Does H2-receptor antagonist alter the renal function of cyclosporine-treated kidney grafts?

Histamine-type 2 antagonists (H₂-blockers) as represented by cimentidine have been shown to adversely affect renal allograft function, particularly when coadministered with cyclosporine, currently a major immunosuppressant. To determine whether or not a newer and more powerful H₂-blocker, famotidine, would produce similar adverse effects, we assessed seven cyclosporine-treated renal allograft recipients with regard to changes in their renal function on or off the H₂-blocker over a one-week period. Neither the administration nor withdrawal of famotidine (20–40 mg/day) resulted in any significant changes in serum creatine, BUN, urine output or cyclosporine trough levels, suggesting that famotidine can be safely administered as an H₂-blocker to cyclosporine-treated renal allograft recipients.     

Endothelium-derived relaxing factor released by 5-HT: distinct from nitric oxide in basilar arteries of normotensive and hypertensive rats.

1. The role of the endothelium in cerebrovascular responses to 5-hydroxytryptamine (5-HT) was investigated in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) in vitro. 2. Cumulative addition of 5-HT caused concentration-dependent contractions in ring preparations of SHR basilar arteries; the contractile response was smaller in WKY basilar arteries. 3. Removal of the endothelium enhanced markedly the contractile responses to 5-HT in WKY arteries but had only a slight effect in SHR arteries. The responsiveness to 5-HT in WKY arteries after removal of endothelium was comparable to that in SHR arteries. 4. The endothelium-dependent relaxation induced by acetylcholine in WKY basilar arteries was almost abolished by treatment with 10 microM methylene blue or 10 microM NG-nitro-L-arginine (L-NOARG). However, the response to 5-HT was not affected by treatment with methylene blue, L-NOARG or indomethacin. 5. Application of 10-20 mM K+ or 3.2 mM tetraethylammonium (TEA) did not change significantly, or only increased slightly, the resting tension, but markedly enhanced the contractile response to 5-HT in WKY arteries with endothelium. In contrast, the submaximal response to 5-HT in SHR arteries with endothelium was significantly enhanced by 0.3 mM TEA. 6. In the presence of 1 mM TEA, the application of 10 microM L-NOARG further enhanced the responses of 5-HT in WKY arteries with endothelium. In SHR arteries with endothelium, 10 microM L-NOARG per se enhanced slightly but significantly the responses to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Microheterogeneity of regional myocardial blood flows in low-perfused rat hearts evaluated by double-tracer digital radiography.

Using (3)H- and (125)I-labeled desmethylimipramine (DMI) for regional flow tracers, we established a two-time measurement method for the spatial pattern of myocardial perfusion in cross-circulated rat hearts. Myocardial extractions and retentions of these tracers were confirmed to be satisfactory; however, the latter were less than 90% after 3 min at a perfusion rate of 2.9 ml/min/g, limiting the present application to a short-time perfusion measurement. Distributions of myocardial depositions were separated by subtraction digital radiography with 400-microm pixel resolution. Its feasibility was examined by regression analysis between local deposition densities of (3)H- and (125)I-DMI injected simultaneously. The slope, y-intercept, and correlation coefficient (r) of the regression line were 0.98+/-0.04, 0.02+/-0.04, and 0.95+/-0.03, respectively, indicating the validity of the present image subtraction technique. The spatial pattern of myocardial perfusion in response to flow reduction was evaluated by the injections of (3)H- and (125)I-DMI, respectively, before and after a nearly 70% flow reduction. A significant correlation between normalized density distributions of these tracers was found in both subepicardium (r=0.77+/-0.12) and subendocardium (r=0.73+/-0.20), indicating the stable pattern of myocardial perfusion. However, the coefficient of variation of tracer densities showed a decrease of subendocardial flow heterogeneity from 35+/-15% to 31+/-16%. Thus, flow differences between originally high- and low-flow regions in subendocardium were reduced on a relative basis during low perfusion.     

Accumulation of cyanide and thiocyanate in haemodialysis patients.

