for two weeks. RESULTS: Compared to WKY + Veh, the elevated BP of SHR + Veh (153 +/- 3 vs 115 +/- 3 mm Hg; P < 0.001) was normalized by Cand (117 +/- 4) or HHR (113 +/- 5 mm Hg). The reduced renal blood flow of SHR + Veh (2.4 +/- 0.3 vs. 4.1 +/- 0.3 mL. min-1. 100 g-1) was increased (P < 0.05) by Cand (3.6 +/- 0.3) and HHR (3.2 +/- 0.2). Compared to WKY + Veh, SHR + Veh had a 50% reduction in TNa: (16.9 +/- 2.0 vs. 7.8 +/- 0.9 micromol: micromol-1, P < 0.01) that was unchanged by HHR (8.6 +/- 1.1), but was increased by Cand (13.2 +/- 1.4; P < 0.01). The pO2 of outer cortex was lower in SHR + Veh than WKY + Veh (31 +/- 3 vs. 41 +/- 2 mm Hg; P < 0.05) and it was not changed significantly by HHR (37 +/- 2) but was normalized by Cand (44 +/- 3 mm Hg; P < 0.01). The pO2 in the deep cortex also was lower in SHR + Veh than WKY + Veh (18 +/- 3 vs. 30 +/- 3 mm Hg; P < 0.005) and was not changed significantly by HHR (19 +/- 2), but was increased by Cand (25 +/- 3 mm Hg; P < 0.05). CONCLUSIONS: The reduced pO2 in outer and inner cortex, and inefficient utilization of O2 for Na+ transport in the SHR kidney can be ascribed to the effects of AT1-R, largely independent of blood pressure.

Animals↗
PubMed2003

Induction of cytokine tolerance in rodent hepatocytes by chylomicron-bound LPS is low-density lipoprotein receptor dependent.

We examined the role of lipoprotein receptors in mediating chylomicron-bound lipopolysaccharide (CM-LPS)-induced cytokine tolerance in rodent hepatocytes. We found that 2 h of pretreatment with CM-LPS (5 mg TG/mL) was sufficient to induce cytokine tolerance, as measured by decreased nitric oxide (NO) production by hepatocytes (20% of the Control group, P < 0.03). Tolerance was evident as early as 2 h after pretreatment and disappeared after 40 h. Furthermore, we evaluated the roles of the low-density lipoprotein (LDL) receptor (LDLR) and LDL receptor-related protein (LRP) in the induction of cytokine tolerance in hepatocytes. Biochemical inhibition of the receptors or use of hepatocytes from LDLR-deficient mice revealed that functional LDLR was necessary for the induction of tolerance. However, by increasing the pretreatment time, the LRP compensated for the absence of the LDLR in induction of cytokine tolerance. In conclusion, CM-LPS-mediated induction of cytokine tolerance to proinflammatory cytokines is a time- and dose-dependent process that requires functional lipoprotein receptors. These findings underscore an interrelationship between TG-rich lipoprotein metabolism and innate immunity.

Adenoviridae↗
PubMed2002

Chronic hyperosmolarity mediates constitutive expression of molecular chaperones and resistance to injury.

Renal medullary cells are exposed to elevated and variable osmolarities and low oxygen tension. Despite the harsh environment, these cells are resistant to the effects of many harmful events. To test the hypothesis that this resistance is a consequence of these cells developing a stress tolerance phenotype to survive in this milieu, we created osmotically tolerant cells [hypertonic (HT) cells] by gradually adapting murine inner medullary collecting duct 3 cells to hyperosmotic medium containing NaCl and urea. HT cells have a reduced DNA synthesis rate, with the majority of cells arrested in the G(0)/G(1) phase of the cell cycle, and show constitutive expression of heat shock protein 70 that is proportional to the degree of hyperosmolarity. Unlike acute hyperosmolarity, chronic hyperosmolarity failed to activate MAPKs. Moreover, HT cells acquired protein translational tolerance to further stress treatment, suggesting that HT cells have an osmotolerant phenotype that is analogous to thermotolerance but is a permanent condition. In addition to osmotic shock, HT cells were more resistant to heat, H(2)O(2), cyclosporin, and apoptotic inducers, compared with isotonic murine inner medullary duct 3 cells, but less resistant to amphotericin B and cadmium. HT cells demonstrate that in renal medullary cells, hyperosmotic stress activates biological processes that confer cross-tolerance to other stressful conditions.

