Effects of single-dose and fractionated cranial irradiation on rat brain accumulation of methotrexate.

The effects of single-dose and fractionated whole-brain irradiation on brain methotrexate (MTX) has been studied in a rat model. The amount of MTX present in the brain 24 hr after a single i.p. dose (100 mg/kg) was the same wether animals were sham irradiated or given a single dose of 2000 rads 6 or 48 hr prior to the drug (6.9, 8.3, and 6.8 pmol MTX/g, wet weight, respectively). Animals sham irradiated or given 2000 rads in 10 fractions over 11 days and treated with an average dose of 1.2 mg MTX/kg i.p. twice a week for 24 weeks did not differ significantly in their brain MTX concentration (7.9 and 8.3 pmol MTX/g, wet weight, respectively). Chronically MTX-treated animals became folate deficient whether they were irradiated or not (450 and 670 pmol folate/g, wet weight, brain in MTX-treated and control animals). Thus, MTX accumulates in the brain with acute or chronic administration, and this accumulation is not altered by this amount of brain irradiation.

Neutrophil cathepsin G is specifically decreased under vitamin A deficiency.

Vitamin A deficiency leads to an increased susceptibility to infections, increased severity of infections and increased mortality. Because the neutrophil is the first cell to respond to infection, this study explores the effect of vitamin A deficiency on neutrophil proteinases. We found that neutrophils from vitamin A-deficient rats had lower levels of two cathepsin G-like enzymes (28 and 24 kDa) when compared to neutrophils from weight-matched pair-fed rats, vitamin A-deficient rats which were repleted with retinyl palmitate and nonrestricted vitamin A complete diet rats. The 28 kDa cathepsin G-like enzyme, which migrated with the same mobility as elastase on SDS-polyacrylamide gels, was quantified using Western blots. The 24 kDa cathepsin G-like enzyme was quantified using zymogram gels. This activity was inhibited by chymostatin. Other neutrophil proteinases, elastase, plasminogen activators and gelatinase, were not altered significantly by vitamin A deficiency. The low levels of cathepsin G may contribute to differences in the inflammatory process observed under vitamin A deficiency.

ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy.

Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway. Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy; an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

Intermittent use of a perfluorochemical emulsion (Fluosol-DA 20%) and carbogen breathing with fractionated irradiation.

Oxygen carrying perfluorochemical emulsions have been shown to enhance the response of animal tumors to large single doses of radiation. Clinically, however, perfluorochemical emulsions are being used with only some fractions in multiple fraction radiation courses. To test the efficacy of a perfluorochemical emulsion under conditions that are closer to those used in current clinical trials, BA1112 rat sarcomas were treated with three fractions per week of 6 Gy per fraction. Once a week, animals were infused i.v. with a perfluorochemical emulsion at 15 ml/kg, and allowed to breathe carbogen (95% O2:5% CO2) for 30 minutes prior to and during irradiation. The 50% tumor control dose was 93.1 (87.9-103.1) Gy in the control arm compared to 74.3 (64.9-83.9) Gy for the animals given the perfluorochemical infusion plus carbogen breathing. The dose modification factor for intermittent perfluorochemical infusion and carbogen breathing was 1.26 (1.15-1.40). In a similar fractionated schedule, the hypoxic cell radiosensitizer, misonidazole, given once per week at 600 mg/kg, gave a dose modification factor of 1.22 (1.14-1.32).

Late toxicity of total body irradiation with bone marrow transplantation in a rat model.

In defined-flora, barrier-maintained rats, radiation nephritis is the principle late toxicity seen after high dose-rate total body irradiation (TBI), when hematologic toxicity is prevented by bone marrow transplantation (BMT). Pneumonitis develops only if rats are placed in a conventional microbiological environment during and after BMT. Low dose-rate TBI gives qualitatively similar late toxicity, but at radiation doses twice as large. Fractionation of the TBI has little effect on the bone marrow ablation doses, but results in increased gastrointestinal and renal tolerance. The addition of immunosuppressive or cytotoxic drugs (cyclosporine-A, methotrexate, cis-platinum) after TBI and BMT greatly decreases the dose of TBI that can be tolerated. The use of a cyclophosphamide plus cytosine arabinoside conditioning regimen prior to TBI and BMT increases the bone marrow ablation dose, but has no effect on acute gastrointestinal toxicity or on renal toxicity. These results indicate that substantial late toxicity may be associated with the TBI conditioning regimens used for BMT even in the absence of cytotoxic and antibiotic drugs, immunosuppressive agents, infection and graft-versus-host disease; and that radiation may be a contributing factor in the nephritis sometimes observed after TBI and BMT.

