Intriguing structural and magnetic properties correlation study on Fe3+-substituted calcium-copper-titanate.

This communication presents a detailed study on a Fe3+ modified CaCu3Ti4O12 cubic perovskite system (CaCu3-xTi4-xFe2xO12 with x = 0.0-0.7) by performing X-ray powder diffractometry, DC SQUID magnetization and 57Fe Mössbauer spectroscopy. The first ever Mössbauer studies on the system supported the reported peculiarity of the structure. Mössbauer analysis for the compositions x = 0.1, 0.3, and 0.5 suggest Fe3+ ions in two different environments. The site with larger quadrupole splitting corresponds to Fe3+ in the octahedral symmetry, while the site with lower chemical shift and quadrupole splitting belongs to Fe3+ in the square-planar (A'-) configuration. With the increase in Fe-substitution, Fe3+ appears to prefer A'- symmetry. Antiferromagnetic features are retained up to x = 0.3, but weak ferromagnetic characteristics appear with higher Fe3+ substitution. The switching of antiferromagnetic to ferromagnetic behavior was related to the preferential occupation of Fe3+ in square-planar symmetry accommodating Cu2+.

Frequency and reporting of complications after Dupuytren's contracture interventions: A systematic review and meta-analysis.

INTRODUCTION: Numerous complications are reported following interventions for Dupuytren's contracture; however, their incidence, management, and outcomes remain poorly reported. The aims of this review were to report the proportions of complications, compare likelihood of complications between interventions, and evaluate reporting of complications, including assessment, grading, management, and subsequent reporting of their impact on patient outcomes. METHODS: Extracted data included patient demographics, intervention details, complications, their management, and final outcomes. Analysis of descriptive data enabled review of complications reporting. Meta-analysis(MA) of non-comparative datasets enabled estimation of proportions of patients experiencing complications. Network meta-analysis(NMA) of comparative studies estimated the relative occurrence of complications between interventions. Risk of bias analysis was performed. RESULTS: 26 studies, comprising 10,831 patients, were included. Interventions included collagenase injection, percutaneous needle fasciotomy(PNF), limited fasciectomy(LF), open fasciotomy(OF), and dermofasciectomy(DF). Overall quality and consistency of outcomes reporting was poor. MA enabled estimates of probabilities for three common complications(infection, nerve injury, complex regional pain syndrome(CRPS)) across all interventions; the reported rates for LF were 4.5% for infection, 3% for nerve injury, and 3.3% for CRPS. As the commonest intervention, LF was used as the reference intervention for comparison of the commonest complications via NMA, including haematoma [OF OR 0.450(0.277, 0.695); PNF OR 0.245(0.114, 0.457)], infection [PNF OR 0.2(0.0287, 0.690); DF OR 2.02(1.02, 3.74)], and neuropraxia [PNF OR 0.0926(0.00553, 0.737)]. We noted that the complication incidence was higher the more invasive the intervention. CONCLUSIONS: There was limited reporting of complication occurrence, management, and outcomes following interventions, contributing to a gap in information for informed patient consent. MA was possible for reporting of proportions for infection, nerve injury, and CRPS across interventions. NMA enabled direct comparison of the six commonest complications between interventions. These findings can guide intervention selection. Improving consistency and quality in complications reporting is essential to aid counselling of patients regarding the true rates and consequences of the risks of interventions. TYPE OF STUDY/LEVEL OF EVIDENCE: 2.

Proximal humerus fractures: A review of current practice.