BACKGROUND: Cyanide is a toxic agent, and its detoxification product, thiocyanate, may be a major pathogenetic substance in uraemia. Recent studies examining the myeloperoxidase(MPO)/thiocyanate system have suggested a link between thiocyanate and atherosclerosis. However, inaccuracies in conventional assays for cyanide and thiocyanate have limited the understanding of their metabolism in haemodialysis (HD) patients. METHODS: We used high-performance liquid chromatography to measure cyanide in erythrocytes and thiocyanate in plasma in 43 HD patients and in a group of 46 healthy controls that included 15 current smokers. To clarify the metabolic conversion of cyanide to thiocyanate in uraemic patients, we also measured cysteine and sulfate. We then used stepwise regression analysis to analyse factors that determine erythrocyte cyanide and plasma thiocyanate. RESULTS: Mean cyanide and thiocyanate were significantly greater in HD patients than in non-smoking controls. However, cyanide was far below lethal concentrations in dialysis patients. Thiocyanate was six to seven times greater in HD patients than in non-smoking controls, and decreases in thiocyanate following dialysis were only 19.3+/-3.5%. Multiple regression analysis showed a positive correlation between cyanide and thiocyanate in controls, but a negative correlation in HD patients. In patients, an inverse relationship between thiocyanate and BUN was also observed. CONCLUSIONS: The elevation of thiocyanate in patients undergoing dialysis probably is secondary to both limited efficiency of HD and deranged metabolism of cyanide and thiocyanate. Because thiocyanate is a preferred substrate for MPO, it may play a role in uraemic complications including cardiovascular events.     

Skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) by inhibiting activation of the IGF-I signaling pathways.

We showed that unloading markedly diminished the effects of IGF-I to activate its signaling pathways, and the disintegrin echistatin showed a similar block in osteoprogenitor cells. Furthermore, unloading decreased alphaVbeta3 integrin expression. These results show that skeletal unloading induces resistance to IGF-I by inhibiting activation of the IGF-I signaling pathways at least in part through downregulation of integrin signaling. INTRODUCTION: We have previously reported that skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) with respect to bone formation. However, the underlying mechanism remains unclear. The aim of this study was to clarify how skeletal unloading induces resistance to the effects of IGF-I administration in vivo and in vitro with respect to bone formation. MATERIALS AND METHODS: We first determined the response of bone to IGF-I administration in vivo during skeletal unloading. We then evaluated the response of osteoprogenitor cells isolated from unloaded bones to IGF-I treatment in vitro with respect to activation of the IGF-I signaling pathways. Finally we examined the potential role of integrins in mediating the responsiveness of osteoprogenitor cells to IGF-I. RESULTS: IGF-I administration in vivo significantly increased proliferation of osteoblasts. Unloading markedly decreased proliferation and blocked the ability of IGF-I to increase proliferation. On a cellular level, IGF-I treatment in vitro stimulated the activation of its receptor, Ras, ERK1/2 (p44/42 MAPK), and Akt in cultured osteoprogenitor cells from normally loaded bones, but these effects were markedly diminished in cells from unloaded bones. These results were not caused by altered phosphatase activity or changes in receptor binding to IGF-I. Inhibition of the Ras/MAPK pathway was more impacted by unloading than that of Akt. The disintegrin echistatin (an antagonist of the alphaVbeta3 integrin) blocked the ability of IGF-I to stimulate its receptor phosphorylation and osteoblast proliferation, similar to that seen in cells from unloaded bone. Furthermore, unloading significantly decreased the mRNA levels both of alphaV and beta3 integrin subunits in osteoprogenitor cells. CONCLUSION: These results indicate that skeletal unloading induces resistance to IGF-I by inhibiting the activation of IGF-I signaling pathways, at least in part, through downregulation of integrin signaling, resulting in decreased proliferation of osteoblasts and their precursors.     

A case of Cushing's syndrome caused by an adrenal black adenoma

A black adenoma of the adrenal cortex was surgically removed from an 18-year-old female who had clinical and laboratory findings characteristic of Cushing's syndrome. The electron microscopic study revealed typical features of steroid-producing cells, including a prominent smooth and rough endoplasmic reticulum, and mitochondria. In addition, many of the adenoma cells contained numerous pigmented granules which were lipofuscin. Three months after the surgery, the hormone levels returned to the normal range. The Japanese literature of functional black adenoma is reviewed.     

