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M E Parsons

Publications and source records attributed to M E Parsons.

At least 55 records · Page 3Linked to original sources
PubMed1991

Histamine receptors: an overview.

Histamine is widely distributed throughout the body and has a broad range of pharmacologic effects. The advent of selective agonists and antagonists has allowed the identification and characterization of three types of histamine receptor. These same compounds have helped in our understanding of physiologic and pathologic roles for histamine. Clearly, histamine plays a central role in the physiologic control of gastric acid secretion, and this fact has led to the use of H2 antagonists such as cimetidine, and ranitidine is the therapy of acid-related diseases such as peptic ulcer. Histamine is also one of the prime mediators of a variety of allergic reactions, and H1 antagonists play a therapeutic role in this context. However, despite the widespread distribution of histamine receptors in, for example, the central nervous, respiratory, cardiovascular, and immune systems, other physiologic roles for histamine have not been established. It is to be hoped that future research will alter this situation and possibly lead to other therapeutic indications for histamine agonists and antagonists.

Cimetidine↗
PubMed1990

Reversible inhibitors of the gastric (H+/K+)-ATPase. 1. 1-Aryl-4-methylpyrrolo[3,2-c]quinolines as conformationally restrained analogues of 4-(arylamino)quinolines.

The 4-(arylamino)quinoline 4, previously described as an antiulcer compound, is shown to be an inhibitor of the gastric (H+/K+)-ATPase. It is postulated that 1-arylpyrrolo[3,2-c]quinolines 6 act as conformationally restrained analogues of 4. A series of derivatives of 6 has been prepared and shown to be potent inhibitors of the target enzyme in vitro. Substitution in the ortho position of the aryl ring is important for activity. Unsaturation in the 5-membered ring makes little difference, but introduction of heteroatoms into the same ring markedly reduces activity. In more detailed kinetic experiments, 15c and 4 both show reversible, K(+)-competitive binding to the enzyme, with submicromolar Ki values. The compounds appear to act at the lumenal face of the enzyme and to require protonation for activity. Several compounds in the series are shown to be potent inhibitors of pentagastrin-stimulated acid secretion in the rat.

Adenosine Triphosphatases↗
PubMed1990

BY 1023/SK&F 96022 INN pantoprazole, a novel gastric proton pump inhibitor, potently inhibits acid secretion but lacks relevant cytochrome P450 interactions.

The novel H+/K(+)-adenosine triphosphatase inhibitor (gastric proton pump inhibitor), BY 1023/SK&F 96022, was found to be more potent than omeprazole in some rat models and slightly less potent in a dog model. Overall, both compounds are of a similar potency and efficacy. BY 1023/SK&F 96022 exhibited a somewhat longer duration of the antisecretory action than omeprazole in the Ghosh-Schild rat. In the modified Shay rat, on the basis of equieffective doses in terms of the initial effect, both compounds had a comparable duration of action. However, the p.o./i.v. dose ratio upon acute administration was larger for omeprazole, possibly reflecting its lower stability in the acidic environment of the secreting stomach, compared to BY 1023/SK&F 96022. As in vivo, both compounds were equipotent to inhibit acid production in rabbit isolated fundic glands. However, omeprazole interacted with the 7-ethoxycoumarin dealkylase in vitro with high affinity (Ki = 38.5 mumol/l), in contrast to BY 1023/SK&F 96022 (Ki = 135 mumol/l). Compared to omeprazole, BY 1023/SK&F 96022 also showed less interaction with the cytochrome P450 enzyme hydroxylating ionazolac. Moreover, this difference between the two compounds was also found in the rat in vivo with respect to their interaction with diazepam. Thus, both compounds displayed a comparable antisecretory potency in vivo and in vitro but showed a different interference with cytochrome P450 in favor of less interaction by BY 1023/SK&F 96022.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1989

Adrenergic and purinergic neurotransmission in arterial resistance vessels of the cat intestinal circulation.