The management of proximal humeral fractures (PHF) remains controversial. Its incidence is increasing. Patients should be meticulously assessed clinically for co-morbidities and neuro-vascular injuries. Radiological investigation helps provide information on the fracture configuration and dislocations. Enhanced by 3-dimensional CT scanning, these further help in decision making and operative planning. PHF classifications have been demonstrated to have poor intra-observer and inter-observer reliability. Research has identified some radiographic predictive factors for humeral head ischaemia and likely failure of surgical fixation. The range of management options include non-operative treatment, operative fixation, intramedullary nailing and arthroplasty (hemiarthroplasty, reverse shoulder replacement). The majority of PHFs are stable injuries and non-operative management is usually successful. Some degree of malunion is readily tolerated especially by elderly patients. Surgical management of significantly displaced, unstable proximal humerus fractures should aim to stabilise the fracture adequately and provide satisfactory function for the long term. Management of the greater tuberosity is pivotal for the eventual outcome. When fixation may appear to be compromised by poor bone quality, likely poor function, age related rotator cuff degeneration or likely humeral head ischaemia clinicians may opt for arthroplasty. Successful hemiarthroplasty outcomes are dependent on sufficient healing of the tuberosity and recovery of the rotator cuff integrity. Reverse shoulder replacement can predictably deliver good functional outcomes for the shoulder in elderly patients, where rotator cuff dysfunction is suspected or as a revision procedure following failure of other surgical interventions. As opposed to hemiarthroplasty, which has shown a downward trend, there has been an increasing trend towards the use of reverse shoulder replacement in proximal humeral fractures. The management of PHFs should be patient specific, fracture specific and meet the functional demands and needs of the individual patient. The surgeon's skill set and clinical experience also plays an important role in the options of management available.

Novel oxazole containing phenylpropane derivatives as peroxisome proliferator activated receptor agonists with hypolipidemic activity.

alpha-Alkoxy arylpropanoic acids containing 2-phenyloxazole-4yl-alkyl moiety are found to be potent hypolipidemic agents. These compounds were potent activators of the peroxisome proliferator activated receptor gamma (PPARgamma), with moderate PPARalpha activity and known to cause adverse effects such as weight gain and edema, which are essentially attributed to PPARgamma activation. Although extensive work has been done on the phenylpropanoic acid class of compounds, other phenyl propane derivatives such as alcohols, amines, ethers etc. have not received much attention. In order to develop predominant PPARalpha agonists as hypolipidemic agents with minor chemical modifications on compound III, we have synthesised few (2S)-ethoxyphenylpropane derivatives containing a 2-phenyl-5-methyloxazole-4ylalkoxy moiety of the general formula IV and evaluated by PPARalpha and gamma transactivation assay in conjugation with in vivo studies in male Swiss albino mice model. Compounds 3c and 3d showed the desired predominant PPARalpha activity and excellent tryiglyceride reduction in vivo and were selected as lead compounds for further development as hypolipidemic agents.

Comparison of Short vs Long Anti-rotation in Treating Trochanteric Fractures.

Introduction: A comparative evaluation of the surgical treatment and outcome of patients with pertrochanteric fractures treated with short versus long proximal femoral nail antirotation. Materials and methods: A retrospective review was conducted of patients with pertrochanteric fractures treated between January 2011 and June 2012. In all 80 patients were enrolled in the study, of which 40 were treated with short PFNA and the remaining with long PFNA. Comparative analyses of demographic data, peri-operative outcome and complications were carried out. Results: There was no significant difference noted in the two groups with regards to Arbeitsgemeinschaft fur Osteosynthesefragen (AO) fracture classification, time from injury to surgery, blood transfusion post surgery and hospital stay. The surgical duration for a short PFNA procedure was significantly less (58 minutes) when compared to that of a long PFNA (87 minutes). Similarly intra-operative blood loss was significantly higher in the long PFNA group as compared to the short PFNA. Conclusions: A relatively quicker surgical time of just under an hour , lesser blood loss and better learning curve with trainee surgeons make short PFNA a better implant choice in the treatment of pertrochanteric fractures.

Changes in membrane polypeptides, polyphosphoinositides and phosphatidate in dense fractions of sickle cells.

