G-protein-coupled receptors for peptide hormones: angiotensin II receptors.
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Amino Acid Substitution↗
Biomedical subjects
S G Ball
Publications and source records attributed to S G Ball.
Hypothalamic adipsic syndrome: diagnosis and management.
Patients with hypothalamic adipsic syndrome, especially in conjunction with diabetes insipidus, pose management difficulties. They are at risk of both under- and over-hydration. We present 4 patients with hypothalamic adipsic syndromes, due to different causes, illustrating the practical difficulties encountered in this condition. The principles of management, with a sliding scale of water intake related to changes in daily body weight, are discussed.
Adolescent↗
Activation of protein kinase C-alpha and translocation of the myristoylated alanine-rich C-kinase substrate correlate with phorbol ester-enhanced noradrenaline release from SH-SY5Y human neuroblastoma cells.
The aim of this study was to investigate the mechanism by which short-term pretreatment with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA; 100 nM) enhances noradrenaline (NA) release from the human neuroblastoma cell line SH-SY5Y. Subcellular fractionation and immunocytochemical studies demonstrated that an 8-min TPA treatment caused translocation of the alpha-subtype of protein kinase C (PKC) from the cytosol to the plasma membrane. In contrast, TPA altered the distribution of PKC-epsilon from cytosolic and membrane-associated to cytoskeleton- and membrane-associated. TPA had no effect on the cytosolic location of PKC-zeta. Subcellular fractionation studies also showed that the myristoylated alanine-rich C-kinase substrate (MARCKS), a major neuronal PKC substrate that has been implicated in the mechanism of neurotransmitter release, translocated from membranes to cytosol in response to an 8-min TPA treatment. Under these conditions the level of phosphorylation of MARCKS increased threefold. The ability of TPA to enhance NA release and to cause the translocation and phosphorylation of MARCKS was inhibited by the PKC inhibitor Ro 31-8220 (10 microM). Selective down-regulation of PKC subtypes by prolonged exposure to phorbol 12,13-dibutyrate (100 nM) attenuated the TPA-induced enhancement of NA release and the translocation of MARCKS over an interval similar to that of down-regulation of PKC-alpha (but not -epsilon or -zeta). Thus, we have demonstrated a strong correlation between the translocation of MARCKS and the enhancement of NA release from SH-SY5Y cells due to the TPA-induced activation of PKC-alpha.
Alanine↗
Occurrence of two types of secretory vesicles in the human neuroblastoma SH-SY5Y.
Western blot analysis showed that the human neuroblastoma SH-SY5Y expresses the proteins synaptotagmin l, synaptobrevin, synapsin-l, rab3a, syntaxin, SNAP-25, NSF, alpha-SNAP, and munc-18, which have been implicated in the movement, docking, and fusion of vesicles during exocytosis from other neuroendocrine cells. The subcellular localization of secretogranins I and II, synaptotagmin l, neuropeptide Y, rab3a, synaptobrevin, synaptophysin, and syntaxin was investigated by immunofluorescence microscopy and revealed punctate staining patterns characteristic of secretory vesicles. The comigration of noradrenaline, secretogranin II, and dopamine-beta-hydroxylase on sucrose-D2O gradient fractions indicates the presence of a population of noradrenaline-containing large dense-cored vesicles (LDCVs). In addition, a lighter vesicle population is also present that does not appear to be noradrenergic and contains a 48-kDa synaptophysin antigen absent from the large dense-cored vesicles. Immunocytochemical experiments show that not all of the vesicles that express synaptotagmin l contain secretogranin II. Thus, our studies suggest that two types of vesicle are present in SH-SY5Y cells, one of which, the LDCVs, contains noradrenaline. These findings confirm our previous studies suggesting that depolarization-evoked release of noradrenaline from SH-SY5Y occurs by LDCV exocytosis. This enhances the value of SH-SY5Y as a cell line in which to study the mechanism by which noradrenaline release is regulated.
Antibody Specificity↗
Biochemical assessment of pancreatic disease in human immunodeficiency virus infected men.
