Free radical scavenging reverses fructose-induced salt-sensitive hypertension

We have previously reported that a moderate dietary supplementation of 20% fructose but not glucose leads to a salt-sensitive hypertension related to increased proximal sodium-hydrogen exchanger activity and increased renal sodium retention. We also found that while high salt increased renal nitric oxide formation, this was retarded in the presence of fructose intake. We hypothesized that at least part of the pathway leading to fructose-induced salt-sensitive hypertension could be due to fructose-induced formation of reactive oxygen species and inappropriate stimulation of renin secretion, all of which would contribute to an increase in blood pressure. We found that both 20% fructose intake and a high-salt diet stimulated 8-isoprostane excretion. The superoxide dismutase (SOD) mimetic tempol significantly reduced this elevated excretion. Next, we placed rats on a high-salt diet (4%) for 1 week in combination with normal rat chow or 20% fructose with or without chronic tempol administration. A fructose plus high-salt diet induced a rapid increase (15 mmHg) in systolic blood pressure and reversed high salt suppression of plasma renin activity. Tempol treatment reversed the pressor response and restored high salt suppression of renin. We conclude that fructose-induced salt-sensitive hypertension is driven by increased renal reactive oxygen species formation associated with salt retention and an enhanced renin-angiotensin system

Free radical scavenging reverses fructose-induced salt-sensitive hypertension

We have previously reported that a moderate dietary supplementation of 20% fructose but not glucose leads to a salt-sensitive hypertension related to increased proximal sodium-hydrogen exchanger activity and increased renal sodium retention. We also found that while high salt increased renal nitric oxide formation, this was retarded in the presence of fructose intake. We hypothesized that at least part of the pathway leading to fructose-induced salt-sensitive hypertension could be due to fructose-induced formation of reactive oxygen species and inappropriate stimulation of renin secretion, all of which would contribute to an increase in blood pressure. We found that both 20% fructose intake and a high-salt diet stimulated 8-isoprostane excretion. The superoxide dismutase (SOD) mimetic tempol significantly reduced this elevated excretion. Next, we placed rats on a high-salt diet (4%) for 1 week in combination with normal rat chow or 20% fructose with or without chronic tempol administration. A fructose plus high-salt diet induced a rapid increase (15 mmHg) in systolic blood pressure and reversed high salt suppression of plasma renin activity. Tempol treatment reversed the pressor response and restored high salt suppression of renin. We conclude that fructose-induced salt-sensitive hypertension is driven by increased renal reactive oxygen species formation associated with salt retention and an enhanced renin-angiotensin system

Synthesis of 125 I‐labeled 14‐iodo‐9‐tetradecynoic acid

The synthesis and radioiodide exchange labelling of 14‐iodo‐9‐tetradecynoic acid (1), a potential suicide inhibitor of acyl‐CoA dehydrogenase or enoyl‐CoA isomerase, is presented. Tissue distribution data in dogs are reported.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90063/1/2580180911_ftp.pd

Role of neuropeptide Y in the development of two-kidney, one-clip renovascular hypertension in the rat

AbstractObjective: Along with the renin-angiotensin system, sympathetic stimulation may contribute to renovascular hypertension. The vasoactive peptide neuropeptide Y (NPY) is co-released with and potentiates the pressor effects of norepinephrine through the Y-1 receptor. NPY, by exaggerating sympathetic activity, may contribute to renovascular hypertension, possibly by augmenting adrenergic-mediated renin release. This was studied by determining the effect of continuous Y-1 blockade on the development of two-kidney, one-clip renovascular hypertension and the effect of NPY on in vitro renin release. Methods: Mean arterial pressure and renal blood flow responses to NPY (10 μg/kg, administered intravenously) were measured in five anesthetized Sprague-Dawley rats before and after BIBO3304TF administration to test the Y-1 antagonist BIBO3304TF. In hypertension studies, 28 rats underwent left renal artery clipping. Of these, 13 were implanted with a mini-osmotic pump for continuous BIBO3304TF infusion (0.3 μg/h, administered intravenously); the other 15 underwent sham implantation. Systolic blood pressure was then monitored for 4 weeks. Finally, in vitro renin release was measured from renal cortical slices (n = 6-12) incubated with NPY (10–8 to 10–6 mol/L) or NPY plus the adrenergic agonist isoproterenol (10–4 mol/L). Results: BIBO3304TF attenuated the NPY-induced increase in mean arterial pressure by 54% (P <.02) and the NPY-induced decrease in renal blood flow by 38% (P <.05). In 4-week hypertension studies, systolic blood pressure in clipped controls increased from 130 ± 3 mm Hg to 167 ± 6 mm Hg (P <.01), whereas BIBO3304TF-treated rats had no significant increase (125 ± 3 mm Hg to 141 ± 8 mm Hg). Final systolic blood pressure was 26 mm Hg lower in BIBO3304TF-treated rats than in controls (P <.01). In renal cortical slices, no NPY effect was observed in basal or isoproterenol-stimulated renin release. Conclusions: The Y-1 receptor antagonist BIBO3304TF attenuated acute pressor responses to NPY and blunted the development of two-kidney, one-clip renovascular hypertension in rats. NPY may contribute to the hypertensive response in this renovascular hypertension model. Our in vitro data do not suggest that this is due to NPY enhancement of renin release. (J Vasc Surg 2000;32:1015-21.