The contribution of adrenoceptors and purine receptors in mediating neurogenic vasoconstriction was investigated in the autoperfused intestinal circulation of anaesthetised cats treated with atropine and propranolol. Prazosin (0.5 mg/kg) and yohimbine (1.5 mg/kg) reduced but did not abolish the vasoconstrictor responses to stimulation of the efferent sympathetic nerves. The inhibitory actions of the two antagonists were additive but even after alpha 1- and alpha 2-adrenoceptor blockade nerve stimulation still elicited a residual, frequency-related vasoconstriction. The initial, rapid, phase of this response was completely abolished after desensitisation of P2x-purinoceptors with a high dose (1.5 mg i.a.) of alpha,beta-methylene ATP. In the absence of alpha-adrenoceptor antagonists, alpha,beta-methylene ATP reduced neurogenic vasoconstriction particularly at low frequency (1 Hz) nerve stimulation, but also caused a short-lasting decrease in noradrenaline and methoxamine responses which indicates that the drug may have some non-specific effects on arterial smooth muscle. The results suggest that neurotransmission in arterial resistance vessels of the cat intestinal circulation is predominantly under adrenergic control mediated by postsynaptic alpha 1- and alpha 2-adrenoceptors, with a possible purine involvement in the initial rapid response of the blood vessels, particularly to low frequency nerve stimulation.

Adenosine Triphosphate↗
PubMed1989

The effects of adenosine triphosphate and related purines on arterial resistance vessels in vitro and in vivo.

The distribution of P2-purinoceptors in pre-capillary resistance vessels was studied in vitro, using Krebs perfused rabbit ears and in vivo, in autoperfused hindquarters, intestinal and renal vasculatures of pentobarbitone anaesthetised cats. ATP (10(-10)-10(-6) mol i.a.) caused dose-dependent vasodilatation which, in the rabbit ear, was antagonised by reactive blue 2 (10(-5)-10(-4) M). At the highest concentration of reactive blue 2, ATP responses were reversed and a dose-dependent vasoconstriction was seen. Reactive blue 2, also reduced the vasodilator responses to carbachol and to a lesser extent papaverine which suggests that the antagonist has limited selectivity. The rank order of potency of ATP analogues as vasodilators, 2-methylthio ATP greater than ADP greater than ATP greater than alpha,beta-methylene and beta,gamma-methylene ATP, suggests P2y purinoceptors are involved. The selective P2x-purinoceptor agonist, alpha,beta-methylene ATP, caused pronounced vasoconstriction in the rabbit ear and cat intestinal vasculature which was not antagonised by phenoxybenzamine. In contrast, alpha,beta-methylene ATP had little effect in the autoperfused hindquarters and renal vasculatures suggesting a very heterogeneous distribution of P2x-purinoceptors in the cat. The results are consistent with the proposal that two distinct types of P2-purinoceptors are present on blood vessels.

Adenosine Triphosphate↗
PubMed1989

2-[[(4-Amino-2-pyridyl)methyl]sulfinyl]benzimidazole H+/K+-ATPase inhibitors. The relationship between pyridine basicity, stability, and activity.

The benzimidazole sulfoxide class of antisecretory H+/K+-ATPase inhibitors need to possess high stability under neutral physiological conditions yet rearrange rapidly at low pH to the active sulfenamide 2. Since the initial reaction involves internal nucleophilic attack by the pyridine nitrogen, control of the pyridine pKa is critical. In this paper we show that by utilizing the powerful electron-donating effect of a 4-amino substituent on the pyridine, moderated by the electron-withdrawing effect of a 3- or 5-halogen substituent, a combination of high potency (as inhibitors of histamine-stimulated gastric acid secretion) and good stability under physiological conditions can be obtained. Furthermore, the role of the steric interaction between the 3/5-substituents and the 4-substituent in modifying the electron-donating ability of the 4-amino group is exemplified, and additional factors affecting stability are identified. One compound, in particular, 2-[[(3-chloro-4-morpholino-2- pyridyl)methyl]sulfinyl]-5-methoxy-(1H)-benzimidazole (3a, SK&F 95601), was chosen for further development and evaluation in man.

Adenosine Triphosphatases↗
PubMed1989

Skin tags are not a risk factor for colorectal polyps.

To ascertain whether acrochordons (simple skin tags) are associated with a higher risk for colon polyps, we prospectively studied 218 male and female patients, age 40 or older without history of colon cancer, polyps, ulcerative colitis, familial polyposis, or recent lower intestinal symptoms. Each patient was assessed for the presence of skin tags. A screening flexible sigmoidoscopy was then performed without knowledge of the dermatologic findings. All polypoid lesions were recorded, and patients with polyps greater than or equal to 3 mm in diameter underwent full colonoscopy and polypectomy. Twenty patients (9.2%) had documented adenomatous polyps on colonoscopy. Nineteen other patients had hyperplastic polyps and mamillations. There was no significant difference in the prevalence of polypoid lesions in those with skin tags compared with those without skin tags, either analyzed as group totals or stratified by age, sex, or type of polyp. We conclude that skin tags are not associated with a higher than usual risk for colonic polyps and should not be used as a marker for more intensive screening.