When sickle erythrocytes were fractionated on discontinuous isotonic stractan gradients the denser fractions, which were rich in irreversibly sickled cells contained less polyphosphoinositides and more phosphatidate than either lighter sickle cell fractions or normal cells. These changes could be due to activation of a polyphosphoinositide phosphodiesterase in the denser cells. Membrane polypeptide analysis of the denser fractions also showed a marked depletion of band 4.1 and a protein of molecular mass about 110 kDa but an increased amount of a 180 kDa polypeptide which might be a breakdown product of ankyrin. These biochemical alterations could be consequences of Ca2+ accumulation in the denser sickle cells and may contribute to the structural alterations which give rise to irreversibly sickled cells.

A sphingomyelinase-resistant pool of sphingomyelin in the nuclear membrane of hen erythrocytes.

Experiments in which hen erythrocytes were exposed to the action of exogenous sphingomyelinase (Staphylococcus aureus) or to their endogenous plasma membrane sphingomyelinase showed that about 15% of the total sphingomyelin was resistant to breakdown either in intact or lysed cells. This resistant pool of sphingomyelin seems likely to reside in the nuclear membranes of the cells, so that essentially all the plasma membrane sphingomyelin can be broken down by exogenous sphingomyelinase acting on intact cells, suggesting that plasma membrane sphingomyelin is exclusively localised in the outer lipid leaflet. Paradoxically, introduction of Ca2+ into the intact cells using A23187 causes the breakdown of up to 30% of total cell sphingomyelin inside the cells but without apparently affecting the putative nuclear pool of sphingomyelin and this suggests that Ca2+ may alter the original disposition of sphingomyelin in the membrane so that originally outer leaflet sphingomyelin becomes accessible to the endogenous sphingomyelinase inside the cells. No differences were seen in the fatty acid compositions of sphingomyelin degradable by exogenous sphingomyelinase, sphingomyelin degradable in the presence of A23187/Ca2+ or the enzyme-resistant pool of sphingomyelin.

Phospholipid asymmetry in the membranes of intact human erythrocytes and in spectrin-free microvesicles derived from them.

Phospholipase A2 from bee venom and Naja naja has been used to study the orientation of phospholipids present in the membrane of intact human erythrocytes and in spectrin-free microvesicles derived from the cells by treatment with Ca2+ and A23187. Little difference between the cells and microvesicles was observed in the apparent accessibility of phospholipids to the enzyme, suggesting that the original lipid asymmetry was maintained in the absence of spectrin. However, incubation of the microvesicles for 16 h at 37 degrees C did lead to partial loss of asymmetry in the transmembrane distribution of phosphatidylcholine and phosphatidylethanolamine but not of phosphatidylserine. Despite the similarity of lipid asymmetry in cells and fresh microvesicles, the latter were about 40-fold more sensitive to phospholipase treatment than were cells. Although they retained the lipid asymmetry of intact cells, the microvesicles resembled ghosts in their great sensitivity to phospholipase A2 attack, suggesting that the lipid packing in microvesicles and ghosts was similar. This conclusion was supported by the results of experiments with a fluorescent probe Merocyanine 540.

Relationship of hemolysis buffer structure, pH and ionic strength to spontaneous contour smoothing of isolated erythrocyte membranes.

Isolated human erythrocyte membranes crenate when suspended in isotonic medium, but can use MgATP to reduce their net positive curvature, yielding smooth discs and cup forms that eventually undergo endocytosis. An earlier report from this laboratory (Patel, V.P. and Fairbanks, G. (1981) J. Cell Biol. 88, 430-440), has described a phenomenon of ATP-independent shape change in which ghosts prepared by hemolysis and washing in synthetic zwitterionic buffers crenated at 0 degree C, but underwent conversion to smooth discs and cups when warmed in the absence of MgATP. We have further explored the effect of the hemolysis condition on the requirement for ATP in ghost shape change. 25 hemolysis buffers were applied at 10 mM (pH 7.4, 0 degree C). Eight anionic buffers with relatively high ionic strength (e.g., phosphate and diethylmalonic acid (DMA] yielded ghosts requiring ATP for shape change, while two cationic buffers (Bistris and imidazole) and ten synthetic zwitterionic buffers (e.g., Tricine and Hepes) with lower ionic strength produced ghosts that smoothed spontaneously at 30 degrees C. Hemolysis at intermediate ionic strength yielded mixed populations in which spontaneous smoothing was expressed in all-or-none fashion. Maximal ATP-independent shape change was induced by hemolysis at pH 7.3-7.7, while ATP was required after hemolysis at pH less than or equal to 7.1 even when the ionic strength at hemolysis was low. Ghosts requiring ATP could be converted to ATP independence by washing at low ionic strength, but ATP independence could not be reversed readily by washing at high ionic strength. Exposure to low ionic strength at pH greater than 7.1 presumably changes membrane organization in a way that alters the temperature dependence of tensions within the bilayer or skeleton of the composite membrane.