Dot-based ELISA and RIA: Two rapid assays that screen hybridoma supernatants against whole live cells

Two assays are described that are suitable for the screening of large numbers of hybridoma supernatants as well as for the screening of a wide range of tissues for the distribution of a given cell surface antigen. These assays use whole live cells as targets, avoiding fixation or extraction, which could alter the antigenic structural profile. The assays are rapid, simple and inexpensive. Their advantages and applications are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24666/1/0000079.pd

Applications of [131I]m-iodobenzylguanidine ([131I]MIBG)

The development of the aralkylguanidine [131I]m-iodobenzylguanidine ([131I]MIBG) in the University of Michigan Nuclear Medicine Division has led to diagnostic and therapeutic evaluations of all the neuroendocrine tumors. These tumors share the property of uptake, storage and release of [131I]MIBG uptake in chromaffin granules. This property has allowed the detection of pheochromocytomas, the detection of metastases in 46% of such patients, the treatment of malignant pheochromocytomas, the detection of neuroblastoma metastases, the treatment of neuroblastomas and the detection of a percent of apudomas. We have learned how to improve our results and this is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26908/1/0000474.pd

High-dose, unlabeled, nonspecific antibody pretreatment: influence on specific antibody localization to human melanoma xenografts

Nonspecific uptake of radiolabeled monoclonal antibodies in normal tissues is a significant problem for tumor imaging. A potential means of decreasing nonspecific antibody binding is to “blockade” nonspecific antibody binding sites by predosing with cold, nonspecific isotypematched antibody, before injecting specific antibody. Nontumor-specific murine monoclonal antibody LK2H10 (IgG1) or Ab-1 (IgG2a) was given i.v. at doses of 0 to 3.5 mg to nude mice with xenografts of human melanoma. These mice were then given i.v. 4 μg of 131 I anti-high molecular weight antigen of melanoma (HMWMAA) monoclonal antibody 763.24T (IgG1) or 225.28S (IgG2a), respectively. These mice were also given a tracer dose of 125 I LK2H10 or Ab-1, respectively. Specific tumor uptake of anti-HMWMAA antibodies was see in all cases. No drop in tumor or nontumor uptake was demonstrated for either of the tumor-specific or nonspecific monoclonal antibodies due to nonspecific monoclonal antibody pretreatment. These data suggest that high doses of isotype-matched unlabeled nonspecific monoclonal antibody given before 131 I tumor-specific monoclonal antibody, will not enhance tumor imaging.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46853/1/262_2004_Article_BF00205633.pd

Improved radioimmunolocalization of human tumor xenografts following subcutaneous delivery of monoclonal antibodies

The localization of a radiolabeled murine monoclonal antibody reactive with choriocarcinomas to human choriocarcinoma xenografts following intravenous and subcutaneous injection was evaluated by gamma scanning and tissue sampling. Tumor xenografts were established in the popliteal node region of athymic nude mice after repeated innoculations of the hind foot pads with BEWO choriocarcinoma cells. In dual label specific antibody studies, tumor/non tumor uptake ratios following subcutaneous (resulting in considerable intralymphatic uptake) injection of 131 I-5F9.3 were significantly higher than those achieved post simultaneous intravenous injection of 125 I-5F9.3. Double label experiments with 131 I-5F9.3 and a nonspecific antibody, 125 I-UPC-10, following subcutaneous injection, demonstrated that the high localization to popliteal region tumors was largely due to antibody specificity. Gamma scans following subcutaneous antibody administration of specific antibody to tumor bearing animals showed tumors soon after subcutaneous injection, at times earlier than those typically seen following intravenous delivery. Similar subcutaneous injections showed little normal nodal uptake in BALB/c control animals on gamma scans. No correlation was seen between tumor localization by specific antibody between the intravenous and intralymphatic routes, implying a difference in the mechanisms of tumor uptake of antibody by these two routes. The subcutaneous approach to antibody delivery offers advantages over intravenous delivery in tumors of human origin, including higher tumor/non tumor ratios and earlier imaging times. This was true even though these tumors were many times larger than normal lymph nodes. This subcutaneous delivery advantage should be exploitable in imaging nodal metastases of human tumors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46825/1/259_2004_Article_BF00256630.pd

Extra-adrenal and metastatic pheochromocytoma: The role of 131 I meta-iodobenzylguanidine ( 131 I MIBG) in localization and management