Adult↗
PubMed1989

3-Aminopropylphosphinic acid--a potent, selective GABAB receptor agonist in the guinea-pig ileum and rat anococcygeus muscle.

1. 3-Aminopropylphosphinic acid, a gamma-aminobutyric acid (GABA) analogue, was tested for activity on guinea-pig isolated ileum and rat isolated anococcygeus muscle preparations. The effects of 3-aminopropylphosphinic acid were compared with those of GABA and baclofen. 2. In the electrically stimulated ileum, 3-aminopropylphosphinic acid, like GABA and baclofen, caused a concentration-dependent inhibition of the cholinergic twitch contraction, the IC50 value being 1.84 +/- 0.23 microM (n = 12). Unlike GABA, but like baclofen, 3-aminopropylphosphinic acid did not produce an initial contraction. 3. The inhibitory effects of 3-aminopropylphosphinic acid and baclofen in the guinea-pig ileum were not significantly antagonized by bicuculline (10 microM), phentolamine plus propranolol (both 1 microM), yohimbine (1 microM), naloxone (1 microM), impromidine (1 microM) or 8-phenyltheophylline (10 microM). The inhibitory effects of 3-aminopropylphosphinic acid, but not of baclofen, were however antagonized by phaclofen (500 microM). In addition the effects of 3-aminopropylphosphinic acid were abolished by baclofen desensitization in the guinea-pig ileum. 4. 3-Aminopropylphosphinic acid, GABA and baclofen reduced the twitch contraction evoked by electrical field stimulation in the rat anococcygeus muscle. The IC50 for 3-aminopropylphosphinic acid inhibition of the anococcygeus contraction was 0.89 +/- 0.15 microM (n = 8). 5. It is concluded that 3-aminopropylphosphinic acid is a potent, selective GABAB agonist, being seven times more potent than baclofen in the guinea-pig ileum and five times more potent than baclofen in the rat anococcygues muscle preparations.

Animals↗
PubMed1989

Resistance to acid of canine kidney (MDCK) and human colonic (T84) and ileo-caecal (HCT-8) adenocarcinoma epithelial cell monolayers in vitro.

Monolayers of canine kidney (MDCK) and human lower intestinal (T84 and HCT-8) cell lines generated significant transepithelial electrical resistance (700-5000 omega cm2). Electrical integrity was maintained upon acidification of the apical and/or basolateral surfaces to pH 3.0, and this was associated with increased transepithelial electrical resistance, and generation of a potential difference at pH less than 4.5. These results indicate that resistance to acid is a general phenomenon of epithelial layers, and that monolayers of epithelial cells, including those of human origin, are a homogeneous and simple model for studying epithelial barrier function in vitro.

Adenocarcinoma↗
PubMed1989

A role for histamine and H2-receptors in opioid antinociception.

To investigate the role of brain H2-receptors in opioid antinociceptive mechanisms, the effects of several antagonists of histamine H2-receptors were determined on morphine (MOR)-induced antinociception, opioid-mediated footshock-induced antinociception (FSIA) and on other opiate effects in rats. Zolantidine dimaleate (ZOL), the first brain-penetrating H2 antagonist (0.03-1.6 mumol/kg s.c.) caused a dose-related inhibition of MOR antinociception in both the tail-flick and hot-plate tests, with no effect on base-line responding. ZOL also inhibited opioid FISA with a similar potency. MOR-induced locomotor activity was also reduced by ZOL, but no effect was seen on MOR-induced hyperthermia, catalepsy or lethality. ZOL (10(-5) M) was inactive at mu, delta or kappa opioid receptors and showed at least 35-fold higher affinity at the H2-receptor than at receptors for serotonin, dopamine, norepinephrine or acetylcholine in brain. To clarify further the role of H2-receptors in ZOL's antiopiate activity, the potencies of seven structural congeners of ZOL were determined on the H2-receptor and on MOR antinociception. Over 3 orders of magnitude, the rank order of potencies of the compounds for inhibiting MOR antinociception was highly correlated with their potencies as H2 antagonists. Cimetidine, unlike other H2 antagonists, potentiated MOR antinociception, potentiated opioid FSIA and increased brain MOR levels, actions that are not likely to be due to blockade of H2-receptors. These findings strongly suggest that stimulation of opioid receptors leads to antinociception by mechanisms that include activation of brain H2-receptors.

Analgesia↗
PubMed1988

Zolantidine (SK&F 95282) is a potent selective brain-penetrating histamine H2-receptor antagonist.

