Hemodynamic characterization of YM435, a novel dopamine DA1 receptor agonist, in anesthetized dogs

In previous studies on experimental renal failure, hypertrophy of cardiomyocytes, diminished capillarization, and increased intercapillary distances had been observed, abnormalities that will expose the heart to reduced ischemia tolerance. It has not been established, however, whether such structural alterations are unique for the heart (eg, as a consequence of left ventricular hypertrophy) or are demonstrable in other tissues as well. Clarification of this point is important to test hypotheses on some potential mechanisms for cardiac undercapillarization. To address this issue further, we compared capillary length density (by stereologic techniques) in perfusion-fixed skeletal muscle (m. psoas) and hearts of subtotally nephrectomized (SNX) rats with moderate renal failure to those in sham-operated pair-fed controls. The duration of renal failure was 8 weeks. SNX rats had significantly higher mean systolic blood pressure (128 mm Hg v 109 mm Hg), serum creatinine, and urea levels. Despite pair feeding, the mean body weight was significantly lower in the SNX rats (409 g v 471 g), but the left ventricular weight to body weight ratio tended to be higher than in the sham-operated controls (2.39 mg/g v 2.13 mg/g). In the heart, myocyte mean cross-sectional area (675 +/- 112 microm2 v 545 +/- 111 microm2) and volume density of nonvascular interstitial tissue (3.47 +/- 1.04 v 1.33 +/- 0.22) were significantly higher in the SNX rats than in the controls. In parallel, myocardial capillary length density was significantly reduced after subtotal nephrectomy (3,036 +/- 535 mm/mm3 v 3,916 +/- 615 mm/mm3). In contrast, in skeletal muscle, myocyte cross-sectional area (3,109 +/- 783 microm2 v 3,042 +/- 639 microm2), capillary length density (718 +/- 248 mm/mm3 v 717 +/- 184 mm/mm3), and three-dimensional capillary fiber ratio (2.10 +/- 0.26 v 2.13 +/- 0.4) were similar in SNX and control rats. These data document a selective defect of capillarization in the heart of animals with moderate renal failure, pointing to tissue-specific abnormalities of cardiac capillarogenesis.     

Mechanisms of cellular injury in ischemic acute renal failure

Poisoning often does not require toxicology laboratory analysis, though support is necessary from the departments of hematology and biochemistry. There are some compounds, such as paracetamol (acetaminophen), lithium, and methanol, for which quantitative or qualitative analysis is essential for effective patient management. Standard methods such as immunoassays, chromatography, and spectrophotometry have been extended by mass spectrometry and will be enhanced by nuclear magnetic resonance and by hyphenated techniques (e.g., LC-MS-MS). The new perspectives that can be gained with these techniques may greatly improve our knowledge of toxicokinetics and enable better patient management. Comatose patients and those with suspected brain death comprise a difficult group requiring comprehensive toxicologic screens. Although current immunoassay-chromatography methods are adequate, it is to be hoped that more comprehensive screens are achievable. The author has performed trials on TLC-FABMS-MS as a potential procedure and has obtained satisfactory preliminary results. This and other spectrometric-spectroscopic methods may be the techniques of the future for reference centers.     

Leukocytes, cell adhesion molecules and ischemic acute renal failure

Ischemic acute renal failure (ARF) is a common clinical syndrome, associated with high morbidity and mortality, for which there is no specific therapy. Polymorphonuclear neutrophils (PMN) recruited during reperfusion have been implicated as mediators of renal parenchymal injury in ischemic ARF. Leukocyte adhesion molecules appear to facilitate PMN recruitment in this setting. Complementary studies using monoclonal antibodies, antisense oligonucleotides and gene "knock-out" indicate that blockade of CD11/CD18 integrins and intercellular adhesion molecule-1 (ICAM-1) attenuates ARF in some experimental models of renal ischemia. These exciting observations may herald the development of novel anti-adhesion strategies for use in human disease.     