Adaptation, Psychological↗
PubMed2002

Adenosine A1 receptor antagonists in the kidney: effects in fluid-retaining disorders.

Adenosine A(1) receptor antagonists have been used effectively as potassium-sparing and renal-function-protective diuretics in new studies. In addition, the role of adenosine--acting through adenosine A(1) receptors--in renal autoregulation has been clarified. Finally, the application of adenosine receptor antagonists has been implicated in protection from acute renal failure associated with radiocontrast media treatment.

Animals↗
PubMed2002

Serum levels of Hsp 72 measured early after trauma correlate with survival.

BACKGROUND: Experimental studies have shown that hemorrhagic shock is associated with the expression of inducible heat proteins, especially heat shock protein (Hsp) 72, in liver, brain, heart, and kidney. Moreover, induction of Hsp 72 by various stressors before the onset of shock has been associated with the attenuation of organ injury caused by hemorrhage. However, it is not known whether Hsp 72 is expressed after severe trauma in humans. The purpose of this study was therefore to determine whether Hsp 72 could be detected in the serum of patients early after severe trauma and whether serum levels of Hsp 72 might correlate with survival of trauma patients or the severity of the postinjury inflammatory response. METHODS: Clinical data were collected prospectively over a 3-year period for trauma patients mechanically ventilated for more than 2 days who met the following inclusion criteria: Injury Severity Score > or = 16, and age > 18 years. Physiologic data for quantitative assessment of organ dysfunction were collected for each patient. Hsp 72 and nitrate and nitrite levels were measured in the serum of trauma patients collected at or 12 to 48 hours after the admission to the emergency department. RESULTS: Sixty-seven patients with severe trauma were enrolled in the study. Hsp 72 was detected in the serum of all trauma patients. All patients with high initial serum levels of Hsp 72 (serum levels > 15 ng/mL) survived, whereas 29% of the patients with low Hsp 72 serum levels died from their traumatic injuries (p = 0.01). The overall mortality was 21%, occurring within 5 to 7 days. Patients who died were older (mean age, 54 +/- 15 years) than those who survived (mean age, 36 +/- 15 years) (p < 0.0.05). The cause of death was attributable to head injury in 79%, although the severity of head injury (Abbreviated Injury Scale score) was not statistically different between survivors with high serum values of Hsp 72 and patients who died. There was no correlation between the initial serum Hsp 72 values and the severity of organ dysfunction or clinical indicators of the inflammatory response. CONCLUSION: Hsp 72 can be detected in the serum of severely traumatized patients within 30 minutes after injury. Elevated initial serum levels of Hsp 72 (serum levels > 15 ng/mL) are associated with survival after severe trauma, but are not related to the incidence or severity of the postinjury inflammatory response or organ dysfunction.

Analysis of Variance↗
PubMed2002

Chylomicron-bound endotoxin selectively inhibits NF-kappaB activation in rat hepatocytes.

