Biomedical subjects

M J Field

Publications and source records attributed to M J Field.

At least 19 recordsLinked to original sources

PubMed1992

Tubular sodium handling and tubuloglomerular feedback in compensatory renal hypertrophy.

Tubular sodium handling and tubuloglomerular feedback (TGF) activity were assessed in established compensatory renal hypertrophy in Sprague Dawley rats. Hyperfiltration at the level of the single nephron was confirmed 4-6 weeks following a reduction in renal mass. TGF activity, determined as the difference between late proximal and early distal measurements of single-nephron glomerular filtration rate (SNGFR), was significantly increased in compensatory renal hypertrophy, being 7.8 +/- 1.0 vs 23.3 +/- 1.9 vs 25.5 +/- 2.6 nl/min (P for analysis of variance less than 0.05) following sham operation, unilateral nephrectomy, and 1 1/3 nephrectomy, respectively. Enhanced net tubular Na transport was also observed, with total Na reabsorption up to the late proximal site being 1.8 +/- 0.2 vs 2.7 +/- 0.1 vs 3.1 +/- 0.3 nmol/min (P less than 0.05), and to the early distal site being 3.4 +/- 0.5 vs 5.8 +/- 0.6 vs 7.9 +/- 0.8 nmol/min (P less than 0.05) in the three animal groups respectively. Comparison of proximal tubular length demonstrated a 71.9 +/- 8.1% increase in uninephrectomised vs sham-operated animals. This increase was proportionately greater than the increase in proximal Na reabsorption (50.0 +/- 4.0%) observed in the corresponding animal groups. Concurrent electron microprobe experiments in uninephrectomised and sham-operated animals demonstrated that the proximal tubular intracellular Na concentration was significantly lower following uninephrectomy (16.8 +/- 0.6 vs 18.9 +/- 0.5 mmol/kg wet weight, P less than 0.01), in association with evidence of reduced basolateral Na/K-ATPase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Prolongation of canine islet allograft survival by 15-deoxyspergualin.

Previously we have shown that nonsteroidal, multimodal immunosuppression consisting of cyclosporine (CsA), azathioprine (AZA), and RBC-absorbed goat anti-dog lymphoblast globulin (ALG), at doses considered tolerable in humans, results in limited canine islet allograft survival. Regimens including the diabetogenic agent prednisone are even less successful. In our search for an immunosuppressive regimen that could be applied to human islet transplantation, we tested the effect of 15-deoxyspergualin (DSG) in a canine model. Animals received either CsA, 20 mg/kg/day; AZA, 2.5 mg/kg/day; and ALG, 20 mg/kg/day x 14 days (Group I) or CsA, AZA, ALG at the same doses with the addition of low dose DSG, 0.5 mg/kg/day (Group II). Trough CsA levels by high pressure liquid chromatography ranged in both groups between 100 and 200 micrograms/liter. Rejection of the islets was diagnosed when serum glucose remained greater than 200 mg/dl for 3 consecutive days. There was no significant difference in the number of islets per kilogram of body weight of recipient transplanted in Group I and Group II (5754 +/- 2544 islets/kg versus 7953 +/- 3440 islets/kg, respectively). Animals receiving ALG, CsA, and AZA alone achieved a median islet allograft survival of 4 days, with a mean of 10.8 days. However, with the addition of low-dose DSG, median islet allograft survival was improved to 22 days, with a mean of 32.4 days (P = 0.012, Mann-Whitney test). We conclude that the addition of low-dose DSG to an ALG induction, cyclosporine-based immunosuppressive regimen enhances canine islet allograft survival and has potential for application in clinical islet allotransplantation.

Animals↗

PubMed1992

Evidence for activation of tubuloglomerular feedback following nephrectomy in human subjects.

The intrarenal regulation of glomerular filtration rate (GFR) following a reduction in renal mass was evaluated in six normal subjects, studied before and 4 to 6 weeks after undergoing unilateral nephrectomy, performed for the purpose of living-related transplantation. The role of the tubuloglomerular feedback (TGF) system in regulating the final GFR on both occasions was assessed by determining the increase in GFR over baseline levels following blockade of TGF by a single dose of bumetanide, care being taken to replace sodium and water losses. Before donor nephrectomy, baseline GFR was 115 +/- 7 mL/min, which increased by 9.5% +/- 2.5% to 126 +/- 9 mL/min following the removal of TGF. Four to six weeks following donor nephrectomy, the baseline GFR was 83 +/- 8 mL/min, confirming significant hyperfiltration in the remaining kidney. After administration of bumetanide, the GFR increased by 15.6% +/- 3.1% to 96 +/- 9 mL/min. This greater fractional increase (P < 0.025) indicates an increase in tonic TGF activity in the uninephrectomized state compared with that demonstrated before nephrectomy. The results suggest that the hyperfiltration response following unilateral nephrectomy is limited by an appropriately activated TGF system. This phenomenon may be of importance in the maintenance of Na and water homeostasis, as well as limiting the pathological consequences that may result from, or be exacerbated by, an excessively high filtration rate in the remaining nephrons. Thus, dietary or therapeutic maneuvers that impair the TGF response may be best avoided following a reduction in renal mass.

Adult↗

PubMed1992

Simulation analysis of triose phosphate isomerase: conformational transition and catalysis.