Influence of nephrotoxic drugs on the late renal toxicity associated with bone marrow transplant conditioning regimens.

The total body irradiation that is given as part of bone marrow transplant conditioning regimens is a factor in the renal toxicity that is observed after bone marrow transplant, but it may not be the only factor. We hypothesize that nephrotoxic drugs used in prior chemotherapy can precipitate renal radiation damage. Studies were designed to determine if nephrotoxic antineoplastic drugs could shorten the latent period for the development of radiation nephritis. Rats were given bilateral renal irradiation using a radiation schedule that produced moderate nephritis. Cisplatinum, BCNU, or mitomycin were given before, during, or after irradiation at doses that produced only mild nephrotoxicity. All cisplatinum-radiation sequences resulted in decreased renal function, with radiation prior to cisplatinum producing the greatest dysfunction. BCNU increased renal dysfunction equally in all schedules, but mitomycin had only minimal effects. Most drug schedules, including those with mitomycin, produced earlier development of morbidity after fractionated renal irradiation. In a second set of studies, rats were given single doses of the same nephrotoxic drugs, followed 3 months later by total body irradiation plus bone marrow transplant. The drugs had no effect on the marrow ablation dose, but BCNU and cisplatinum decreased gastrointestinal tolerance. Four months after total body irradiation, rats which received drugs alone or total body irradiation alone have essentially normal renal function, but rats which received cisplatinum plus total body irradiation or BCNU plus total body irradiation show a dose-dependent decrease in renal function. These studies show that radiation nephritis can be precipitated by low doses of nephrotoxic drugs, and may help to explain the incidence of early radiation nephritis in bone marrow transplant patients conditioned with total body irradiation.

Treatment of radiation nephropathy with ACE inhibitors.

PURPOSE: A previous study showed that radiation nephritis could be treated with captopril, an angiotensin-converting-enzyme inhibitor. These studies were designed to determine whether other angiotensin-converting-enzyme inhibitors would be effective, whether captopril would inhibit the development of the histopathologic lesions typical of radiation nephritis, and whether captopril could be used to treat the nephropathy observed in bone marrow transplant recipients conditioned with total body irradiation. METHODS AND MATERIALS: In radiation nephritis studies, rats were given 17-27 Gy bilateral renal irradiation in 5 fractions. Six months after irradiation animals were stratified by blood urea nitrogen and assigned to no treatment, or treatment with captopril (500 mg/l) or enalapril (50 mg/l) in the drinking water. A subset of animals was sacrificed for histopathology after 3 months; the remaining animals continued on drugs for 7 months. In the bone marrow transplant nephropathy study, rats received 14-17 Gy total body irradiation in 6 fractions over 3 days followed by syngeneic bone marrow transplant. Six months after irradiation, animals were stratified by blood urea nitrogen and assigned to no treatment, or treatment with captopril (500 mg/l). Animals remained on drugs for 6 months. In all studies animals were followed with periodic renal function tests. RESULTS: In the radiation nephritis study, survival and renal function were significantly enhanced by both captopril and enalapril, but there were no significant differences between the drugs. The histopathologic severity of the lesions of radiation nephritis correlated with the degree of renal dysfunction; and in irradiated animals with equal initial azotemia, captopril-treated rats developed less severe renal lesions. Finally, captopril also prolonged survival and preserved renal function in this rat bone marrow transplant nephropathy model. CONCLUSION: Angiotensin-converting-enzyme inhibitors are an effective treatment for both radiation nephritis and bone marrow transplant nephropathy.

Tumor and normal tissue tolerance for fractionated low-dose-rate radiotherapy.

