PubMed Health⌕ Search

Biomedical subjects

A M White

Publications and source records attributed to A M White.

At least 19 recordsLinked to original sources
PubMed1996

Nitric oxide-induced mobilization of intracellular calcium via the cyclic ADP-ribose signaling pathway.

Cyclic adenosine diphosphate ribose (cADPR) is a potent endogenous calcium-mobilizing agent synthesized from beta-NAD+ by ADP-ribosyl cyclases in sea urchin eggs and in several mammalian cells (Galione, A., and White, A. (1994) Trends Cell Biol. 4, 431 436). Pharmacological studies suggest that cADPR is an endogenous modulator of Ca2+-induced Ca2+ release mediated by ryanodine-sensitive Ca2+ release channels. An unresolved question is whether cADPR can act as a Ca2+-mobilizing intracellular messenger. We show that exogenous application of nitric oxide (NO) mobilizes Ca2+ from intracellular stores in intact sea urchin eggs and that it releases Ca2+ and elevates cADPR levels in egg homogenates. 8-Amino-cADPR, a selective competitive antagonist of cADPR-mediated Ca2+ release, and nicotinamide, an inhibitor of ADP-ribosyl cyclase, inhibit the Ca2+-mobilizing actions of NO, while, heparin, a competitive antagonist of the inositol 1,4,5-trisphosphate receptor, did not affect NO-induced Ca2+ release. Since the Ca2+-mobilizing effects of NO can be mimicked by cGMP, are inhibited by the cGMP-dependent-protein kinase inhibitor, Rp-8-pCPT-cGMPS, and in egg homogenates show a requirement for the guanylyl cyclase substrate, GTP, we suggest a novel action of NO in mobilizing intracellular calcium from microsomal stores via a signaling pathway involving cGMP and cADPR. These results suggest that cADPR has the capacity to act as a Ca2+-mobilizing intracellular messenger.

ADP-ribosyl Cyclase↗
PubMed1994

Parental concerns following a child's discharge from a bone marrow transplant unit.

The purpose of this descriptive study was to explore the concerns of parents following a child's discharge from a bone marrow transplant unit. A qualitative approach which included components of grounded theory was used to explore the posttransplant experience from the parents' perspective. Seven parents of five children who were transplanted for a variety of malignancies at a number of out-of-state centers were interviewed about their experiences. Chart analysis and participant observation provided additional sources of data. Initial coding of audio-taped interviews revealed 32 topics of concern voiced by the parents. Use of the constant comparative analysis technique resulted in the emergence of six major themes of the posttransplant experience. The Return Home, Changing Relationships, Working with This, Learning the Rules, The New Norm, and The Uncertain Future were components of this transitional period for each family. Similarities were found between the experiences of study parents and the parents of chronically ill children and parents or spouses of organ transplant recipients. Awareness of posttransplant concerns may facilitate the efforts of both transplant and referral center staff to educate, support, and care for these children and their families.

Adaptation, Psychological↗
PubMed1993

Cyclic ADP-ribose-induced Ca2+ release from rat brain microsomes.

Cyclic ADP-ribose (cADPR), an endogenous NAD+ metabolite in many mammalian and invertebrate tissues, is a potent mediator of calcium mobilization in sea urchin eggs. Our results show that cADPR also stimulates calcium release from rat brain microsomes, marked release occurring over the concentration range 10-250 nM. This is not inhibited by concentrations of heparin which completely abolish inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release. Ryanodine (100 microM) inhibits the cADPR response. Our results are consistent with cADPR being an endogenous messenger mediating Ca2+ release from ryanodine-sensitive pools in brain.

Adenosine Diphosphate Ribose↗
PubMed1993

Comparison of Ins(1,4,5)P3 receptors from rat cerebellum and bovine adrenal cortex.

Ins(1,4,5)P3 receptors in adrenal cortical and cerebellar membranes can be distinguished by their affinities for Ins(1,4,5)P3 as well as the potencies with which heparin and Mg2+ inhibit binding. We have found that the differences in Ins(1,4,5)P3 affinity and heparin inhibition are maintained upon receptor solubilization and purification. In contrast to this, heparin-agarose affinity purification of solubilized cerebellar receptors reduces the potency of Mg2+ inhibition to that in adrenal cortex. These results suggest that Ins(1,4,5)P3 receptors in adrenal cortex are structurally distinct from those in cerebellum. Monoclonal antibodies raised against C- and N-terminal regions of mouse cerebellar Ins(1,4,5)P3 receptors recognize 250-300-kDa proteins in both rat cerebellum and bovine adrenal cortex.