Transcription factor Sp1 is expressed by three different developmentally regulated messenger ribonucleic acids in mouse spermatogenic cells.

Gene expression during spermatogenesis is highly cell- and stage-specific and involves the complex interplay of multiple developmentally regulated transcription factors. Recent evidence suggests that the DNA-binding protein Sp1 functions as an important trans-activator during cell development and differentiation. In the present study, the developmental expression of Sp1 was characterized during mouse spermatogenesis. Three distinct Sp1 transcripts were detected in mouse spermatogenic cells, each with a distinct developmental pattern; an 8.2-kilobase (kb) messenger RNA (mRNA) identical in size to the somatic mRNA expressed in spermatogonial cells, a larger mRNA approximately 8.8 kb in size present in meiotic cells, and a 2.4 kb mRNA in meiotic and postmeiotic germ cells. The 8.8- and 2.4-kb Sp1 transcripts were not observed in somatic cells and, thus, are male germ cell specific. Northern, ribonuclease protection, and RT-PCR assays revealed that the 2.4-kb Sp1 transcript is truncated in both the 5'- and 3'-untranslated regions relative to the somatic mRNA and lacks a short segment of the N-terminal coding region. Polysome analysis further indicated that these germ cell-specific Sp1 mRNAs are translated, albeit with a lower efficiency than the somatic transcript. Consistent with these results, spermatogenic cells were shown to contain approximately 9-fold lower concentrations of Sp1 proteins that are approximately the same size as the somatic form. Of particular interest, the apparent affinity of Sp1 DNA-binding activity in nuclear extracts from mouse germ cells was 5-fold greater than that in extracts from mouse somatic tissues. This may reflect the existence of mechanisms within mouse spermatogenic cells that compensate for the lower nuclear concentrations of Sp1 protein. These results suggest that cell- and stage-specific regulation of Sp1 gene expression and activity may be an important component of the mouse spermatogenic cell developmental program.

Characterization of the 5' flanking region and gene encoding the mouse interferon-gamma receptor.

The purpose of this investigation was to characterize the gene that encodes the receptor for mouse interferon-gamma (IFN-gamma R), including determination of its size, intronic boundaries and its transcription start points (tsp). The mouse IFN-gamma R gene is 22-kb long, with six introns that range in size from approx. 1 to 7 kb. The first six exons encode the extracellular and transmembrane (TM) domains of the protein, while the last exon of about 1 kb encodes most of the intracellular domain. No canonical TATA box can be found in the 5' flanking sequence of the gene, and primer extension analysis indicates multiple tsp. In addition, the gene's 5' promoter region was sequenced to identify candidate responsive elements that might regulate expression of the gene. Among the putative regulatory motifs identified by computer-assisted analysis are multiple SP1 and AP-2 sites, an NF1 and CCAAT box, as well as a potential cyclic AMP-responsive element (CRE).

Identification of differentially expressed genes in dorsal root ganglia following partial sciatic nerve injury.