Radiobiological evidence suggests that an improved therapeutic ratio might be achieved through the use of smaller than conventional dose fractions. The ultimate in small dose fractions for external beam radiotherapy would be fractionated low-dose-rate (LDR) irradiation, and clinical trials of fractionated external beam LDR therapy are already in progress. Using the BA1112 rat sarcoma, we have determined the 50% tumor control dose for LDR and for conventional-dose-rate (CDR) fractionated radiotherapy. These tumor control doses were compared to normal tissue tolerance doses for hemi-body irradiation in similar CDR and LDR schedules. Animals were treated 3 times per week without anesthesia using 10-19 fractions. LDR radiotherapy was done with 60Co at dose rates of 0.028-0.033 Gy/min; CDR radiotherapy was done with 250 kVp X rays at dose rates of 0.54-2.1 Gy/min. The tumor control dose modification factor (DMF) for LDR compared to CDR irradiation was 1.3 (1.0-1.5). For LDR and CDR hemi-body irradiation, the dose modification factor for 7 day lethality (gastrointestinal damage) was 1.7 (1.5-1.9), for 100 day morbidity was 1.8 (1.6-2.2), and for radiation nephritis at 90 days was 1.9 (1.7-2.3). The therapeutic gain factor for fractionated low-dose-rate irradiation compared to conventional-dose-rate fractionated radiotherapy was therefore 1.8/1.3 = 1.4 (1.2-1.8). The study shows that there is an experimental as well as a theoretical basis for anticipating a therapeutic benefit from the use of external beam fractionated LDR radiotherapy, and implies that the recognized therapeutic efficacy of brachytherapy is not due solely to the high localized dose.

Effect of nephrotoxic drugs on the development of radiation nephropathy after bone marrow transplantation.

PURPOSE: Chronic renal failure is a significant cause of late morbidity in bone marrow transplant patients whose conditioning regimen includes total body irradiation (TBI). Radiation is a major cause of this syndrome (bone marrow transplant nephropathy), but it may not be the only cause. These studies use a rat syngeneic bone marrow transplant model to determine whether nephrotoxic agents used in conjunction with bone marrow transplantation (BMT) could be enhancing or accelerating the development of radiation nephropathy. METHODS AND MATERIALS: Rats received 11-17 Gy TBI in six fractions over 3 days followed by syngeneic bone marrow transplant. In conjunction with the bone marrow transplants, animals received either no drugs, cyclosporine, amphotericin, gentamicin, or busulfan. Drugs were given in schedules analogous to their use in clinical bone marrow transplantation. Drug doses were chosen so that the drug regimen alone caused detectable acute nephrotoxicity. Animals were followed for 6 months with periodic renal function tests. RESULTS: Gentamicin had no apparent interactions with TBI. Amphotericin increased the incidence of engraftment failure, but did not enhance radiation nephropathy. Cyclosporin with TBI caused late morbidity that appeared to be due to neurological problems, but did not enhance radiation nephropathy. Busulfan resulted in a significant enhancement of radiation nephropathy. CONCLUSION: Of the nephrotoxins used in conjunction with bone marrow transplantation only radiation and busulfan were found to be risk factors for bone marrow transplant nephropathy.

Hepatic function and drug pharmacokinetics after total body irradiation plus bone marrow transplant.

Radiation nephritis is the principle late toxicity seen after total body irradiation in barrier-maintained rats when hematologic toxicity is prevented by bone marrow transplantation. Renal dysfunction is observed for single doses as low as 7.5 Gy. Hepatic blood flow, as measured by indocyanine green clearance, is decreased after 8.5-9.5 Gy single-dose total body irradiation. Serum albumin levels are decreased after 9.5 Gy single-dose total body irradiation. Hypoalbuminemia is a symptom of hepatic damage, but can also be caused by renal damage or edema. No decrease in total serum protein is observed, indicating that proteinuria resulting from renal damage is not the cause of hypoalbuminemia. No edema and some dehydration are observed. These data indicate that hepatic damage as well as renal damage may be occurring after total body irradiation plus bone marrow transplantation. Animals given total body irradiation plus bone marrow transplantation show decreased tolerance to a wide variety of immunosuppressive and cytotoxic drugs, even when these drugs are given months after total body irradiation. Altered drug clearance after total body irradiation plus bone marrow transplantation is observed for cis-platinum, vincristine, and adriamycin. The increase in cis-platinum toxicity after total body irradiation plus bone marrow transplantation is caused by decreased renal drug clearance. The decrease in vincristine tolerance and the alterations in adriamycin and vincristine pharmacokinetics are caused by altered drug distribution after total body irradiation plus bone marrow transplantation. These results indicate that bone marrow transplant survivors may show altered clearance of, and decreased tolerance to, a wide variety of drugs that are used after bone marrow transplantation.