1. The novel benzthiazole derivative zolantidine (SK&F 95282) is a potent antagonist of histamine at H2-receptors in guinea-pig atrium and rat uterus. Only apparent pA2 values of 7.46 and 7.26 respectively could be calculated since the slopes of the Schild plots were significantly less than unity. 2. Zolantidine is equally potent as an antagonist at histamine H2-receptors in guinea-pig brain. The compound inhibited histamine stimulated adenylate cyclase (pKi 7.3) and dimaprit stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation (approx pA2 7.63), and competed with [3H]-tiotidine binding (pKi 7.17). 3. Zolantidine is at least 30 fold more potent at H2-receptors than at other peripheral and central receptors investigated. 4. Infusion of zolantidine into rats produces a brain concentration greater than the plateau blood concentration (brain/blood ratio 1.45). 5. Zolantidine is thus characterized as a potent selective brain-penetrating H2-receptor antagonist, and will be a valuable pharmacological tool for investigating possible physiological and pathological roles for histamine in the central nervous system.

Animals↗
PubMed1988

Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa.

1. Gastric acid secretory responses to pentagastrin were characterized in the rat isolated gastric mucosa. In particular, the mechanisms underlying fade, declining response upon continued stimulation, and tachyphylaxis, progressively reduced responses upon repeated stimulation, were investigated. 2. Pentagastrin, 10(-9)-10(-7) M, resulted in concentration-related increases in acid secretion, with a mean maximum of 2.65 mumol cm-2 h-1 in response to pentagastrin, 10(-7) M. Higher concentrations of pentagastrin produced sub-maximal secretory rates; we define this as auto-inhibition. The responses to all concentrations of pentagastrin demonstrated fade. The rate of fade was correlated with the maximum acid secretory rate, declining at about 36% of the peak over the first 16 min. 3. The PO2, PCO2, [HCO3-], pH, [glucose], [lactate], [Na+] and [K+] did not decline during the fade of the acid secretory response to pentagastrin, 10(-7) M. Addition of a second aliquot of pentagastrin was not able to reverse fade, but these tissues were responsive to histamine. Replacement of the serosal solution, before addition of a second aliquot of pentagastrin, increased the acid response from 3% to 24% of the first response. 4. Serosal solution from donor tissues, allowed to respond to pentagastrin and then the acid secretion to fade, was able to stimulate secretion in fresh recipient tissues, although at lower rates. 5. Acid secretory responses to a second dose of pentagastrin were not significantly different, whether the tissues were previously unstimulated, or stimulated with pentagastrin washed out after attaining its peak secretory response (after 10-20 min). The second response was significantly reduced if the first response was allowed to fade with the pentagastrin in contact for 100 min; i.e. fade significantly influenced the extent of tachyphylaxis. 6. Proglumide, 10(-2) M, a gastrin receptor antagonist, and omeprazole, 10(-5) M, an inhibitor of the gastric (H+ + K+)-ATPase, both inhibited pentagastrin-stimulated acid secretion to similar extents. The second response to pentagastrin after pentagastrin alone, or pentagastrin plus omeprazole were both reduced compared to responses after no stimulation or omeprazole alone, respectively. After pentagastrin plus proglumide, the second response to pentagastrin was not lower than after proglumide alone. Proglumide, but not omeprazole, therefore, prevented pentagastrin tachyphylaxis. 7. It is concluded that gastrin fade and tachyphylaxis are related phenomena. Part of the fade may be due to release of an inhibitor(s). The major proportion of tachyphylaxis is a result of specific interaction of gastrin with its receptors.

Animals↗
PubMed1986

N-Methyldimaprit (SK&F92054). A chemical control for the histamine H2-receptor agonist dimaprit.

Dimaprit analogues having alkyl substituents on the isothiourea group have no detectable H2-agonist activity on the guinea-pig atrium. N-Methyldimaprit [S-[3-(N,N-dimethylamino)propyl]-N'-methylisothiourea] (SK&F92054) is identified as a compound which may serve as a suitable chemical control when studying the actions of dimaprit at putative H2-histamine receptors. Concentrations of N-methyl-dimaprit (up to 3 X 10(-3) M) had no agonist activity in vitro on the guinea-pig atrium (less than 0.005% of the activity of histamine), rat uterus (up to 2 X 10(-3) M,) or as a stimulant of guinea-pig ventricular adenylate cyclase (up to 10(-3) M). N-Methyldimaprit at 10(-3) M also did not significantly stimulate acid secretion in the rat isolated stomach preparation; it was a very weak stimulant of gastric acid secretion (less than 0.2% of the activity of histamine) in vivo in the lumen-perfused stomach of the anaesthetised rat but exhibited marked tachyphylaxis on repeated administration. N-Methyldimaprit has two basic centres, macroscopic pKa values 8.31 and 9.58 at 40 degrees C.

