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H Wise

Publications and source records attributed to H Wise.

At least 37 records · Page 2Linked to original sources
PubMed1997

Cyclic AMP-independent activation of neutrophil-like HL-60 cells by prostaglandin E2.

The role of cAMP in mediating prostaglandin E2 (PGE2)-stimulated aggregation of neutrophil-like HL-60 cells has been investigated. Although the EP2 receptors appear to couple to Gs-proteins, PGE2 stimulated HL-60 cell aggregation appears to be a cAMP-independent process. This response to PGE2 in independent of calcium and tyrosine kinase activity, appears to involve activation of phosphatidylinositol 3-kinase which is negatively regulated by phosphatidic acid generated from phospholipase D activity, and is partially dependent on protein kinase C activity. In contrast, although the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) produces a similar aggregation response to PGE2, FMLP uses a distinct intracellular signalling pathway. The aggregation response to FMLP involves activation of Gi-proteins, is partially dependent on extracellular calcium, is negatively regulated by protein kinase C, and is independent of phosphatidylinositol 3-kinase, phospholipase D and tyrosine kinase activity. The possibility exists that EP2 receptor activation leads to Gs-dependent, but cAMP-independent, stimulation of phosphatidylinositol 3-kinase activity in HL-60 cells.

Cell Aggregation↗
PubMed1997

Relaxant actions of nonprostanoid prostacyclin mimetics on human pulmonary artery.

The specific prostacyclin (IP) receptor agonist cicaprost relaxed human pulmonary artery preparations precontracted with phenylephrine [50% inhibitory concentration (IC50) approximately 0.6 nM], U-46619 (IC50 approximately 0.9 nM), and K+ (approximately 40% maximal relaxation); endothelium removal had little effect on relaxant activity. Ranking of relaxant potencies for prostacyclin and five of its analogs was 17 alpha, 20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-9063) > or = cicaprost > iloprost > prostacyclin > taprostene > benzodioxane prostacyclin > 15-deoxy-16 alpha-hydroxy-16 beta,20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-3356). The potency of the isocarbacyclin TEI-3356 may have been under-estimated because of its contractile (EP3 receptor agonist) activity. The potency ranking of four nonprostanoid prostacyclin mimetics was 3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy] acetic acid (BMY 45778; IC50 approximately 2.5 nM) > > 2-[3-[2-(4, 5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (BMY 42393) > octimibate > CU 23 (a novel diphenylindole). From IP receptor binding affinities obtained on human platelet membranes, it is suggested that the slightly shallower log concentration-response curves for BMY 45778, BMY 42393, and CU 23 may reflect the near-maximal receptor occupancy required for complete relaxation. A fifth nonprostanoid, CU 602, had much shallower log concentration-response curves than cicaprost against phenylephrine tone but not against U-46619 tone; this may indicate IP receptor partial agonism coupled with TP receptor antagonism. The relaxant actions of the nonprostanoid mimetics were more persistent than those of the prostacyclin analogs on washout of the organ bath; by the inhalation route, this type of compound may be retained within pulmonary tissue and thus afford greater pulmonary/systemic selectivity than currently used pulmonary vasodilators.

Acetates↗
PubMed1996

The inhibitory effect of prostaglandin E2 on rat neutrophil aggregation.

Rat peritoneal neutrophils stimulated by N-formyl-methionyl-leucyl-phenylalanine (fMLP) produce an aggregation response that can be inhibited by prostaglandin E2 (PGE2) with an IC50 value of 2.6 x 10(-9) M. Although PGE2 can stimulate [3H]cAMP production in neutrophils (EC50 4.3 x 10(-8) M), the anti-aggregation response cannot be significantly attenuated by inhibitors of adenylate cyclase or protein kinase A, neither can it be potentiated by inhibition of phosphodiesterase activity. Despite these observations, it still remains possible that PGE2-mediated inhibition of rat neutrophil aggregation is a cAMP-dependent response mediated by highly localized changes in neutrophil cAMP. The inhibitory effect of PGE2 does not appear to depend on effects on intracellular calcium or K(ATP) channels. Similarities exist between PGE2 and the profile of activity of phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors, suggesting that PI 3-kinase is a possible target for PGE2 action in rat neutrophils.

Adenine↗
PubMed1996

Focus on prostacyclin and its novel mimetics.

Prostacyclin (PGI2) has been traditionally regarded as an important regulator of haemostasis, mediating its effects through prostacyclin (IP) receptors coupled to adenylate cyclase. Recent evidence suggests, however, that IP receptor agonists can activate multiple signalling pathways via the same IP receptor. Moreover, IP receptor agonists have interesting actions outside of the cardiovascular system, even extending to the release of non-adrenergic non-cholinergic (NANC) transmitters from enteric neurones. Here, Helen Wise and Robert Jones highlight some of this new information on PGI2 and its receptors, describe the properties of some chemically novel PGI2 mimetics, and report on current therapeutic uses of PGI2.