AIM: To determine the usefulness of measuring amylase activity as an indicator of pancreatic disease in human immunodeficiency virus (HIV) positive patients. METHODS: A prospective study of 129 ambulant HIV positive males. Total amylase, pancreatic amylase, and lipase activities were assayed using commercial test kits on an automated analyser. Samples with raised amylase were examined for the presence of macroamylasaemia using cellulose acetate electrophoresis. RESULTS: Thirty six (28%) of the subjects had raised total amylase activities compared with healthy, age matched blood donors. However, almost half of these were because of an increase of the salivary fraction. Four subjects were found to have macroamylasaemia. Pancreatic amylase and lipase assays, more specific indicators of pancreatic disease, produced significantly fewer abnormal results. There was no association between abdominal symptoms and elevated enzyme levels. CONCLUSIONS: Total amylase is a poor indicator of pancreatic disease in HIV infected outpatients. Specific assays for pancreatic amylase offer advantages over the traditional total amylase assay. The lipase assay produced the least number of abnormal results and its use could improve the biochemical identification of patients with possible pancreatic disease and allow a more selective investigation of these cases.
Adult↗
Deletion of the thyroid hormone beta1 receptor increases basal and triiodothyronine-induced growth hormone messenger ribonucleic acid in GH3 cells.
The conserved diversity, restricted distribution, and differential regulation of the thyroid hormone receptor (TR) isoforms raise the possibility of isoform-specific functions. We have addressed the roles of individual TRs in GH gene expression in GH3 cells by using an isoform-specific antisense RNA to delete TRbeta1. An antisense RNA vector, directed against the isoform-specific coding sequence of the parent TRbeta1 complementary DNA, was constructed. Stable transfected GH3-derived cell lines expressing this construct were established. Appropriate control cell lines were established in parallel. Depletion of TRbeta1 in cells expressing the antisense construct was confirmed at both the messenger RNA and protein levels. Total TR expression was maintained in these cells by a reciprocal increase in TRbeta2 levels. This perturbation of the TR population was associated with a 10.5-fold increase in basal and a 5.0-fold increase in T3-stimulated GH gene expression, but no increase in total T3 binding of nuclear extracts. In transient cotransfection experiments, there were no differences between control cells and those expressing the antisense construct in either basal or T3-stimulated expression of reporters containing a variety of thyroid hormone response elements. Depletion of TRbeta1 in GH3 cells results in a reciprocal increase in TRbeta2. These changes are associated with increased basal and T3-stimulated GH gene expression, which are not due to a nonspecific enhancement of basal or hormone-stimulated transcription. We demonstrate that TRbeta1 is not required for T3 induction of the GH gene in GH3 cells and that TRbeta1 and TRbeta2 are not equivalent in their effects on basal repression of the GH promoter. The data illustrate the potential for isoform- and promoter-specific dissociation of the repression and activation properties of the TRs.
Animals↗
3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro.
Recent data have suggested that the iodothyronine, 3,5-diiodo-l-thyronine (T2), has selective thyromimetic activity. In vivo, T2 has been shown to suppress TSH levels at doses that do not produce significant peripheral manifestations of thyroid hormone activity. Furthermore, T2 has been shown to produce smaller increments in peripheral indices of thyroid status than does T3, when doses resulting in equivalent suppression of circulating TSH are compared. We have assessed the selective thyromimetic activity of T2 in vivo and in vitro, and performed in vitro studies to assess the potential molecular basis for these selective properties. T2 was 100-fold less potent than T3 in stimulating GH mRNA levels in GH3 cells. In contrast, the iodothyronines were almost equivalent in their ability to downregulate TRbeta2 mRNA levels in this cell line. Both 3,3'-diiodo-L-thyronine and thyronine exhibited no significant thyromimetic effects on either process. In vivo, doses of T2 and T3 that were equivalent in their induction of hepatic malic enzyme (ME) mRNA did not produce equivalent suppression of circulating TSH, with T2 being only 27% as effective as T3. T2 was up to 500-fold less potent than T3 in displacing [125I]-T3 from in vitro translated specific nuclear receptors (TRs) and GH3 cell nuclear extracts. Electrophoretic mobility shift assays, assessing the ability of T2 to produce dissociation of TRbeta1 homodimers from inverted palindrome T3 response elements, indicated that T2 was also 1000-fold less potent than T3 in this respect. These data confirm that T2 has significant thyromimetic activity, and that this activity is selective both in vivo and in vitro. However, there are no data to support a selective central effect, T2 being relatively more potent in stimulating hepatic ME mRNA than in suppression of TSH in vivo. The basis for this differential thyromimetic activity is not selective affinity of the different TR isoforms for T2, or divergent properties of T2 in competitive binding and functional assays in vitro.