Partial sciatic nerve injury, a model of neuropathic pain, elicits a variety of neurochemical, electrophysiological and neuroanatomical changes in primary sensory neurons. We have used the technique of messenger RNA differential display to identify genes with altered expression in these neurons which may contribute to the development of aberrant sensation following such peripheral nerve damage. This approach identified 14 distinct complementary DNA clones, representing transcripts with increased ipsilateral expression in L4/5 dorsal root ganglia, two weeks after unilateral partial ligation of the rat sciatic nerve. Both Zucker diabetic fatty rats and their lean counterparts were used in this study but none of the transcripts identified showed an induction that was confined to one of the two groups. The majority of the clones did not show significant sequence similarity to previously reported genes and therefore may represent novel messenger RNA sequences or, alternatively, unknown regions of partially characterised messenger RNAs. Two of the clones represented transcripts for the known proteins muscle LIM protein and acidic epididymal glycoprotein, neither of which had previously been associated with expression in the nervous system. Reverse transcriptase-polymerase chain reaction analysis and in situ hybridization confirmed that the messenger RNA expression of both muscle LIM protein and acidic epididymal glycoprotein was induced in an ipsilateral-specific manner. Their localisations, examined with in situ hybridization in L5 dorsal root ganglia, were limited in each case to a sub-population of neuronal profiles. Those neuronal profiles that demonstrated muscle LIM protein hybridization were distributed across the profile size range, whereas the distribution of acidic epididymal glycoprotein-positive profiles appeared to be skewed towards smaller profiles. The induction of muscle LIM protein and acidic epididymal glycoprotein in dorsal root ganglia may play an important functional role in the adaptive response of primary sensory neurons following partial sciatic nerve injury.

Tonabersat (SB-220453) a novel benzopyran with anticonvulsant properties attenuates trigeminal nerve-induced neurovascular reflexes.

1. The effects of tonabersat (SB-220453) were evaluated on trigeminal nerve ganglion stimulation-induced sensory-autonomic neurovascular reflexes in the anaesthetized cat. Comparisons were made to intravenous administration of carabersat (SB-204269), and to valproate, gabapentin and lamotrigine following intraduodenal administration. 2. There were no effects on resting blood pressure, heart rate, carotid blood flow or carotid vascular resistance for any compound evaluated. 3. Trigeminal nerve ganglion stimulation increased carotid blood flow by 65% and reduced vascular resistance by 41% with minimal effect on blood pressure (< 10%) and no effect on heart rate. Intravenous infusion of tonabersat or carabersat (both 3.4 micromol h(-1)) produced time related reductions in stimulation-induced responses with a maximal inhibition (relative to control) of 30 +/- 7% (n=4), at 240 min for tonabersat and 33+/-4% (n=3) at 180 min for carabersat. Tonabersat (11.5 micromol h(-1)) produced a similar inhibitory effect (32 +/- 9%, n=4) after 120 min of infusion. 4. Following intraduodenal administration of tonabersat, the maximal inhibition of nerve stimulation-induced responses was 55 +/- 4% at 120 min (n=4) for tonabersat 10 mg kg(-1), and 24+/-2% after 180 min for 1 mg kg(-1) (n=4). 5. Intraduodenal administration of sodium valproate (10 or 100 mg kg(-1) n=4/group) had no effect on neurovascular reflexes. Maximal inhibition of nerve ganglion-stimulated reductions in carotid vascular resistance were observed at 150 min for lamotrigine (50 mg kg(-1), 52+/-12%, n=4) and gabapentin (100 mg kg(-1), 17+/-13%, n=3). Lamotrigine 10 mg kg(-1) produced 22+/-11% (n=3) inhibition after 180 min. 6. These data demonstrate blockade of trigeminal parasympathetic reflexes with tonabersat, carabersat and other anticonvulsants. These agents may therefore have therapeutic benefit in conditions where this type of reflex is evident.

Trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the anaesthetized cat: role of endothelin(B) receptors in carotid vasodilatation.