Adenylyl Cyclases↗
PubMed1985

The histamine H2 receptor agonist impromidine: synthesis and structure-activity considerations.

Impromidine (1) is a potent and selective histamine H2 receptor agonist and its structure comprises a strongly basic guanidine group containing two different imidazole-containing side chains. In this paper we report the synthesis of analogues in which both of the side chains and the guanidine group are modified and tested as agonists or antagonists at histamine H2 receptors on guinea pig atrium. A protonated amidine group linked by a chain of three carbon atoms to a tautomeric imidazole ring appears to be an essential feature for agonist activity and it is suggested that the second imidazole-containing side chain in impromidine mainly contributes toward affinity for histamine H2 receptors.

Animals↗
PubMed1984

Comparison of effect of peptide length and sulphation on acid secretory potency of gastrin in the cat in vivo and in vitro.

The gastric-acid secretory potency of gastrin peptides was investigated in vivo, in conscious cats prepared with gastric fistula, and in vitro, with kitten isolated gastric mucosae. The influence of peptide length on potency was investigated by comparing synthetic human gastrin heptadecapeptide, non-sulphate (shG17ns) with a synthetic gastrin butyloxycarbonyl hexapeptide (G6ns), and the influence of sulphation by comparison of G6ns with its sister sulphated peptide (G6s). When exogenous doses were compared, shG17ns was the most potent peptide (mean exogenous dose for half-maximal stimulation (EDe50) : 0.33 nmol kg-1 h-1), and was 15.8 times more potent than G6ns (EDe50:5.14 nmol kg-1 h-1). This potency ratio was reduced to 9.4 when circulating immunoreactive concentrations of the two peptides were compared (mean circulating concentration for half-maximal stimulation (EDc50) : shG17ns, 201 pM; G6ns, 1890 pM). The greater potency ratio when exogenous doses were compared was due to the greater metabolic clearance rate (m.c.r.) of the shorter gastrin (m.c.r.: shG17ns, 37 ml kg-1 min-1; G6ns, 121 ml kg-1 min-1). In vitro, shG17ns (mean concentration for half-maximal stimulation (EC50) : 1.99 nM) was 2.8 times more potent than G6ns (EC50: 5.57 nM). Sulphation of the hexapeptide increased its potency 3.6-fold when exogenous doses were compared (EDe50 G6s: 1.42 nmol kg-1 h-1). The greater potency of the sulphated peptide appeared to be due to its lower m.c.r. (20 ml kg-1 min-1), and was eliminated when circulating concentrations were compared; potency ratio G6ns: G6s, 1.1. We conclude that the increased potency of short gastrin peptides observed upon sulphation is likely to be due to increased resistance to metabolic clearance. Part of the increased potency observed with increasing peptide length can also be explained by increased resistance to clearance, but the small potency difference in vitro may reflect greater affinity for gastrin receptors.

Animals↗
PubMed1984

Effect of cimetidine on net ion fluxes across the rat gastric mucosa during mucosal damage after gastric ischemia and after intravenous acetylsalicylic acid.

This study was performed to determine the relationship between net ion fluxes across the rat gastric mucosa and gastric mucosal damage after gastric ischemia and after intravenous administration of acetylsalicylic acid, and to determine the effect of cimetidine on these parameters. Gastric mucosal blood, albumin, and fluid loss that occurred after gastric ischemia was not associated with an increase in net H+ flux from mucosa to serosa. A significant increase in net Na+ and K+ flux from serosa to mucosa occurred. In the presence of cimetidine (150 mg/kg X h, i.v.), which reduced gastric damage, net H+ flux increased significantly, whereas there was an inhibition of Na+ and K+ fluxes. Acetylsalicylic acid-induced gastric hemorrhage preceded an increase in net H+ flux from serosa to mucosa, although net Na+ and K+ fluxes were unaffected. Cimetidine (150 mg/kg X h, i.v.) potentiated gastric hemorrhage and this was associated with an increase in net K+ flux from serosa to mucosa. These studies demonstrate that overt damage to the rat gastric mucosa can occur without changes in net ion fluxes across the gastric mucosa.

Animals↗