Animals↗
PubMed1996

Activation of neutrophil-like HL-60 cells by prostaglandin E2.

The effect of prostaglandins on neutrophil activation has been studied using the human promyelocytic leukemic cell line HL-60, differentiated with dimethyl sulfoxide (DMSO). Prostaglandin E(2) (PGE(2)) directly stimulated HL-60 cell aggregation with an EC(50) value of 30 nM. Studies with prostanoid receptor-selective agonists suggest that the activation of HL-60 cells by PGE(2) was mediated via the EP(2) receptor. Human neutrophils did not aggregate in response to PGE(2), but PGE(2) inhibited the N-formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated increase in intracellular calcium ([Ca(2+)i]) in both neutrophils and HL-60 cells. In contrast with the aggregation response to FMLP the aggregation response of HL-60 cells to PGE(2) was independent of extracellular calcium and did not involve mobilization of intracellular calcium.

Alprostadil↗
PubMed1996

The inhibitory effects of non-prostanoid prostacyclin mimetics on rat neutrophil function.

The effects of three non-prostanoid prostacyclin mimetics on rat peritoneal neutrophil activity have been investigated and compared with the effects of the prostacyclin analogues cicaprost and iloprost. Cicaprost, iloprost, BMY 22389 (octimibate), BMY 42393 and BMY 45778 inhibited N-formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated neutrophil aggregation with IC50 values of 2.1, 4.5, 286, 462 and 20 nM, respectively. Cicaprost and iloprost produced clear concentration-related increases in [3H]cyclic AMP accumulation; EC50 values were 20 and 44 nM, respectively. In contrast, the three BMY compounds showed low efficacy as activators of adenylyl cyclase. The inhibitory effect of prostacyclin mimetics does not appear to depend on effects on intracellular calcium concentration, or on KATP channels. Extensive studies using cyclic AMP mimetics and antagonists suggest that the anti-aggregatory activity of the non-prostanoid prostacyclin mimetics on rat neutrophils may involve highly localized increases in cyclic AMP.

Acetates↗
PubMed1995

A study of prostacyclin mimetics distinguishes neuronal from neutrophil IP receptors.

The prostacyclin mimetics BMY 45778 (3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid), BMY 42393 (2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid) and EP 185 (rac 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-(p-methoxyphenyl- phenyl-methylazino)-bicyclo[2.2.2]oct-2-ene) inhibited rat neutrophil aggregation stimulated by N-formyl-methionyl-leucyl-phenylalanine (IC50 = 20, 462, and 1195 nM respectively). In contrast only BMY 45778 (1-10 microM) produced any significant inhibition (10-20%) of the spontaneous activity of rat colon. BMY 45778 (10 microM) also attenuated the inhibitory effect of the prostacyclin analogue cicaprost on rat colon, whereas BMY 42393 and EP 185 did not. BMY 45778 appears to be a low affinity partial agonist at prostacyclin receptors on rat colon and its low potency in rat colon compared with rat neutrophils suggests the presence of a different prostacyclin receptor located on enteric neurones.

Acetates↗
PubMed1994

Characterization of prostanoid receptors on rat neutrophils.

1. The effects of various prostanoid agonists have been compared on the increase in intracellular free calcium ([Ca2+]i) and the aggregation reaction of rat peritoneal neutrophils induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP). 2. Prostaglandin E2 (PGE2) and the specific IP-receptor agonist, cicaprost, both inhibited the FMLP-induced increase in [Ca2+]i (IC50 33 nM and 18 nM respectively) and the FMLP-induced aggregation reaction (IC50 5.6 nM and 7.9 nM respectively). PGD2, PGF2 alpha, and the TP-receptor agonist, U 46619, were inactive at the highest concentration tested (1 microM). 3. The EP1-receptor agonist, 17-phenyl-omega-trinor PGE2, and the EP3-receptor agonists, GR 63799X and sulprostone, had no inhibitory effect on FMLP-stimulated rat neutrophils. 4. PGE1 (EP/IP-receptor agonist) and iloprost (IP-receptor agonist) inhibited the FMLP-induced increase in [Ca2+]i with IC50 values of 34 nM and 38 nM respectively. The EP2-receptor agonists, butaprost and misoprostol (1 microM), inhibited both FMLP-stimulated [Ca2+]i and aggregation. However another EP2-receptor agonist, AH 13205, was inactive in both assays. 5. Prostanoid receptors present on rat neutrophils were further characterized by measuring [3H]-adenosine 3':5'-cyclic monophosphate ([3H]-cyclic AMP) accumulation. Only those agonists capable of stimulating [3H]-cyclic AMP accumulation were able to inhibit both FMLP-stimulated [Ca2+]i and aggregation. 6. These results indicate that rat neutrophils possess inhibitory IP and EP-receptors; the relative potencies of PGE2, misoprostol and butaprost are those expected for the EP2-receptor subtype. No evidence for DP, FP, TP or EP1 and EP3-receptors was obtained.