1. The effects of intravenous administration of endothelin (ET) receptor antagonists SB-209670 (0.001-10.0 mg kg(-1)), SB-217242, SB-234551 (0.01-10.0 mg kg(-1)) and BQ-788 (0.001-1.0 mg kg(-1)) were investigated on trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the carotid vasculature of the anaesthetized cat. Comparisons were made with sumatriptan (0.003-3.0 mg kg(-1)) and alpha-CGRP8-37 (0.001-0.1 mg kg(-1)). 2. Trigeminal nerve ganglion stimulation produced frequency related increases in carotid blood flow, reductions in carotid vascular resistance and non-frequency related increases in blood pressure. Guanethidine (3 mg kg(-1), i.v.) blocked trigeminal nerve ganglion-induced increases in blood pressure but had no effect on changes in carotid flow or resistance. Maximal reductions in carotid vascular resistance was observed at 10 Hz, and this frequency was selected to investigate the effects of drugs on trigeminal nerve ganglion stimulation-induced responses in guanethidine treated cats. 3. Saline, alpha-CGRP8-37 SB-209670 and BQ-788 had little or no effect on resting haemodynamic parameters. SB-217242 (10 mg kg(-1), n=3) produced a 56% reduction in arterial blood pressure whereas SB-233451 (10 mg kg(-1), n=3) produced a 30% reduction in carotid vascular resistance. Sumatriptan produced dose-related reductions in resting carotid flow and increases (max. 104% at 0.3 mg kg(-1), n = 5) in vascular resistance. 4. SB-209670 (n=6-7), SB-217242 (n=3) and BQ-788 (n=3) produced inhibition of trigeminal nerve ganglion stimulation-induced reductions in carotid vascular resistance. Saline, SB-234551, alpha-CGRP8-37 and sumatriptan had no effect. 5. These data demonstrate ET(B) receptor blockade attenuates the vasodilator effects of trigeminal nerve ganglion stimulation in the carotid vascular bed of guanethidine pretreated anaesthetized cats.

Induction of cytochromes P450IA1 and P450IA2 as determined by solution hybridization.

Two oligodeoxyribonucleotides were synthesized that were specific for the messenger RNAs for the polycyclic hydrocarbon-inducible cytochromes P450IA1 and P450IA2. The solution hybridization technique was modified for the use of these oligodeoxyribonucleotide probes so as to increase the sensitivity and specificity of this method. Using this technique, the steady-state levels of the mRNAs for cytochromes P450IA1 and P450IA2 in control rat liver were determined to be less than 3 and 6 molecules/cell, and 1.8 and 4.0 attomol/micrograms poly (A)+ RNA, respectively. At 15 hr after induction with 3-methylcholanthrene, the steady-state levels of the mRNAs for P450IA1 and P450IA2 were 68 and 200 molecules/cell, and 41.6 and 123 attomol/micrograms poly (A)+ RNA.

Carrageenan-induced thermal hyperalgesia in the mouse: role of nerve growth factor and the mitogen-activated protein kinase pathway.

NGF is an important link between inflammation and hyperalgesia and interacts with many different mediators of inflammation, including the MAPK signaling pathway. In these studies, carrageenan-induced thermal hyperalgesia was evaluated in the mouse and the role of NGF and the MAPK pathway investigated. Carrageenan induced a time-dependent inflammation and thermal hyperalgesia, which was maximal 4 h post administration. Both indomethacin (0.3, 1.0 and 10 mg/kg s.c., 30 min pre-carrageenan) and morphine (0.4, 1.2, 4.0 mg/kg; s.c., 30 min pre-hyperalgesia measurement) significantly inhibited carrageenan-induced thermal hyperalgesia and indomethicin inhibited paw inflammation, demonstrating the model as suitable for the assessment of anti-hyperalgesic and anti-inflammatory agents. Anti-NGF (0.67 mg/kg sc, 60 min pre-carrageenan) produced a significant inhibition of thermal hyperalgesia, but not inflammation. NGF itself produced a time-dependent hyperalgesia, but not inflammation, following intraplantar injection. The specific MAPK pathway inhibitor, PD98059 (0.1, 0.3 and 1 mg/kg sc, 30 min pre-carrageenan) significantly inhibited carrageenan-induced hyperalgesia, but not inflammation. These data demonstrate a role for both NGF and the MAPK signaling pathway in the production of thermal hyperalgesia, but not inflammation, in the mouse.