Antidepressant effects of pramipexole, a novel dopamine receptor agonist

These studies compared the effects of the 5-HT1B/1D receptor agonists sumatriptan, CP-122 288 ((R)-N-methyl-[3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl] methanesulphonamide succinate) and CP-93 129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one dihydrochloride) on neurogenic dural extra-vasation and vasodilation in anaesthetized rats. Dural extravasation, evoked by high intensity (1.2 mA) stimulation of the trigeminal ganglion, was measured using the radioactive plasma marker 125I-labelled bovine serum albumin. Dural vasodilation produced by lower intensity (50-300 microA) stimulation of trigeminal fibres, was measured through a closed cranial window using intravital microscopy. All compounds inhibited dural extravasation (rank order of potency: CP-122 288 > > sumatriptan > CP-93 129) and dural vasodilation (rank order of potency: CP-93 129 > > sumatriptan = CP-122 288). Comparison of the potency of these compounds with their potencies in an in vitro functional model, agonist-induced [35S]GTP gamma S binding, suggests that blockade of dural extravasation was consistent with an action at rat 5-HT1D receptors, but activity at another, unknown, "extravasation receptor" could also be involved. In contrast, inhibition of dural vasodilation was consistent with an action at rat 5-HT1B receptors. We suggest that in our preparations, production of dural vasodilation involves activation of trigeminal A delta-fibres whereas production of dural extravasation involves activation of trigeminal C-fibres. The differential effects of compounds on dural extravasation and vasodilation may therefore be due to the different receptor subtypes involved and to the selective localization of these subtypes on different populations of trigeminal sensory fibre.     

Macrophage and myofibroblast involvement in ischemic acute renal failure is attenuated by endothelin receptor antagonists

BACKGROUND: Endothelin (ET) may be a mediator of injury following ischemia-induced acute renal failure (ARF). ET receptor (ETR) antagonists have been reported to increase survival rates and lower serum creatinines when administered postrenal ischemia-reperfusion injury in the rat. Renal cellular and extracellular matrix responses to this therapy have not been addressed. METHODS: We investigated the use of ETR antagonists, PD 156707 (ETA) and SB 209670 (ETA and ETB) in the treatment of sublethal postischemic ARF. The right kidney of female Sprague-Dawley rats weighing approximately 200 g was removed. After five days, the left renal pedicle was occluded for 45 minutes. Twenty-four hours after renal ischemia, one of two ETR antagonists, PD 156707 (N = 7) or SB 209670 (N = 8), was administered. Experimental animals were compared with an ischemic group receiving only saline (N = 9). Three nephrectomized groups that did not undergo ischemia but that received infusions of saline (N = 6), PD 156707 (N = 6), and SB 209670 (N = 6), respectively, were also studied. Animals were sacrificed one week postischemia. Quantitation of monocytes and macrophages (Mo/Mphi), alpha-smooth muscle actin-positive myofibroblasts, and collagens type III and IV was performed by immunohistochemical staining. Cell kinetics were examined by staining for apoptosis with terminal deoxyuridine triphosphate (dUTP) nick end labeling and for proliferation with proliferating cell nuclear antigen. RESULTS: All ischemic groups of rats initially developed raised serum creatinine levels; however, no significant difference was observed between the groups (Kruskal-Wallis). Creatinines returned to preischemic values in all groups by the time of sacrifice. No significant difference in kidney weights or body weights was found between groups. Histologically, infiltration of Mo/Mphi was significantly reduced in groups treated with ETR antagonists (P < 0.001). The presence of myofibroblasts was also significantly reduced in the antagonist-treated groups (P < 0. 001). This was also paralleled by reduced quantities of collagen IV in the treated rat groups (P < 0.001). The interstitial area was also significantly greater in the saline group (P < 0.001). The amount of collagen III did not significantly differ between rat groups. Apoptosis was reduced (P < 0.001) by treatment with ETR antagonists, whereas proliferation was enhanced (P < 0.005). All non-ischemic groups showed no variation in any parameter studied at this time point. CONCLUSIONS: Treatment of ischemic ARF in the rat with ETR antagonists PD 156707 and SB 209670 attenuated cellular infiltration and matrix accumulation. An advantage of one antagonist over the other could not be determined in this study. The marked discrepancy between function and pathology (former unchanged, latter markedly improved) may be due to the time frame of this experiment, and longer outcome measures need to be assessed.     

Effect of prostaglandin E administration in a nephrotoxic and a vasoconstrictor model of acute renal failure

This study examines certain aspects of the interaction of acridines with DNA. A comparative study of the methods available for the determination of the association constants (Kap) for compounds which interact with DNA has been pursued. A new equation which permits the spectrophotomeric determination of Kap has been derived. This equation can be applied to compounds which upon interaction with a polymer exhibit discrete absorption changes. Application of this equation to substituted acridines and tetrahydroacridines yields some preliminary information on the effect of ring substituents on the interaction of acridines with DNA. Low levels of DNA/dye ratios have been used in the studies reported herein.     