Adrenal Cortex↗
PubMed1993

Two tRNA gene clusters associated with rRNA operons rrnD and rrnE in Bacillus subtilis.

Sequence analysis of cloned rescued DNA fragments from a Bacillus subtilis strain with an inserted recombinant plasmid in ribosomal operon rrnE revealed the presence of two tRNA genes for Met and Asp at the 3' end of the operon. Probing chromosomal DNA from a strain carrying a plasmid inserted in rrnD with a fragment containing the genetically unassigned cluster of 16 tRNA genes revealed that the cluster is located immediately following the rrnD operon. Our findings show that all 10 rrn operons in B. subtilis are associated with tRNA gene clusters.

Amino Acid Sequence↗
PubMed1991

Influence of Mg2+ and pH on n.m.r. spectra and radioligand binding of inositol 1,4,5-trisphosphate.

We and others have shown that the binding of Ins(1,4,5)P3 to its receptor is pH-sensitive and can be inhibited by Mg2+. In the present study we have used 1H- and 31P-n.m.r. spectroscopy to study whether these effects results from increased ionization of Ins(1,4,5)P3 and a direct interaction with Mg2+ respectively. Under near-physiological conditions of ionic strength (100 mM-KCl), three ionizable groups were observed. The pH titration curve of the 1-phosphate was monophasic, with a pKa of 6.3. The titration curves of the 4- and 5-phosphates were biphasic, suggesting that these groups interact; the pKa values for the 4-phosphate determined by 31P-n.m.r. were 5.7 and 7.8, and for the 5-phosphate they were 5.3 and 7.9. 1H- and 31P-n.m.r. measurements suggest that Mg2+ binds weakly to Ins(1,4,5)P3 at physiological pH. Mg2+ non-competitively inhibited binding of Ins(1,4,5)P3 to its receptor in rat cerebellum and bovine adrenal cortex. Inhibition curves for rat cerebellum at pH 7.1 and 8.5, and also for bovine adrenal cortex at pH 8.5, appeared to be monophasic, with IC50 values (concn. of displacer giving 50% inhibition of specific binding) of 214 microM, 572 microM and 9.1 mM respectively. Scatchard analysis revealed that Mg2+ inhibited binding of Ins(1,4,5)P3 to bovine adrenal cortex at pH 8.5 in a non-competitive manner. Our results suggest that the previously reported pH-sensitivity of the binding of Ins(1,4,5)P3 may be caused by ionization of the phosphate groups in positions 4 and 5, and that the ability of Mg2+ to inhibit the binding of Ins(1,4,5)P3 is not mediated by direct chelation but through a site located on, or close to, the Ins(1,4,5)P3 receptor. Inhibition by Mg2+ is pH-sensitive and can vary at least 10-fold between tissues, suggesting possible receptor heterogeneity. Mg2+ may exert an important regulatory control on the release of Ca2+ by Ins(1,4,5)P3.

Adrenal Cortex↗
PubMed1991

Airway responsiveness to inhaled methacholine in patients with irritable bowel syndrome.

We examined whether patients with irritable bowel syndrome have increased airway responsiveness by measuring forced expiratory volumes in 1 second (FEV1) after inhalation of increasing concentrations of methacholine. Responses obtained in 11 IBS patients were compared with those obtained in 11 normal subjects and in 11 subjects with organic disease of the gut or its related organs. All subjects were selected so that other factors that might contribute to increased airway responsiveness were excluded. The methacholine concentration that caused a 20% fall in the FEV1 (PC20), as well as the reduction in FEV1 induced by each methacholine concentration, were used to assess airway responsiveness. The geometric mean PC20 was 197.6 mg/mL (%SEM, 1.15) for normal subjects, 83.9 mg/mL (%SEM, 1.51) for subjects with organic bowel disease (P = 0.012), and only 12.8 mg/mL (%SEM, 1.74) for IBS patients (P less than 0.0001). The 22.5% +/- 2.5% decrease in FEV1 induced by 64 mg/mL of methacholine in IBS patients was significantly greater than that of 12.3% +/- 1.5% observed in healthy subjects (P = 0.003). In contrast, the 15.7% +/- 2.0% decrease in FEV1 observed in patients with organic disease was not different from that seen in normal subjects (P = 0.189). We conclude that IBS is associated with increased airway responsiveness following challenge with methacholine.