Animals↗
Do ACE inhibitors provide protection for the heart in the clinical setting of acute myocardial infarction?
Large randomised clinical trials have shown ACE inhibitors to improve survival after acute myocardial infarction (AMI). The precise mechanism underlying this benefit is not fully established, despite extensive research. There is also controversy with regard to the clinical use of these drugs, particularly the need for selection of patients prior to treatment and the timing of drug initiation and withdrawal for maximum benefit. Animal models of AMI used to assess drug effects are of limited value in understanding the mechanisms of benefit because they involve significantly different pathophysiology from that which occurs in humans. Here we propose that the benefit of ACE inhibitor therapy is largely confined, post-AMI, to those with evidence of left ventricular dysfunction clinically or on investigation, and suggest the continuing importance of treatment distant from the acute event. We argue that the beneficial effects are, at least in part, related to a reduction in the direct toxic effects of angiotensin II and catecholamines on cardiomyocytes resulting from the long term excess stimulation of the renin-angiotensin and sympathetic systems in these patients. Importantly, we believe that for some patients after AMI there is little or no benefit to be gained from treatment and that, in fact, careful analysis of the trials suggests that ACE inhibitors may be associated with adverse outcomes in some individuals. Finally, since ACE inhibitors also potentiate bradykinin and other peptides, their beneficial action may not simply be due to reducing the formation of angiotensin II. The proportion of the benefit that may be via bradykinin is difficult to assess, especially in humans. However, the advent of the angiotensin receptor antagonists has provided the opportunity to investigate this important issue.
Angiotensin II↗
Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators.
BACKGROUND: The importance of the effects of ACE inhibitors on sudden death, progressive heart failure and recurrent infarction to the reduction in overall mortality in heart failure and after myocardial infarction is disputed. METHODS: The AIRE study randomized 2006 patients with clinical or radiological evidence of heart failure within 2-9 days of a myocardial infarction to receive ramipiril 5 mg b.d. or matching placebo. Outcomes were assessed independently by members of an end-points committee blinded to treatment allocation. RESULTS: Fewer patients developed severe resistant heart failure as their first validated end-point on rampril, despite the greater number of at-risk survivors, compared to placebo (n = 143 vs 178; risk reduction 23%; CI 5 to 39%; P = 0.017). Ramipril did not alter the rate of reinfarction or stroke. Irrespective of treatment allocation 182 (46%) patients developed resistant heart failure prior to death. A validated acute or remote myocardial reinfarction occurred in 76 (19%) patients prior to death and chest pain occurred in 90 (23%) patients around the time of death suggesting an ischaemic element to these deaths Eighty deaths occurred on the index admission, 167 during re-admission and 145 out-of-hospital. Sudden death accounted for 54% of all deaths and 93% of out-of-hospital deaths. Ramipril reduced the risk of sudden death by 30% (95% CI: 8-47%; P = 0.011). However, overall, 45% of those patients who died suddenly had severe or worsening heart failure prior to their death. Only 39% of sudden deaths were considered to be due to arrhythmias. Ramipril reduced the risk of death from circulatory failure by 18%, but this did not reach statistical significance (95% CI; 41 to -14%; P = 0.237). The magnitude of the effects on sudden death and death due to circulatory failure were not significantly different. However, 38% of the reduction in overall mortality was from the subgroup with sudden death who had developed prior severe resistant heart failure (placebo n = 35, ramipril n = 15), again emphasizing the marked benefit in preventing failure. Ramipril did not selectively alter the proportion of in- to out-of-hospital deaths. CONCLUSION: Ramipril reduces mortality and progression to resistant heart failure among patients with evidence of heart failure early after myocardial infarction. Retarding the progression of heart failure appears to be a major factor contributing to the reduction in mortality both by reducing circulatory failure and by reducing sudden death.
Adult↗
Regulation of [Ca++]i in human neuroblastoma (SH-SY5Y) cells expressing recombinant rat angiotensin1A receptors by angiotensin II and carbachol.
