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.     

Biological activity of carboxy-terminal gastrin analogs

Amidated forms of gastrin are derived by post-translational processing of a large precursor peptide and stimulate gastric acid secretion via the gastrin/CCK(B) receptor. Non-amidated biosynthetic intermediates may exert biological effects through other mechanisms, but their effect on gastric acid secretion is unclear. Amidated gastrins stimulate acid secretion mainly by releasing histamine from mucosal enterochromaffin-like cells. This study examines the effects on histamine release from the vascularly perfused rat stomach of amidated gastrin-17, COOH-terminal glycine-extended gastrin-17, gastrin-17 extended at the COOH-terminal including the remaining progastrin sequence, and carboxy-terminal progastrin fragments (SAEDEN and GRRSAEDEN). Carboxy-terminal extended gastrins induced histamine release which was inhibited by the gastrin/CCK(B) antagonist L-740,093, but had to be given in concentrations 100-fold higher than amidated gastrin-17 to produce comparable effects. These progastrin-derived peptides are found in high concentrations in some patients with the Zollinger-Ellison syndrome and may contribute to acid hypersecretion and other gastrin/CCK(B) receptor mediated responses.     

Long-term effect of norepinephrine on iodide uptake in FRTL-5 cells

The sympathetic nervous system plays a role in the regulation of thyroid function. In FRTL-5 rat thyroid cells, norepinephrine (NE) acutely depresses intracellular I- by increasing I- efflux. The present study was undertaken to determine the effect of NE on iodide transport after a longer time period. NE inhibited the ability of thyrotropin (TSH) to induce iodide uptake by FRTL-5 cells after 48 or 72 hours, but not after 24 hours. The effect of NE was more evident with increasing concentrations of TSH. NE did not modify the rate of I- efflux. Inhibition was associated with a decrease in the Vmax and no change in the Km for iodide influx. To determine if this was a generalized effect of NE on thyroid cell membrane, the uptake of alpha-aminoisobutyric acid (a nonmetabolizable aminoacid) and of 2-deoxyglucose was measured. NE did not inhibit TSH stimulation of the uptake of the two compounds. NE inhibited the action of dibutyryl cAMP (dbcAMP) on iodide uptake in a similar manner to TSH, but did not alter the cyclic adenosine monophosphate (cAMP) levels increased by TSH. The effects of different adrenoreceptor agonists and antagonists demonstrated that norepinephrine acts through an alpha1-adrenergic receptor.     

The nitric oxide synthase inhibitor L-NAME (N omega-nitro-L-arginine methyl ester) does not produce discriminative stimulus effects similar to ethanol

Three key aspects of Florence Nightingale remarkable life are examine. First, the influence during her formative years: the education and guidance provided by her father, the resistance by her family when she decided to become a nurse; and the rejection by Nightingale of the societal expectations of a woman in the Victorian era. Secondly, her professional life is examined, in particular how she appears to have been viewed by certain members of society, and how it turn she viewed them. It is anticipated that her position as an early feminist will be postulated and illuminated. Thirdly, an analysis of her personal and professional life indicates a way forward for the nursing profession.