Triglyceride-rich lipoproteins (chylomicrons and very low-density lipoproteins) bind endotoxin (lipopolysaccharide [LPS]), forming lipoprotein-LPS complexes, and protect against endotoxic shock and death in rodent models of gram-negative sepsis. Hepatocytes play a central role in the protective process, as demonstrated by the increased uptake of chylomicron (CM)-bound LPS by these cells. We have previously reported that CM-LPS complexes inhibit nitric oxide (NO) production by hepatocytes as compared with LPS or CM alone. Herein, we report that CM-LPS selectively inhibits NF-kappaB in hepatocytes. Pretreating cultured primary hepatocyte spheroids with CM-bound LPS inhibited cytokine-induced NF-kappaB activation by approximately 60% vs. untreated control cells (P < 0.03). The lipoprotein-mediated inhibition of NF-kappaB was non-toxic, selective, and associated with inhibition of IkappaB degredation. These data indicate that the mechanism by which CM protect against LPS involves inhibition of the hepatocellular response to proinflammatory stimulation and also support a role for triglyceride-rich lipoproteins as components of the innate host immune response to infection.

Animals↗
PubMed2002

What is brain nitric oxide synthase doing in the kidney?

Brain, or type I, nitric oxide synthase is expressed strongly in the macula densa of the kidney. Functional studies show that it blunts the tubuloglomerular feedback response that causes vasoconstriction of the renal afferent arteriole in response to sodium chloride reabsorption at this site, and regulates renin release from the juxtaglomerular apparatus. Studies published this year have made great progress in defining the mechanism of action of type I nitric oxide synthase on tubuloglomerular feedback. Macula densa-derived nitric oxide can act via both the autocrine and probably the paracrine routes. Nitric oxide bioactivity in the juxtaglomerular apparatus is strongly curtailed by oxidative stress in hypertensive models. The signalling pathways within macula densa cells have been examined in detail. Nitric oxide synthase type I in the macula densa probably adapts renal hemodynamics and possibly renin secretion to changes in blood pressure and salt intake.

Animals↗
PubMed2002

A mouse model of angiotensin II slow pressor response: role of oxidative stress.

ABSTRACT. The slow pressor response to prolonged infusions of angiotensin II (AngII) entails a delayed rise in BP. This study investigated the hypothesis that the response depends on the generation of oxidative stress. The BP and renal functional response of mice to graded doses (200, 400, and 1000 ng. kg(-1). min(-1)) of subcutaneously infused AngII was studied. The SBP of conscious mice increased by day 3 at AngII1000 but showed a delayed rise by days 9 to 13 (slow pressor response) at the lower rates of AngII infusion. By day 13, there was a graded increase in SBP with the rate of AngII infusion (Vehicle, -2.6 +/- 2.6%; AngII200, +14.1 +/- 5.0%; AngII400, +31.9 +/- 1.9%; AngII1000, +43.2 +/- 5.5%). The MAP measured under anesthesia rose significantly (P < 0.001) with AngII400 at 14 d (Vehicle, 85 +/- 2 mmHg; AngII400, 100 +/- 3 mmHg). When studied at day 6, the MAP of AngII400 rats was not elevated (88 +/- 2 mmHg; NS versus vehicle), yet the GFR was higher (1.05 +/- 0.05 versus 1.25 +/- 0.05 ml. min(-1). g(-1); P < 0.05) accompanied by an increase in the filtration fraction (FF) (28.8 +/- 1.2 versus 37.2 +/- 0.8%; P < 0.001). From day 6 through day 14, the MAP had increased (P < 0.01) in AngII400, accompanied by a significant reduction in GFR to 1.05 +/- 0.04 ml. min(-1). g(-1) (P < 0.01) and elevation of renal vascular resistance (RVR) (day 6 versus day 14, 15.3 +/- 0.6 versus 19.2 +/- 1.2 mmHg. ml(-1). min(-1). g(-1); P < 0.05). Renal excretion of 8-iso PGF(2alpha) was increased in AngII400 group at day 12 (2.52 +/- 0.35 versus 5.85 +/- 0.78 pg. day(-1); P < 0.01). The permeant superoxide dismutase mimetic tempol reduced the effects of AngII400 on the SBP (-1.7 +/- 5.8%; P < 0.01), the MAP (87 +/- 4 mmHg; P < 0.01), and the RVR (15.2 +/- 0.5 mmHg. ml(-1). min(-1). g(-1); P < 0.05) at day 14 and the renal 8-iso PGF(2alpha) excretion (3.53 +/- 0.71 pg. d(-1); P < 0.05) at day 12. It is concluded that the AngII infused mouse is a valid model for the slow pressor response. There is an early rise in GFR and FF, consistent with increased postglomerular vascular resistance and a late rise in RVR with a fall in GFR, consistent with increased preglomerular vascular resistance that is accompanied by a rise in BP. There is evidence of increased oxidative stress that is implicated in the increase in the BP and RVR in this model.