Renal irradiation and the pharmacology and toxicity of methotrexate and cisplatinum.

We used a rat model to study the effects of renal irradiation on the pharmacology of methotrexate (MTX) and cisplatinum (cis-Pt). Unanesthetized rats were given bilateral kidney irradiation (20 Gy in 9 fractions). At 9 months after irradiation, 3% of the animals had died and survivors showed moderately impaired renal function. At 15 months, 30% of the animals had died and survivors showed severely impaired renal function. Some animals were given i.v. MTX 1 week to 15 months after irradiation. In irradiated rats, the area under the MTX plasma clearance curve equaled that of controls through 6 months, and was significantly above controls from 9 months on. Other animals were given i.p. cis-Pt 1 week to 9 months after irradiation. The acute toxicity of cis-Pt was the same in control and irradiated rats when cis-Pt was given immediately before or after irradiation. Beginning 3 months after irradiation there was a progressive increase in cis-Pt toxicity and a simultaneous decrease in urinary platinum excretion. Irradiated animals that survived cis-Pt treatment showed increased radiation nephritis; the greatest effect occurred when cis-Pt was given 3 months or more after irradiation. MTX and cis-Pt clearance decreased when renal dysfunction was first observed and changes in renal function preceded changes in drug clearance and toxicity.

Development of a rat lung cancer model.

A rat lung cancer model based on intrabronchial instillation of a tumor cell suspension has been developed for use in therapy and toxicity testing. Two tumors were used in this study, a sarcoma and an adenocarcinoma, both of which were of spontaneous origin in the strain of rats used. The inoculated tumor cells implant on the bronchiolar mucosa, forming a detectable single "primary" tumor resembling the spontaneous lung cancers arising in humans. The tumor growth is detectable by use of diagnostic radiographs, weight loss and other "clinical" signs. The tumors appear on chest radiographs 3 to 5 weeks after inoculation, and the implant rate is proportional to the number of tumor cells inoculated. Untreated animals have a median survival (after radiographic detection of the tumor) of 8 days, and die of local complications of tumor growth. When a slow growing transplantable tumor line of lung origin is developed, this model will be used to evaluate radiotherapy and chemotherapy schedules.

Chronic effects of fractionated renal irradiation on the pharmacokinetics of intravenous methotrexate.

the chronic effects of renal irradiation on the pharmacology of methotrexate was studied in a rat model. Unanesthetized rats received 2 doses of bilateral fractionated kidney irradiation (16.2 Gy or 19.8 Gy in 9 fractions). Alterations in renal function were first seen at 3 months in the 19.8 Gy group and 12 months in the 16.2 Gy groups. Life table analysis showed a shift in the survival curve of about 3 months between the 2 radiation doses. The pharmacokinetics of i.v. methotrexate showed an increase in the area under the plasma curve beginning at 9 months in the 19.8 Gy group and at 15 months in the 16.2 Gy group. The volume of distribution of methotrexate was smaller in the irradiated rats than in unirradiated controls. Multiple linear regression models showed significant correlations between parameters of methotrexate clearance and certain renal function tests. Nevertheless, no set of renal function tests consistently predicted alteration in methotrexate clearance in the 2 radiation groups. Furthermore, time after irradiation remained a highly significant variable indicating that renal irradiation causes time dependent change in methotrexate pharmacokinetics that can not be accounted for by the usual tests of renal function.

MRI measurements correctly predict the relative effects of tumor oxygenating agents on hypoxic fraction in rodent BA1112 tumors.