From June, 1980, to August, 1983, 131 I MIBG scintiscans were performed in 353 patients with suspected pheochromocytomas. Extra-adrenal pheochromocytomas were identified in 15 of 18 patients who at operation were proven to have such tumors and normal adrenal glands. Conventional localization studies, often repeated, had failed to localize these tumors in nearly all cases. Nine of the extraadrenal pheochromocytomas were found within the middle mediastinum. This group of unique tumors required further specialized localization studies with augmented computed tomography (CT) scans for specific anatomical delineation. These complementary studies allowed for precise planning of surgical excision of the tumors, which required cardiopulmonary bypass in some patients. Extraadrenal pheochromocytomas were identified in a family with no other endocrinopathies. The tumors in 3 patients from 3 different generations all were perirenal and involved the vena cava. 131 I MIBG scintiscans detected metastatic lesions in 40 patients with malignant pheochromocytomas. Metastases were not readily demonstrated in 4 patients. The diagnosis of malignant and metastatic pheochromocytoma was first made by the scintiscan findings in 5 patients. 131 I MIBG scans were not false-positive in any cases and were falsenegative in 10.5% of 95 patients proven to have pheochromocytomas by biochemical evidence or operation. Ten patients have been treated for malignant pheochromocytomas with therapeutic doses of 131 I MIBG. Five patients have had objective responses with diminution in size of metastases or primary malignant tumor and a decrease in the secretion of catecholamines. This agent has been found to be of great value in detecting pheochromocytomas that often have defied all other means of localization. 131 I MIBG concentrates in most malignant pheochromocytomas, and preliminary results suggest that it will be very useful in the treatment of this disease. De juin 1980 à août 1983, 353 malades suspects d'être porteurs de phéochromocytomes ont été soumis à la scintigraphie à l'iode marqué: I 131 métaiodobenzylguanidine (I 131 MIBG). Des phéochromocytomes extra-surrénaliens ont été découverts chez 15 des 18 sujets suspects d'être porteurs de telles lésions extra-surrénaliennes, ce qui fut constaté lors de l'intervention qui démontra que les surrénales étaient normales. Les autres méthodes conventionnelles n'avaient pas permis de localiser ces tumeurs dans la majorité des cas. Neuf des phéochromocytomes extra-surrénaliens furent découverts dans la partie moyenne du médiastin. Ce groupe de tumeurs implique la mise en oeuvre de techniques particulières en plus du scanner pour localiser la tumeur. Ces explorations complémentaires permettent de planifier l'intervention chirurgicale qui peut nécessiter l'emploi d'une circulation extra-corporelle. Des phéochromocytomes extra-surrénaliens ont été découverts dans une famille qui ne présentait pas d'autres endocrinopathies. Les tumeurs chez 3 malades appartenant à 3 générations différentes siégeaient hors de la surrénale et intéressaient la veine cave. La scintigraphie à l'I 131 marqué a permis de découvrir des métastases chez 40 malades porteurs d'un phéochromocytome malin, mais fut en défaut dans 4 cas. Le diagnostic de phéochromocytome malin avec métastase fut porté initialement chez 5 malades. La scintigraphie ne se solda par aucun faux positif mais 10,5% de faux négatifs furent constatés chez 95 malades où la présence d'un phéochromocytome fut prouvée par les données biologiques ou opératoires. Dix malades atteints de phéochromocytomes malins ont été traités par l'I 131 marqué. Cinq d'entre eux accusèrent une diminution de volume de la tumeur et des métastases et une diminution de la sécrétion des catécholamines. L'iode marqué: I 131 méta-iodobenzylguanidine permet de déceler les phéochromocytomes qui échappent aux autres explorations. Le fait qu'il s'accumule électivement au niveau de la tumeur permet de penser qu'il pourra jouer un rôle actif dans le traitement de l'affection. El diagnóstico de feocromocitoma con frecuencia es más simple que establecer la localización anatómica del tumor, lo cual es difícil, especialmente cuando el feocromocitoma es maligno, extraadrenal o bilateral. Aproximadamente el 10% de los feocromocitomas se origina en tejido cromafino ubicado en algún lugar entre la base del cráneo y la vejiga. La tomografía computadorizada de tercera generación es extremadamente precisa en la localización de lesiones intra-adrenales, pero no es muy util en la identificación de feocromocitomas extra-adrenaleso metastásicos. Hasta muy recientemente no existía modalidad alguna capaz de proveer documentación anatómica y funcional del tumor con anterioridad a la intervención quirúrgica. La síntesis de la I 131 metayodo-benzilguanidina (I 131 MIBG) ha hecho posible obtener imágenes scintigráficas de feocromocitomas y de tejido cromafino hiperplásico.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41315/1/268_2005_Article_BF01654948.pd

Radioiodine therapy of thyroid disease

Ten "ideal" steps used at the University of Michigan to treat well-differentiated thyroid cancer are presented. Using this in 103 patients with well-differentiated thyroid carcinoma and metastases outside their neck, those that were freed of their disease after 131I therapy survived three times as long as those not cured of their disease. Patients successfully cured of their metastases showed better conformity to the "ideal" steps than the patients with residual metastases. Each of the most commonly asked questions about 131I treatment of thyroid carcinoma following surgical treatment are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26907/1/0000473.pd