Administration, Inhalation↗
PubMed1991

Autonomic stimulation.

Therapeutic stimulation of the autonomic nervous system has been limited by lack of qualitative or quantitative evaluation of autonomic mechanisms. This article provides an historical review of knowledge about autonomic pathways and critical evaluation of available tests of autonomic function. Recent developments in evaluation of autonomic dysfunction and improvement in techniques of neurostimulation have facilitated the development of a number of clinically useful treatments for bladder control, sexual problems, peripheral vascular disease, angina pectoris, and seizure disorders. Future therapeutic measures may allow specific control of hypertension, pain, cardiac arrhythmias, trophic disorders and balance.

Autonomic Nervous System↗
PubMed1989

Subacute and chronic in vivo lithium treatment inhibits agonist- and sodium fluoride-stimulated inositol phosphate production in rat cortex.

We have investigated the effects of in vivo lithium treatment on cerebral inositol phospholipid metabolism. Twice-daily treatment of rats with LiCl (3 mEq/kg) for 3 or 16 days resulted in a 25-40% reduction in agonist-stimulated inositol phosphate production, compared with NaCl-treated controls, in cortical slices prelabelled with [3H]inositol. A small effect was also seen with 5-hydroxytryptamine (5-HT) 24 h after a single dose of LiCl (10 mEq/kg). Dose-response curves to carbachol and 5-HT showed that lithium treatment reduced the maximal agonist response without altering the EC50 value. This inhibition was not affected by the concentration of LiCl in the assay buffer. Stimulation of inositol phosphate formation by 10 mM NaF in membranes prepared from cortex of 3-day lithium-treated rats was also inhibited, by 35% compared with NaCl-treated controls. Lithium treatment did not alter the kinetic profile of inositol polyphosphate formation in cortical slices stimulated with carbachol. Muscarinic cholinergic and 5-HT2 bindings were unaltered by lithium, as was cortical phospholipase C activity and isoproterenol-stimulated cyclic AMP formation. [3H]Inositol labelling of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by 3-day lithium treatment. The results, therefore, indicate that subacute or chronic in vivo lithium treatment reduces agonist-stimulated inositol phospholipid metabolism in cerebral cortex; this persistent inhibition appears to be at the level of G-protein-phospholipase C coupling.

Animals↗
PubMed1985

An ultrastructural analysis of the vascular damage in the lethal and sublethal Forssman reaction in the guinea-pig.

The involvement of the complement system and platelets in the sublethal Forssman reaction in the guinea pig has been studied together with the ultrastructural changes observed in the endothelial cells of the pulmonary vasculature. The main ultrastructural change noted was swelling of the endothelium. This did not occur in thrombocytopenic animals or in decomplemented animals, indicating the importance of both platelets and the complement pathways in this reaction. The platelet inhibitors sulphinpyrazone or aspirin had no effect on endothelial swelling in the sublethal reaction. In the lethal reaction the degree of endothelial cell damage was more severe and included lesions in the cell membrane, lifting, necrosis and finally exposure of the basement membrane. This damage only occurred in animals with an intact complement cascade.

Anaphylaxis↗
PubMed1984

Inhibition by heparin of platelet accumulation in vivo.

In vivo platelet aggregation has been studied using a novel, minimally invasive technique. No aggregatory effects of heparin were observed on normal circulating platelets nor was there enhancement of aggregation of platelets during activation by intravenous injection of ADP, collagen, PAF acether or thrombin. On the contrary, high doses of heparin were found to inhibit platelet accumulation induced by ADP, collagen or PAF-acether. Inhibition of these responses necessitated doses of heparin in excess of those required for anti-coagulant effects. The present experiments do not establish a mechanism for such inhibition. Extension to other species, including man, is needed before attributing clinical relevance to the present observations.

Animals↗
PubMed1982

Prolongation of rat tail bleeding time caused by oral doses of a thromboxane synthetase inhibitor which have little effect on platelet aggregation.

N (7-carboxyheptyl) imidazole is an inhibitor of platelet thromboxane synthetase that has no effect on the cyclooxygenase activity. An oral dose of the substance to rats (10 mg/kg) prolonged tail bleeding time from 170 +/- 13 sec to 284 +/- 22 sec. This oral dose also inhibited platelet thromboxane B2 production induced by collagen ex vivo but had little effect on the aggregation dose response curve. There was no effect on thrombin-induced aggregation. Neither the thrombocytopenia induced by the Arthus reaction nor thrombus formation on an implanted cotton thread were inhibited by oral doses of carboxyheptylimidazole up to 30 mg/kg. Similarly neither the prothrombin nor activated partial thromboplastin time were affected. It is postulated that this thromboxane synthetase inhibitor prolongs bleeding time nor by inhibiting platelet aggregation or blood coagulation but rather by preventing the vasoconstriction which would normally be caused by thromboxane A2.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Fibrin, red cell and platelet interactions in an experimental model of thrombosis.