Morphology of ischemic acute renal failure, normal function, and cyclosporine toxicity in cyclosporine-treated renal allograft recipients

To characterize morphologic changes in the early post-transplant period in cyclosporine-treated renal allograft recipients, we examined biopsies from three groups of cyclosporine-treated patients: normal function (N = 9), ischemic acute renal failure or "acute tubular necrosis" (N = 12), and cyclosporine toxicity (N = 7). Groups were compared with each other and with previously studied groups of azathioprine-treated patients and native kidney patients. The interstitial infiltrate commonly observed in normally functioning azathioprine-treated grafts was not observed in normally functioning cyclosporine-treated grafts, but two of nine such grafts had a significant venulitis, a change also seen in three of the patients with cyclosporine nephrotoxicity. "Acute tubular necrosis" (ATN) in cyclosporine-treated graft recipients was characterized by focal necrosis of complete tubular cross sections, a finding normally rare in other types of ATN, and by shedding into the tubular lumen of tubular cells with non-pyknotic nuclei, a finding supporting our previous observation of detachment of viable tubular cells in ATN but not in the normal kidney. Hyaline arteriolar thickening was the only morphologic finding on biopsy which distinguished patients with cyclosporine nephrotoxicity from other groups. In summary, the morphologic changes observed in cyclosporine-treated renal allograft recipients with ATN or normal function are quite different from those observed in azathioprine-treated patients. Cyclosporine appears to enhance the tubular injury observed in ATN. Hyaline arteriolar thickening is the main distinguishing feature of cyclosporine nephrotoxicity.     

Orthostatic acute renal failure in a renal transplant

Complications due to ureteric obstruction are an occasional cause for renal transplant dysfunction. Here we report an unusual case of orthostatic renal failure in a renal transplant recipient. Our patient had the previously reported predisposing risk factors including: female sex, obesity, and lax abdominal musculature. It is important to recognize this unusual complication of renal transplantation early in order to preserve long-term graft function.     

Mechanisms of insulin-like growth factor-I-induced accelerated recovery in experimental ischemic acute renal failure

Every year more than one million fractures of the proximal femur occur in the world, especially in older persons. Given the continuous aging experienced by populations, such fractures will become more frequent from year to year and will constitute a growing public health problem. The largest increase is expected to occur in countries of Latin America around the year 2050. Since nearly 70% of all atraumatic fractures in persons over 45 are due to osteoporosis, a case-control study was conducted in the city of Mar del Plata, Argentina, for the purpose of investigating the incidence of and the risk factors associated with proximal femur fractures due to osteoporosis. Between 1 August 1992 and 31 July 1993, a record was kept of all fractures of the proximal femur due to osteoporosis in persons over 50 years of age that visited any of the city's 30 public and private health centers. A total of 246 cases was recorded. The incidence rate per 100,000 inhabitants in the above-50 population was 259 among women and 92 among men, for a ratio of 2.8:1. The incidence was consistently higher in the older age groups, especially in persons over 75. Factors associated with a statistically significant increased risk of fracture of the proximal femur were: a history of neurologic disorders, psychotherapeutic drug use, alcohol consumption, previous fractures, cardiovascular disease, and a decreased intake of milk products. There were no observed differences between cases and controls with respect to age at menopause, weight, height, previous activity, smoking habits, or sun exposure, nor were such differences detected in terms of the percentage of women who had undergone oophorectomy.     

YM796, a novel muscarinic agonist, improves the impairment of learning behavior in a rat model of chronic focal cerebral ischemia

Four-layered microgyria is associated with many developmental disorders, including mental retardation, epilepsy, and developmental dyslexia. Freezing lesions to the newborn rodent neocortex result in the formation of four-layered microgyria. Previous research had suggested this type of injury acts as an hypoxic/ischemic event to the developing cortical plate. The current study examines the effectiveness of the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) in protecting against freezing injury to the newborn rat cortical plate. Three groups of rats received freezing injury to the cortical plate on the first day of life (postnatal day 1). Two groups were treated with MK-801 (1 or 2 mg/kg) 0.5 h before the lesion and 6 and 14 h after, while one group received saline injections. A fourth group received MK-801 injections, but did not have a freezing lesion. The volume of neocortical abnormality was determined for all three groups in rats killed after postnatal day 7. Treatment with the higher dose of MK-801 (3 x 2 mg/kg) dramatically reduced the effects of freezing injury but also resulted in over 50% mortality in both lesioned and unlesioned groups. Animals in the lesioned group, however, had a decreased volume of abnormal cortex, and there were fewer animals with microsulci than in the untreated group. This is the first demonstration of a significant anatomical neuroprotective effect in newborns leading to a reduction of cortical malformation.     