Intrathecal landiolol inhibits nociception and spinal c-Fos expression in the mouse formalin test

PURPOSE: The purpose of this study was to determine if intrathecal landiolol, a beta1-blocker, can modulate formalin-induced nociception and spinal c-Fos expression in mice, in the absence of anesthesia. METHODS: Thirty-two mice were randomly assigned to one of four groups: the control group (n = 8) received intrathecal normal saline 10 microL, while the other three groups (n = 8 for each) received intrathecal landiolol at escalating doses of 250 microg.kg(-1), 500 microg.kg(-1) and 750 microg.kg(-1) respectively, immediately after induction of anesthesia with isoflurane. After awakening, inflammatory pain was induced by 10 microL of 5% formalin solution injected into the dorsal surface of the right hind paw. The nociceptive behaviours including licking, biting and lifting of the injected paw were cumulatively recorded as seconds of behaviours/min during phase I (0-10 min) and phase II (10-45 min). The c-Fos protein expressions in the spinal dorsal horn were detected with immunohistochemical techniques in the control and landiolol 750 microg.kg(-1) groups. RESULTS: Compared to the control group, intrathecal injection of landiolol 750 microg.kg(-1) significantly decreased pain-related behaviours in phase I, while intrathecal landiolol 250 microg.kg(-1), 500 microg.kg(-1) and 750 microg.kg(-1) significantly decreased pain-related behaviours in phase II during the formalin test. The numbers of c-Fos immunoreactive nuclei in the L5 spinal dorsal horn were significantly lower in the landiolol 750 microg.kg(-1) group compared to the control group (landiolol 750 microg.kg(-1) 2.4 +/- 1.1 vs control 9.2 +/- 3.9; P < 0.01). CONCLUSION: The present study indicates that intrathecally administered landiolol produces significant antinociceptive effects in the formalin test. Although further studies exploring the detailed mechanism are needed, these data suggest a potential role of beta1-adrenoreceptors in spinal nociceptive processing.     

Bezafibrate improves hypertension and insulin sensitivity in humans.

We examined cellular membrane fatty acid composition and insulin sensitivity in patients with mild essential hypertension and hyperlipidemia, and investigated whether bezafibrate, a lipid-lowering drug, could improve elevated blood pressure and insulin sensitivity in these subjects by ameliorating cellular membrane fatty acid composition. Twenty-seven subjects were recruited. Twelve men with mild essential hypertension [systolic blood pressure (SBP) between 140 mmHg and 160 mmHg] and hypertriglyceridemia (plasma triglyceride concentration over 150 mg/dl) were designated the HL group. Fifteen men with mild essential hypertension and normotriglyceridemia (plasma triglyceride concentration below 150 mg/dl) were designated the NL group. Subjects in the HL group were given bezafibrate 400 mg/dl and those in the NL group were given placebo for 3 months. Bezafibrate significantly reduced SBP (140 +/- 2.6 to 131.8 +/- 2.6 mmHg, mean +/- SEM), diastolic blood pressure (DBP) (87.8 +/- 2.0 to 82.8 +/- 2.6 mmHg), fasting plasma triglyceride concentration (225.5 +/- 23.5 to 102.9 +/- 10.9 mg/dl), fasting plasma insulin concentration (9.6 +/- 0.8 to 7.1 +/- 0.8 microU/ml), and homeostasis model assessment scores (HOMA-R, 2.4 +/- 0.2 to 1.7 +/- 0.2), and significantly improved the insulin sensitivity index (56.0 +/- 3.0 to 70.7 +/- 4.8 mg x l2/mmol x mU x min) in the HL group. Regarding erythrocyte membrane fatty acid composition, bezafibrate reduced the percentages of saturated fatty acids (SFA) and increased the percentage of polyunsaturated fatty acids (PUFA). Plasma triglyceride concentrations were positively correlated with HOMA-R (r = 0.50, p < 0.01) and SFA (r = 0.39, p < 0.05), and negatively correlated with PUFA (r = -0.45, p < 0.05) before administration of placebo or bezafibrate. In conclusion, an improvement of hyperlipidemia by bezafibrate may be attributed to reduction of blood pressure and amelioration of insulin sensitivity. Abnormalities in membrane lipid composition may play an important role in these metabolic disorders.