Interaction of estrogen and histamine during ovum implantation in the rat.

The relationship between estrogen and histamine in the initiation of ovum implantation in the rat was studied. Histamine was found to augment the implantation response to suboptimal doses of estradiol in the ovariectomized pregnant rat maintained with Depo-Provera. The effect of histamine was found to involve both H1- and H2-receptors and to be inhibited by treatment with a combination of mepyramine and metiamide. Treatment with this combination of histamine antagonists during early pregnancy in the intact rat did not modify blastocyst attachment. It was concluded that the effect of histamine on the implantation response to exogenous estradiol was due to increased uterine blood flow and/or estrogen uptake but that such histamine-mediated effects were not essential for blastocyst attachment during normal pregnancy.

PIP: The relationship between estrogen and histamine in the initiation of ovum implantation was studied in experimentation with rats. The laboratory procedures are explained and the results tabulated and graphed. The study showed that histamine augments the implantation response to suboptimal doses of estradiol in experimentally induced delayed implantation. The histamine effect depended on both H1- and H2-receptors. The effect was inhibited by treatment with a combination of mepyramine and metiamide. The histamine effect on the implantation response may be due in part to increased availability of estrogen and in part to increased uptake and retention of estrogen. Such histamine-mediated effects are not essential for blastocyst attachment during normal pregnancy.

Tolerance to peripheral, but not central, effects of ropinirole, a selective dopamine D2-like receptor agonist.

Studies were conducted to determine possible development, and underlying mechanisms, of tolerance to the hypotensive effects of ropinirole (4-[2-(dipropylamino)ethyl]-1-3-dihydro-2H-indol-2-one HCl), a selective dopamine receptor agonist, following twice daily oral administration to cynomolgus monkeys and spontaneously hypertensive rats (SHR). Tolerance to the hypotensive effects of the compound developed in both species within one week of repeated dosing. Tolerance which developed in rats was dose-related and could not be attributed to altered plasma/drug concentrations or be overcome by increasing the i.v. challenge dose of ropinirole. Cross-tolerance was shown to the dopamine receptor agonist bromocriptine. Similar hypotensive responses to bethanidine were seen in rats treated with ropinirole or vehicle. Tolerance to hypolocomotor effects of the compound were not apparent in the same time frame. The dopamine D2 receptor antagonist, domperidone, caused hypertension in ropinirole-but not vehicle-treated rats. Results reported in this paper are not consistent with a down-regulation of peripheral dopamine D2-like receptors but suggest a compensatory increase in basal sympathetic tone.

Evidence for homogeneity of thromboxane A2 receptor using structurally different antagonists.

Nine structurally dissimilar thromboxane antagonists (SQ 29548, ICI 185282, AH 23848, BM 13505 (Daltroban), BM 13177 (Sulotroban), SK&F 88046, L-636499, L-640035 and a Bayer compound SK&F 47821) were studied for activity as thromboxane A2 receptor antagonists. The assays used were inhibition of responses induced by the thromboxane mimetic, U46619, on human washed platelet aggregation, rabbit platelet aggregation, rabbit aortic strip contraction, anaesthetised guinea-pig bronchoconstriction, and a radio-labelled ligand (125I-PTA-OH) binding assay as a measure of affinity for the human platelet receptor. The results of the present study, with activities spanning at least four orders of magnitude along with statistically significant correlations (at least P less than 0.01), strongly suggests that between assays, antagonists and species a homogenous population of thromboxane A2 receptors exists. This finding is in contrast to those of a close series of 13-azapinane antagonists studied by other workers which have suggested receptor heterogeneity.