Effect of essential amino acid supplementation in acute renal failure

The effect of intravenous (i.v.) essential amino acids (EAA) in the treatment of acute renal failure was evaluated in 50 patients. Thirty patients (Group A) received daily 13.4 g of i.v. EAA solution [Nephramine (Don Baxter, McGraw) 250 ml/d]+dopamine i.v. 2 micrograms/kg/min + 20% hypertonic glucose solution 500 ml/d as compared with twenty patients (Group B) who received dopamine i.v. 2 micrograms/kg/min + 20% hypertonic glucose solution 500 ml/d. In Group A patients showed lower daily increase in blood urea nitrogen (BUN) (p < 0.05), higher serum total protein and albumin levels on the 15th day of the posttherapy period (p < 0.001), lower complication rate (p < 0.005), lower mortality rate (p < 0.005) and a reverse relation between serum total protein concentration, duration of oliguria and age (p < 0.01, r2 = 0.26; p < 0.001, r2 = 0.32). These data suggest that treatment of such patients with i.v. EAA solutions significantly improves survival.     

Evaluation of myoglobin clearance during continuous hemofiltration in a swine model of acute renal failure

Rhabdomyolysis is characterized by extensive damage of striated muscle, while the major complication of this disease is the development of acute myoglobinuric renal failure. Although first described more than five decades ago very little has changed with regard to the management of this entity as conventional hemodialysis has not been shown to effect myoglobin elimination. However, continuous arteriovenous hemofiltration (CAVH) offers an alternative to conventional hemodialysis as this procedure is more effective particularly for removing larger molecular weight substances such as myoglobin. We studied the effect of CAVH on myoglobin clearance in an animal model of acute myoglobinuric renal failure. Swine (n = 6) were given 4 grams of equine myoglobin intravenously and underwent the CAVH procedure for six hours each. Once the filtering process was initiated there was a rapid and sustained production of ultrafiltrate. The clearance of myoglobin via the hemofilter was 2.05 +/- 1.48 L/day. The amount of myoglobin excreted in the ultrafiltrate over the six hour filtering period was 410 +/- 234 mg which accounts for 10.27 +/- 5.85 percent of the administered dose. Based on these findings, it appears that the hemofiltration system is a viable option for the removal of myoglobin from the systemic circulation.     

Altered sphingomyelinase and ceramide expression in the setting of ischemic and nephrotoxic acute renal failure

In order to make rational decisions for further implementation of picture archiving and communication systems (PACS) in Viennese community hospitals, an assessment of the Sozialmedizinisches Zentrum Ost (SMZO) project was launched by the Viennese community hospital financing body. The aim of the technology assessment was to look at the experiences of day-to-day practice, organizational aspects of, and obstacles to developing the full potential of the PACS installation. The study analyzes the conditions for employment of digital radiology, gathers the experiences of national and international projects, and presents a view on critical points, from which options for further implementation can be derived. In the center of interest stood work organization, handling and user attitudes, perceptions of radiologists and clinicians, realism of expectations regarding economic efficiency, technical aspects, and influence of quality of medical care.     

Risk modeling in acute renal failure requiring dialysis: the introduction of a new model

Predicting patient outcome in acute renal failure has become increasingly important as technology advances and ethical questions arise concerning life supporting therapies. We propose a new model which uses mortality as an endpoint and may be applied to the acute renal failure patient in the ICU setting who requires dialysis. This model is based on our ICU acute renal failure registry and has been prospectively validated for our institution. Our registry for the purposes of developing this model consists of data from 512 ICU patients requiring acute dialysis from 1988 until 1992. The model was developed by testing a variety of potential risk factors for mortality in a univariate analysis (Student's t-test and Chi square), and those factors found to be significant (p < 0.05) were subsequently tested in a multivariate fashion. The factors found significant included male gender, respiratory failure requiring intubation, hematologic dysfunction (platelet count < 50,000, leukocyte count < 2,500, or bleeding diathesis), bilirubin < 2.0 mg/dl, the absence of surgery, serum creatinine on the first dialysis treatment day, an increasing number of failed organ systems, and an increased BUN from the time of admission. Weights are assigned to each variable based on the odds ratio, and a score is generated with a range of 0 to 20. The initial data for the registry demonstrates good fit using the Hosmer and Lemeshow goodness-of-fit table. The model is next validated in 88 patients from 1993 through February 1994, then prospectively tested in 35 additional patients using a standard data collection form, and the model continues to demonstrate good fit. Although this model has been prospectively validated at our institution, this model or any such predictive model should be used with caution if not independently validated at any institution which proposes its use.     