Animals↗
PubMed1991

The pharmacology of fluparoxan: a selective alpha 2-adrenoceptor antagonist.

1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg- 1 orally twice daily. The down-regulation of beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.

Adrenergic alpha-Agonists↗
PubMed1990

Flow cytometric analysis of primary and metastatic bladder cancer.

A total of 22 patients with high grade P2-4N+ transitional cell carcinoma of the bladder underwent flow cytometric analysis of nuclei obtained from paraffin embedded specimens from the primary (bladder) and metastatic (lymph node) sites. Tumor heterogeneity was defined as polyclonal aneuploidy of the primary tumor (not identified in the population studied) or as a difference in the deoxyribonucleic acid index of the primary and metastatic sites of 0.20 or more (8 patients). With these criteria 8 patients (36%) had heterogeneous tumors and 14 (64%) had homogeneous tumors. The median survival of 14 patients with aneuploid and 8 with diploid primary tumors was 17.5 and 8.0 months, respectively (p equals 0.08, Lee-Desu test). When patient survival was compared to the ploidy of the metastatic site, or in patients with diploid primary and metastatic lesions versus deoxyribonucleic acid aneuploidy at either the primary and/or metastatic site, the aneuploid tumors had a longer survival but this difference was not significant (p equals 0.13 and 0.23, respectively). Our study demonstrates the value of flow cytometry to identify primary metastatic tumor heterogeneity. It also suggests that the presence of metastasis may be a more important factor to define the biological potential of transitional cell carcinoma than is deoxyribonucleic acid ploidy.

Aged↗
PubMed1990

Phase II trial of interferon-beta-serine in metastatic renal cell carcinoma.

Interferon-beta-serine (IFN-beta-ser) is a muteine, recombinant IFN that is tolerated at a dose fivefold to 10-fold higher than IFN-alfa and interacts with the same cell membrane receptor as IFN-alfa. We hypothesized that at high doses IFN-beta-ser might induce a higher response rate than IFN-alfa in metastatic renal cell carcinoma. We undertook a phase II trial of IFN-beta-ser in patients with metastatic renal cell carcinoma. Patients were treated three times each week by a 2-hour intravenous infusion. Doses were escalated weekly (.25 to 5.5 mg, 1 mg = 180,000,000 U) until the maximum-tolerated treatment dose (MTTD) was determined. The MTTD is defined as one dose level less than that which caused grade 3 toxicity and was subsequently administered three times weekly for at least 4 weeks. Twenty-nine patients were entered, and 25 were assessable for response and toxicity. The performance status was 0-1 in all patients and only one patient received previous chemotherapy. The MTTD dose was 2.5 mg (range, 0.5 to 5.5 mg per treatment), although in 10 patients, doses were later deescalated because of cumulative toxicity. Initial dose-limiting toxicity and cumulative toxicity were fatigue, malaise, and fever in most patients. Hepatic transaminitis, neutropenia, and elevation of serum creatinine were also observed but were not dose-limiting. There was one complete response (CR) and four partial responses (PRs). All responses but one occurred in pulmonary metastases. The median time to response was 26 days (range, 17 to 102 days). These data demonstrate that IFN-beta-ser given in high doses exhibits significant antitumor activity in renal cell carcinoma; however, the objective response rate is 20%. This is no higher than previous IFN studies; therefore, we reject the hypothesis than IFN-beta-ser at high doses may induce a greater response rate than IFN-alfa. However, we did observe more responses than were seen in a similar trial undertaken with lower dose IFN-beta serine in renal cell carcinoma.

Adult↗
PubMed1985

Why is amitriptyline much weaker than desipramine at decreasing beta-adrenoceptor numbers?

Desipramine is consistently more effective than amitriptyline at causing beta-adrenoceptor down-regulation. Atropine, mepyramine, ketanserin, cyproheptadine and citalopram did not modify this action of desipramine in rats. Therefore inhibition of either muscarinic, histamine-H1, and 5-HT receptors or 5-HT uptake produced by amitriptyline is unlikely to account for its weaker effect on beta-adrenoceptors. A more likely explanation implicates noradrenaline uptake inhibition in vivo since amitriptyline was much weaker than desipramine and only effective after repeated dosing.

Amitriptyline↗