A theoretical approach is employed to study the catalysis of the dihydroxyacetone phosphate (DHAP) to D-glyceraldehyde 3-phosphate (GAP) reaction by the enzyme triose phosphate isomerase (TIM). The conformational change in a loop involved in protecting the active site from solvent is examined by use of X-ray data and molecular dynamics simulations. A mixed quantum-mechanics and molecular mechanics potential is used to determine the energy surface along the reaction path. The calculations address the role of the enzyme in lowering the barrier to reaction and provide a decomposition into specific residue contributions. To obtain a clearer understanding of the electronic effects, the polarization of the substrate carbonyl group by the active site residues is examined and compared with FTIR measurements on the wild-type and mutant forms of the enzyme.

Amino Acid Sequence↗

PubMed1992

Differential effects of preexisting uremia and a synchronous kidney graft on pancreas allograft functional survival in rats.

Pancreas transplant results have been better in uremic recipients of a simultaneous kidney than in nonuremic recipients of a pancreas alone. We studied the relative effect of uremia versus a double transplant on functional survival by performing bladder-drained pancreas transplants alone (PTA), kidney transplants alone (KTA), and simultaneous pancreas/kidney (SPK) transplants from Buffalo donors to diabetic Lewis rat recipients that were or were not made uremic 2-3 weeks before by 1 4/5 native nephrectomy. Pancreas graft exocrine function was monitored by urinary amylase (UA). In the PTA and SPK recipients made diabetic by streptozotocin, endocrine function was monitored by measuring nonfasting plasma glucose (PG) levels. Kidney graft function was monitored by plasma creatinine (Cr). Rejection of the endocrine pancreas was defined as an increase of PG to greater than 200 mg/dl; of the exocrine pancreas, as a decline in UA to less than 6000 U/L or to less than 100 U/24 hr; and of the kidney, as an elevation of Cr to greater than 3 mg/dl. The mean functional survival times (MST) of both the endocrine (12.0 +/- 2.1 versus 10.1 +/- 1.1 days, P = 0.036) and exocrine (8.0 +/- 2.1 versus 6.3 +/- 1.3 days, P = 0.016) components of the pancreas grafts were significantly longer in SPK than in PTA recipients. The MST of kidney allografts, however, was not significantly longer in nonuremic SPK than nonuremic KTA recipients (6.7 +/- 1.4 versus 5.7 +/- 0.7 days, P = 0.13). In parallel experiments in recipients immunosuppressed with cyclosporine, the graft survival times were longer, but the relative differences between the PTA, SPK, and KTA groups persisted. Histologically, lymphocyte infiltration began in the two organs almost simultaneously, but the severity of the rejection was more vigorous in the kidney than in the pancreas in doubly grafted rats, and destruction of pancreas grafts progressed more slowly in SPK than in PTA recipients. Preexisting uremia delayed pancreas rejection in both SPK (exocrine 10.6 +/- 2.3, P = 0.032, and endocrine 14.8 +/- 3.4 days, P = 0.065, versus nonuremics) and PTA (exocrine 8.5 +/- 1.7, P = 0.007, and endocrine 12.6 +/- 2.5, P = 0.026, versus nonuremics) nonimmunosuppressed recipients. The MST of kidney grafts was not significantly longer in uremic (8.9 +/- 2.8 days) than in nonuremic (6.7 +/- 1.4 days) SPK recipients (P = 0.081). A synchronous kidney transplant and uremia independently down-modulate the rejection response to a pancreas graft, and a simultaneous pancreas graft has no detrimental effect on the survival of a kidney graft.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Renal handling of endogenous lithium in experimental diabetes mellitus in the rat.

1. The usefulness of determining the renal handling of endogenous lithium as a marker of proximal tubular sodium reabsorption was assessed in streptozotocin induced diabetes mellitus in the Sprague-Dawley rat. 2. The clearance and fractional excretion of lithium were determined before and following the development of diabetes mellitus, and compared with measurements of proximal tubular reabsorption made directly using micropuncture techniques. Endogenous lithium was measured in order to avoid the toxic tubular effects of exogenously administered lithium salts. 3. Although a trend existed for a reduction in the fractional excretion of lithium in diabetic animals (1.8 +/- 0.3 vs 2.4 +/- 0.5%; P greater than 0.20), this did not reach statistical significance and did not accurately reflect the change in directly measured tubular Na reabsorption. 4. The decrease in proximal tubular Na reabsorption demonstrated in diabetic animals treated with phlorizin was not significantly reflected in the fractional lithium excretion, although again a corresponding trend was evident (1.9 +/- 0.8 vs 0.6 +/- 0.2%; P greater than 0.10. 5. In summary, the significant alterations in tubular Na handling in diabetes mellitus, previously demonstrated directly using micropuncture techniques, are not reflected in the renal handling of endogenous lithium. This indirect method is inadequate to assess proximal tubular Na transport in experimental diabetes mellitus.

Animals↗

PubMed1992

The antagonism of benzodiazepine withdrawal effects by the selective cholecystokininB receptor antagonist CI-988.

The ability of a selective cholecystokininB (CCKB) receptor antagonist, CI-988, to block benzodiazepine withdrawal effects was examined in mice. The discontinuation of twice daily administration of diazepam (1 mg kg-1, i.p.) induced withdrawal anxiogenesis and a proconvulsant effect. In contrast, no such effects were seen following withdrawal from similar administration of CI-988. However, CI-988 dose-dependently (0.001-1.0 mg kg-1, s.c.) antagonized both the anxiogenesis and the proconvulsant effect following diazepam-withdrawal.

Animals↗

PubMed1992