Pharmacology of a mixed 5-hydroxytryptamine1A/dopamine agonist

U-67413B (4-hydroxydipropylaminodihydrophenalene) bound with high affinity to both 5-hydroxytryptamine (HT)1A and D2-dopamine (DA) receptor sites. U-67413B depressed 5-HT and DA cell firing rates and depressed synthesis of both neurotransmitters. The drug depressed mouse body temperatures by an amount similar to that for buspirone, gepirone and ipsapirone, but less than that for 8-hydroxy-N,N-dipropyl-2-aminotetralin. In rats, it produced the 5-HT1A behavioral syndrome. In contrast to 5-HT1A agonists having DA antagonist effects, U-67413B mildly depressed rather than stimulated firing rates of noradrenaline (NA) neurons in the locus ceruleus by a non-alpha-2 receptor mechanism. In behavioral tests designed to measure anxiolytic activities, U-67413B was a slightly more effective anxiolytic than standard 5-HT1A anxiolytics (buspirone, gepirone and ipsapirone). The data are consistent with the hypothesis that effects of 5-HT1A agonists on NA neuron activity are mediated through effects on dopaminergic mechanisms, and that effects on NA neurons could modulate anxiolytic activities of 5-HT1A agonists.     

Reversible acute renal failure induced by losartan in a renal transplant recipient

A 56-year-old man who received a live-related renal transplant in 1988 was started in 1995 on the selective angiotensin II antagonist losartan (Dupont-Merke) to treat worsening hypertension. Two months later because of pulmonary oedema, loop diuretics were started. Within two weeks, serum creatinine had increased from 245 to 571 mumol/l, and the patient became oliguric. A systolic bruit was noted over the graft. Renal angiography showed a 90% stenosis of the transplant renal artery. Losartan was withdrawn, with prompt improvement in renal function. A successful percutaneous transluminal angioplasty performed a few days later resulted in further improvement in renal function accompanied by a significant diuresis.     

Effect of chronic renal failure on the expression of erythropoietin message in a murine model

The anemia of chronic renal failure (CRF) is largely due to decreased production of erythropoietin (EPO) by the kidney. A small amount of EPO also originates from extra-renal sources, and this would be expected to assume a more important role in maintaining erythropoiesis when renal production is impaired. In this study, we examined the production of EPO mRNA by RT-PCR in kidney, liver, and bone marrow tissues isolated from normal mice, mice rendered acutely anemic by phlebotomy, and from mice with surgically induced CRF. The induction of acute anemia results in an expected increase in the expression of EPO mRNA in renal and hepatic tissue. In contrast, while the expression of EPO mRNA was expectedly reduced in the kidney from CRF mice, it was completely absent in the liver of these same animals. EPO mRNA expression was also absent in the bone marrow in both states of acute anemia and CRF. These results show that CRF can directly or indirectly can suppress the extrarenal production of EPO by the liver and that this effect may further aggravate the anemia of CRF.     

The antisecretory effects of clozapine, a dopamine D4 receptor antagonist, are blocked by the dopamine D1 receptor antagonist, SCH23390

Dopaminergic compounds affect gastric secretion and response to experimental gastric mucosal injury. We showed previously that the novel dopamine D4 receptor antagonist, clozapine, significantly reduces gastric acid secretion and restraint stress-induced gastric lesions. Because the selectivity of clozapine for D4 receptors has recently been questioned, we tested the ability of a known D1 receptor blocker, SCH23390, to affect clozapine-induced reduction in gastric acid secretion. SCH23390 given i.p. or i.c.v., at doses that did not affect gastric acid secretion, significantly blocked the anti-secretory effect of clozapine, administered either peripherally or centrally. These data suggest that neither clozapine nor SCH23390 exhibit as high a degree of selectivity for the dopamine D4 and D1 receptor, respectively, as previously believed.