Angiotensin II↗
PubMed2002

Diverse effects of mutations in exon II of the von Hippel-Lindau (VHL) tumor suppressor gene on the interaction of pVHL with the cytosolic chaperonin and pVHL-dependent ubiquitin ligase activity.

We examined the biogenesis of the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) in vitro and in vivo. pVHL formed a complex with the cytosolic chaperonin containing TCP-1 (CCT or TRiC) en route to assembly with elongin B/C and the subsequent formation of the VCB-Cul2 ubiquitin ligase. Blocking the interaction of pVHL with elongin B/C resulted in accumulation of pVHL within the CCT complex. pVHL present in purified VHL-CCT complexes, when added to rabbit reticulocyte lysate, proceeded to form VCB and VCB-Cul2. Thus, CCT likely functions, at least in part, by retaining VHL chains pending the availability of elongin B/C for final folding and/or assembly. Tumor-associated mutations within exon II of the VHL syndrome had diverse effects upon the stability and/or function of pVHL-containing complexes. First, a pVHL mutant lacking the entire region encoded by exon II did not bind to CCT and yet could still assemble into complexes with elongin B/C and elongin B/C-Cul2. Second, a number of tumor-derived missense mutations in exon II did not decrease CCT binding, and most had no detectable effect upon VCB-Cul2 assembly. Many exon II mutants, however, were found to be defective in the binding to and subsequent ubiquitination of hypoxia-inducible factor 1alpha (HIF-1alpha), a substrate of the VCB-Cul2 ubiquitin ligase. We conclude that the selection pressure to mutate VHL exon II during tumorigenesis does not relate to loss of CCT binding but may reflect quantitative or qualitative defects in HIF binding and/or in pVHL-dependent ubiquitin ligase activity.

Carcinoma, Renal Cell↗
PubMed2002

Role of thromboxane receptors in the dipsogenic response to central angiotensin II.

Central angiotensin II (ANG II) regulates thirst. Because thromboxane A2-prostaglandin H2 (TP) receptors are expressed in the brain and mediate some of the effects of ANG II in the vasculature, we investigated the hypothesis that TP receptors mediate the drinking response to intracerebroventricular (icv) injections of ANG II. Pretreatment with the specific TP-receptor antagonist ifetroban (Ifet) decreased water intake with 50 ng/kg icv ANG II (ANG II + Veh, 7.2 +/- 0.7 ml vs. ANG II + Ifet, 2.8 +/- 0.8 ml; n = 5 rats; P < 0.001) but had no effect on water intake induced by hypertonic saline (NaCl + Veh, 8.4 +/- 1.1 ml vs. NaCl + Ifet, 8.9 +/- 1.8 ml; n = 5 rats; P = not significant). Administration of 0.6 microg/kg icv of the TP-receptor agonist U-46,619 did not induce drinking when given alone but did increase the dipsogenic response to a near-threshold dose of 15 ng/kg icv ANG II (ANG II + Veh, 1.1 +/- 0.7 vs. ANG II + U-46,619, 4.5 +/- 0.9 ml; n = 5 rats; P < 0.01). We conclude that central TP receptors contribute to the dipsogenic response to ANG II.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2002

Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney.