The ability of angiotensin II (AII) to regulate [Ca++]i in human neuroblastoma (SH-SY5Y) cells stably expressing recombinant rat AT1A receptors was investigated using microfluorimetric methods, and compared to responses obtained by stimulation of native muscarinic receptors. Applications of AII or carbachol produced biphasic rises of [Ca++]i, but in Ca++-free solutions (containing 1 mM ethylene glycol-bis (beta-aminoethyl ether)N,N,N,'N'-tetraacetic acid), both agonists produced only transient monophasic rises of [Ca++]i, and second applications were without effect. Application of Ca++(o) (2.5 mM) to cells after exposure to either agonist produced a Ni2+-sensitive rise of [Ca++]i in the absence of agonist ("capacitative Ca++ influx"). After removal of Ca++(o), both AII and carbachol elicited a second rise of [Ca++]i. Thapsigargin (1 microM) prevented these second rises of [Ca++]i. During capacitative Ca++ influx, application of AII failed to produce a further rise of [Ca++]i. In contrast, carbachol produced a further rise of [Ca++]i, attributable to activation of both nicotinic and muscarinic receptors, because it was reduced (but not abolished) by mecamylamine (1 microM) and was observed when muscarine was used as the agonist. Thus, activation of recombinant AT1A and muscarinic receptors in SH-SY5Y cells leads to mobilization of Ca++ from a common intracellular pool, and stimulates capacitative Ca++ influx. Muscarinic (but not AII) receptor occupancy is capable of stimulating an additional Ca++ influx pathway.
Angiotensin II↗
Down-regulation or long-term inhibition of protein kinase C (PKC) reduces noradrenaline release evoked via either PKC-dependent or PKC-independent pathways in human SH-SY5Y neuroblastoma cells.
Long-term (8-48 h) treatment of SH-SY5Y neuroblastoma cells with phorbol-12,13-dibutyrate (PDBu; 100 nM) promotes the down-regulation of protein kinase C (PKC) subtypes alpha and epsilon and reduces by up to 60% noradrenaline (NA) release evoked via both PKC-dependent (M3-muscarinic receptor activation) and PKC-independent (depolarization) pathways, over similar time courses. A similar effect on release is observed following long-term (16-48 h) incubation with the PKC inhibitor Ro 31-7549 (10 microM), even after removal of the inhibitor, indicating a mechanism which is not rapidly reversible. Evidence is presented which suggests that long-term treatment with PDBu does not (1) affect calcium entry, (2) modulate levels of proteins important in the secretory mechanism or (3) reduce the number of secretory vesicles. Thus, the decrease in NA release in SH-SYSY cells following down-regulation of PKC appears to be the result of a sustained reduction in PKC activity acting on a component of the secretory pathway not involved in the regulation of calcium entry or vesicle number.
Carcinogens↗
Symptom subtypes of obsessive-compulsive disorder in behavioral treatment studies: a quantitative review.
Recent reviews and meta-analytic studies have provided an encouraging account of the effectiveness of behavioral interventions for obsessive-compulsive disorder (OCD). One question regarding these estimates concerns their degree of generalizability to the range of OCD subtypes encountered in clinical settings. The purpose of the present study was to provide a quantitative description of the prevalence of various OCD subtypes (i.e. type of compulsions) within the behavioral treatment literature. We examined 65 studies that permitted classification of patients according to symptom subtype. Patients with primarily cleaning and/or checking compulsions predominated, accounting for 75% of the treatment population. On the other hand, patients with multiple compulsions or other compulsions, such as exactness, counting, hoarding, or slowness rituals were underrepresented, comprising only 12% of the population, which is markedly less than clinical epidemiological estimates. Rates of improvements in patients with OCD are most applicable to patients with cleaning and checking compulsions, but may not yet be generalizable to patients with other symptoms. These findings encourage studies of the efficacy of existing and novel interventions for patients with counting, repeating, symmetry, hoarding, or multiple compulsions in order to broaden the clinical application of OCD behavioral treatment.
Behavior Therapy↗
Clinical and genetic changes in a case of a Cushing's carcinoma.
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Gene Deletion↗
Cushing's syndrome secondary to ectopic ACTH secretion from a primary ovarian carcinoma.