PURPOSE: We evaluate whether magnetic resonance imaging (MRI) with blood oxygenation level-dependent (BOLD) contrast correctly predicts the relative effects of tumor-oxygenating agents on hypoxic fraction in BA1112 rhabdomyosarcomas in WAG/Rij rats. METHODS AND MATERIALS: The response of ten tumors to carbogen (95% O(2)/5% CO(2)), a perfluorocarbon emulsion (PFC), and the combination of PFC + carbogen was studied with high spectral and spatial resolution MR imaging of the water resonance at 4.7 Tesla. Decreases in MR signal linewidth indicate increases in tumor blood oxygen levels. RESULTS: Average MR signal linewidth was decreased 2.0% by carbogen, 2.5% by PFC + air, and 4.9% by PFC + carbogen. PFC + carbogen caused a larger linewidth decrease than either treatment alone (p < 0.04 by ANOVA). Maps of pixels responding to treatment indicate that combining PFC with carbogen significantly enlarges the area of the tumor in which oxygen levels are increased (p < 0.01 by ANOVA). CONCLUSION: MRI predicts that PFC + carbogen will increase radiosensitivity more than either treatment alone; this agrees with the known effects of these treatments on hypoxic fraction. Utilizing MRI to choose the treatment that maximizes the size and extent of increases in tumor oxygenation could reduce hypoxic fraction.

Radiation nephropathy is treatable with an angiotensin converting enzyme inhibitor or an angiotensin II type-1 (AT1) receptor antagonist.

BACKGROUND AND PURPOSE: Previous studies showed that progression of established radiation nephropathy could be delayed by continuous treatment with high doses of captopril, an angiotensin-converting-enzyme (ACE) inhibitor. The current studies were designed to determine whether a lower dose or a shorter treatment with captopril would be effective and whether an angiotensin II type-1 (AT1) receptor antagonist (AII blocker) would be effective. MATERIALS AND METHODS: In the captopril studies, rats were given renal irradiation at doses sufficient to produce radiation nephropathy. Six months after irradiation, animals were stratified by azotemia and assigned to no treatment, continuous high- or low-dose captopril, or 6 weeks of high-dose captopril. Captopril was given in drinking water at 62.5 mg/l (low dose) or 500 mg/l (high dose). The AII blocker study had a similar design, except that the nephropathy was the result of total body irradiation and bone marrow transplantation and the treatments were no treatment or continuous treatment with an AII blocker, L-158,809 (20 mg/l in drinking water). Animals were followed for 1 year with periodic studies of renal function. RESULTS: Survival and renal function were significantly enhanced by all treatments. Continuous captopril treatment was more effective than the 6-week course of treatment, but there was no difference in effectiveness between the high and low doses of captopril. In continuous therapy, captopril and the AII blocker had roughly equivalent efficacy. CONCLUSIONS: Both the ACE inhibitor and the AII blocker were effective treatments for established radiation nephropathy. The best results with the ACE inhibitor required continuous therapy, but could be achieved with a low dose of the drug.

Noncontinuous use of angiotensin converting enzyme inhibitors in the treatment of experimental bone marrow transplant nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors can be used to prevent the development of radiation nephropathy after BMT. In previous BMT nephropathy studies, ACE inhibitor therapy was started pre-BMT and continued indefinitely. In preparation for clinical trials, studies were designed to determine whether effective prophylaxis could be achieved if ACE inhibitor therapy was started after engraftment, and to determine whether ACE inhibitors needed to be given indefinitely. The present studies in our rat syngeneic BMT model showed that captopril therapy started 25 days post-BMT was as effective as therapy started prior to BMT. When ACE inhibitor therapy was discontinued 28 weeks after BMT, the protective effect was not lost if adequate control of azotemia had been maintained for 26 weeks. If adequate control of azotemia was not maintained for 26 weeks, BMT nephropathy progressed rapidly when ACE inhibitor therapy ended, and slowly when it was continued. Failure to control azotemia was a better predictor of renal failure than failure to control hypertension or proteinuria. Based on these preclinical studies, it would appear that ACE inhibitor therapy will be effective in the prophylaxis of BMT nephropathy even if begun after engraftment, and that ACE inhibitors may not need to be given indefinitely.

Age dependence of radiation nephropathy in the rat.