Phagocytes generate superoxide anion (O(2)(-)) by a classic, 5-component NADPH oxidase. O(2)(-) contributes to hypertension in spontaneously hypertensive rats (SHR). Therefore, we tested the hypothesis that NADPH oxidase expression is enhanced in the SHR kidney. We also analyzed the localization of NADPH oxidase components in SHR kidney. Renal NADPH oxidase was quantified by reverse transcription-polymerase chain reaction and Western blotting and was localized in SHR and Wistar Kyoto rat (WKY) kidney by immunohistochemistry. The mRNA for 5 subunits of phagocyte NADPH oxidase, and also for MOX1 and RENOX (NOX4), was detected in adult rat kidney. Kidneys of adult (10 weeks old) SHR had a significantly (P<0.01) greater mRNA for p47phox (SHR 0.81 +/- 0.05 versus WKY 0.37 +/- 0.01, arbitrary unit), which was confirmed by Western blotting (SHR 0.58 +/- 0.04 versus WKY 0.42 +/- 0.04, arbitrary unit; P<0.05) and by immunohistochemistry. This higher p47phox protein expression was also detected in young prehypertensive SHR (SHR 0.61 +/- 0.05 versus WKY 0.39 +/- 0.04, arbitrary unit; P<0.01). The 10-week-old SHR contained more modest but significantly (P<0.05) greater protein for p67phox (SHR 0.54 +/- 0.02 versus WKY 0.46 +/- 0.02). Immunostaining localized p47phox, p67phox, and p22phox in vasculature, macula densa, distal convoluted tubule, cortical collecting duct, and outer and inner medullary collecting ducts. The kidney of SHR expresses genes for all the main components of phagocyte NADPH oxidase, RENOX, and MOX1. There is a prominent increase in the SHR kidney of the mRNA, and protein expression of p47phox in the vasculature, macula densa, and distal nephron, which precedes development of hypertension.

Animals↗
PubMed2002

Adenosine type 1 receptor antagonists in fluid retaining disorders.

Adenosine is a vasoactive hormone whose action is mediated through at least four receptors. The most prevalent receptors are type 1, which promote vasoconstriction, and type 2, comprised of 2 subtypes (a,b) that promote vasodilation. In the kidney, type 1 receptors located on preglomerular vessels and in the tubule are involved in the regulation of glomerular filtration. Whole body fluid balance is strongly dependent on the ability of the kidney to maintain stable glomerular filtration. Several antagonists to adenosine type 1 receptors have been developed. These agents generate excess fluid (diuresis) and sodium (natriuresis) excretion in control animals and animal models of fluid retention, as well as in normal and oedematous humans. In both animals and humans, these effects are generally achieved without major changes in glomerular filtration. Animal studies have confirmed the location of adenosine type 1 receptors in relevant tissue sites in the kidney. More highly selective antagonists for adenosine type 1 receptors are regularly developed, improving their use in fluid retaining disorders. Clinical trials with these agents have commenced for the treatment of hypertension, renal failure and congestive heart failure, all disorders that include varying levels of fluid retention. The clinical trial results have been mixed. The early results with congestive heart failure suggest great promise for these agents, whereas trials in hypertension and renal failure have been equivocal.

Animals↗
PubMed2002

Initial compound selection for sequential screening.

Initial leads for drug development often originate from high-throughput screening (HTS), where hundreds of thousands of compounds are tested for biological activity. As the number of both targets for screening and compounds available for screening increase, there is a need to consider methods for making this process more efficient. One approach is to screen sequentially, whereby a relatively small set of compounds is assayed and the results are statistically analyzed to produce a mathematical model. The model is used to predict activity and select additional compounds for screening. The new compound bioassay results are added to the results for the initial set and a new model is determined. The process iterates. The focus of this review is on how to select the initial screening set (ISS). It is presumed that the size and quality of the initial set will affect the subsequent model building and, hence, the efficiency of finding active compounds.

Algorithms↗