1 Insertion of a cotton thread into an arteriovenous shunt of an anaesthetized rat causes an increase in the weight of the thread due to deposition of thrombus. 2 The thrombus formed was of the venous (red) type, being sensitive to heparin, yet possessed important characteristics of an arterial thrombus, in that it was dependent on platelets and on rate of blood flow. 3 Thromboxane synthetase inhibitors had no effect on thrombus deposition. 4 Cyclo-oxygenase inhibitors did not significantly depress thrombus formation at doses which inhibited platelet function ex vivo. 5 Compounds which can modify the release or action of adenosine 5' -diphosphate partly inhibited thrombus formation. 6 A depression in clotting factor levels induced by sodium warfarin led to a highly significant reduction in thrombus formation at doses which caused a prolongation of prothrombin clotting time.

Animals↗
PubMed1982

Subcellular localization of 111In in human and rabbit platelets.

In order to examine the subcellular distribution of 111In in 111In-oxine-labeled human and rabbit platelets, we employed a hypothetical grain technique of EM autoradiography analysis. The results indicate that in the rabbit 111In was concentrated within the platelet dense bodies, particularly when the platelets had been labeled in a plasma-free system. Under comparable conditions of labeling, human platelets appeared to accumulate almost all the radiolabel within the cytosol. Using inhibitors of 5-hydroxytrptamine (5-HT) uptake, i.e., cloimipramine, ouabain, sodium fluoride, p-chloromercuribenzoate, and reserpine, we were unable to demonstrate an active uptake process in either species. Both collagen and thrombin were able to cause dose-dependent release of radioactivity from the labeled rabbit platelets only. In the case of collagen, this mimicked endogenous 5-HT release and was inhibited by indomethacin. These results and their implications are discussed.

Animals↗
PubMed1981

The effects of two different dosage regimens of sulphinpyrazone on platelet function ex vivo and blood chemistry in man.

When sulphinpyrazone (either 200 mg q.d.s. for 7 days or 400 mg b.d.s. for 5 days) was administered to human volunteers, inhibition of platelet function was observed ex vivo. The inhibitory effect was measured by the increase in the concentration of sodium arachidonate required to cause platelet aggregation and a decrease in the biosynthesis by the platelets of malondialdehyde from added sodium arachidonate. ADP-induced primary platelet aggregation was statistically significantly inhibited only on 1 day of the two studies. The inhibitory effect did not correlate with the plasma concentrations of unchanged sulphinpyrazone nor with its sulphone metabolite but correlated with the plasma concentration of the thioether metabolite (r = 0.577, p less than 0.001). Platelet count, plasma fibrinogen, beta-thromboglobulin, urea and creatinine concentrations were not changed by the drug but there was a clinically insignificant increase in bleeding time in all but one subject.

Bleeding Time↗
PubMed1980

Sulfinpyrazone: a review of its pharmacological properties and therapeutic use.

Sulfinpyrazone1 has long been recognised as a potent uricosuric agent, but has more recently been studied extensively as a platelet inhibitor and antithrombotic agent. It is active in man following oral administration and has been reported to be effective in reducing the incidence of transient ischaemic attacks, thromboembolism associated with vascular and cardiac prostheses, recurrent venous thrombosis, arteriovenous shunt thrombosis and sudden cardiac death following myocardial infarcton. Sulfinpyrazone has not been demonstrated to be effective in preventing or reducing the risk of stroke or death in patients with cerebrovascular disease with a recent history of cerebral or retinal ischaemioc attacks. The normal total dose of sulfinpyrazone as an antithrombotic agent is 800mg daily. The drug has been used continuously for up to 4 years with no serious adverse reactions or laboratory abnormalities. There has been no apparent diminution of effect with time. Sulfinpyrazone is not a substitute for conventional anticoagulant agents (e.g. the coumarin derivatives) in the treatment of venous thrombosis, but is an important drug for the treatment of conditions associated with arterial thrombosis and possibly for the prophylaxis of recurrent venous thrombosis.

Animals↗