A higher incidence of radiation nephropathy is reported in pediatric than in adult patients. Preliminary experiments showed that juvenile rats had lower renal tolerance than adult rats. The experiments reported here were designed to determine the age at which tolerance changes and the magnitude of the change. Five- to 25-week-old rats were given bilateral kidney irradiation with 15-29 Gy X rays given in five fractions. Renal function was assessed 4 and 6 months after irradiation. Isoeffect doses for renal dysfunction were 15.5-17.5 Gy for rats irradiated at 5-8 weeks of age and 20.2-25.2 Gy for rats irradiated at 12+ weeks of age. At 23 Gy, rats irradiated at 5.5 weeks of age developed renal failure after 16 weeks; this increased to 21 weeks for irradiation at 7.5 weeks of age and to 27+ weeks for irradiation at 12-27 weeks of age. Renal tolerance increased steadily for irradiation at ages between 5-10 weeks, and maximum tolerance was reached by 12-15 weeks of age; a similar dependence on age at irradiation was found for bone marrow transplant nephropathy. The decrease in renal radiosensitivity with age may partially explain the increased incidence of radiation nephropathy in pediatric populations.

Prophylaxis of bone marrow transplant nephropathy with captopril, an inhibitor of angiotensin-converting enzyme.

Chronic renal failure occurs in about 20% of long-term survivors treated with bone marrow transplant (BMT) regimens that include total-body irradiation (TBI); this syndrome is called BMT nephropathy. In a previous study in a syngeneic rat BMT model it was shown that captopril (an inhibitor of angiotensin-converting enzyme) could be used to treat experimental BMT nephropathy. Current studies were designed to determine whether captopril could also be used to prevent BMT nephropathy. Rats received 14 to 18.5 Gy TBI in six fractions over 3 days followed by syngeneic BMT. Seven days before TBI half the rats were started on captopril (500 mg/liter in the drinking water). Blood urea nitrogen, ratios of urine protein to creatinine, serum creatinine, and blood pressure were used to assess renal function. In animals receiving TBI alone, BMT nephropathy developed 3 to 6 months after transplant. At 6 months after TBI, captopril-treated animals had lower systolic blood pressure and better-preserved renal function than animals receiving TBI alone, with dose-modifying factors of about 1.3. The captopril treatment had no effect on bone marrow ablation by TBI. Captopril appears to be safe and effective in the prophylaxis of BMT nephropathy.

Treatment of radiation nephropathy with captopril.

Both experimental and clinical radiation nephropathy are typically progressive, evolving to kidney failure over weeks to months. Other late radiation injuries (spinal cord, lung) are also progressive and have no known specific antidote. Recent reports of the efficacy of captopril in modifying radiation injury of the lung prompted this trial of captopril in treating established radiation nephropathy. Six months after 15-27 Gy in 12 fractions bilateral renal irradiation, 72 rats with blood urea nitrogen > 4.1 mmol/liter were started on captopril (500 mg/liter) or no drug in the drinking water. Subsequent survival was significantly enhanced in rats receiving captopril as opposed to no drug (P = 0.0013), and the rate of rise of blood urea nitrogen was significantly diminished (P < 0.0001) in the animals on captopril. Urine protein excretion was also reduced from initially elevated levels in the rats on captopril compared to levels in rats given no drug. We conclude that captopril therapy preserves kidney function, reduces proteinuria, and enhances survival in experimental radiation nephropathy.

Brief pharmacological intervention in experimental radiation nephropathy.

Brief postirradiation treatment with an angiotensin-converting enzyme (ACE) inhibitor has been shown to be effective in reducing the severity of radiation nephropathy in rats. The efficacy of brief treatment with an ACE inhibitor was shown to be greatest when the animals were young when irradiated and when the treatment was given 4 to 10 weeks after bone marrow transplantation (BMT). In further studies with a BMT nephropathy model, we have shown that brief treatment with an angiotensin II type I receptor antagonist (AII blocker) is even more effective than brief treatment with an ACE inhibitor. We have also shown that an NO synthase inhibitor, which exacerbated radiation nephropathy when given continuously, has no effect when given during the postirradiation interval when ACE inhibitors and AII blockers were most effective. Studies also showed that the loss of efficacy of brief treatment with increased age at irradiation parallels the decrease in radiosensitivity that occurs with increasing age at irradiation, but that this decrease in radiosensitivity is not sufficient to explain the loss of efficacy of brief treatment. These data indicate that the renin-angiotensin system is important in the expression of renal radiation injury, particularly between 4 and 10 weeks after irradiation.