We report a 63-year-old woman who presented with clinical and biochemical features of ACTH dependent Cushing's syndrome secondary to a primary ovarian carcinoma. The tumour produced very high levels of ACTH precursors, consistent with defective POMC processing.
ACTH Syndrome, Ectopic↗
Phorbol ester-enhanced noradrenaline secretion correlates with the presence and activity of protein kinase C-alpha in human SH-SY5Y neuroblastoma cells.
The effect of inhibition and down-regulation of protein kinase C (PKC) subtypes alpha, epsilon, and zeta on noradrenaline (NA) secretion from human SH-SY5Y neuroblastoma cells was investigated. The PKC inhibitor Ro 31-7549 inhibited carbachol-evoked NA release (IC(50) 0.6 microM) but not 100 mM (K+)-evoked release. In addition, Ro 31-7549 inhibited the enhancement of carbachol- and (K+)-evoked release after pretreatment with 12-O-tetradecanoylphorbol 13-acetate (TPA; 100 nM) for 8 min, with IC50 values of 0.7 and 2.4 microM, respectively. Immunoblotting studies showed that prolonged exposure (48 h) of SH-SY5Y cells to phorbol 12,13-dibutyrate (PDBu) or bryostatin-1 caused down-regulation of PKC-alpha and PKC-epsilon but not PKC-zeta. Under these conditions, the acute TPA enhancement of NA release was inhibited. Moreover, the inhibition of TPA-enhanced secretion was also apparent after only 2-h exposure to either PDBu or bryostatin-1, conditions that caused down-regulation of PKC-alpha, but not PKC-epsilon or zeta. The PKC inhibitor Gö-6976 (2 microM), which has been shown to inhibit selectively PKC-alpha and beta in vitro, also inhibited the TPA enhancement of carbachol- and (K+)-evoked NA release by > 50%. These data suggest that in SH-SY5Y cells, the ability of TPA to enhance carbachol- and (K+)-evoked NA secretion is due to activation of PKC-alpha.
Bryostatins↗
How ACE inhibitors reduce death from myocardial infarction: hypotheses from the AIRE study. Acute Infarction Ramipril Efficacy study.
Doctors treat patients, not populations. 'Evidence-based' practice is essential but extrapolation to the individual patient is always necessary and this fact is well illustrated by data from trials of ACE inhibitors post-myocardial infarction. In the AIRE (Acute Infarction Ramipril Efficacy) study, 2,006 patients with some evidence of heart failure, even if transient, after a myocardial infarction, were randomised to receive oral ramipril or placebo in addition to standard treatment. Follow-up was for a minimum of six and an average of 15 months. The risk reduction in total mortality was 27% (95% CI 11-40%; p = 0.002); approximately 40 lives might be expected to be saved for every 1000 patients treated for one year. Benefit was apparent within weeks of starting treatment. Additional data from the AIRE study are considered in relation to the findings of other mortality trials. It is argued that ACE inhibitors offer most to those patients with impaired left ventricular function through a mechanism not related to the prevention of myocardial re-infarction.
Angiotensin-Converting Enzyme Inhibitors↗
Mode of death in chronic heart failure. A request and proposition for more accurate classification.
The proportion of patients reported to die suddenly or from progressive circulatory failure is not consistent among studies of heart failure. Lack of an adequate or consistent classification of how patients die contributes to the current confusion over the mode of death in heart failure. Defining how patients with heart failure die could be important in developing strategies to reduce the continuing high mortality associated with this condition. We identified 27 studies that reported 50 or more deaths among patients with heart failure to ascertain how death was classified. Definitions of sudden death appeared heterogeneous and the majority of studies failed to publish or make reference to how circulatory failure was defined. A framework for the classification of the mode of death has been developed in which clear separation of the activity and place at the time of death, cause of death, mode of death, and events prior to death is made (ACME: Activity, Cause, Mode and Event). This mode of classifying death has been successfully piloted in two mortality studies; AIRE and NETWORK. Classifying mortality in this way will help identify pathways leading to death and hence suggest therapies and strategies to reduce mortality in patients with heart failure, a group of patients whose prognosis remains poor.
Adult↗
Inhibition of the renin-angiotensin system after acute myocardial infarction--treat first, select later?
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Angiotensin-Converting Enzyme Inhibitors↗