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W Howson

Publications and source records attributed to W Howson.

30 records · Page 2Linked to original sources
PubMed1990

Electrophysiological characterization of potent agonists and antagonists at pre- and postsynaptic GABAB receptors on neurones in rat brain slices.

1. Intracellular recordings were made from neurons in striatum (caudate-putamen) and substantia nigra pars compacta in rat brain slices. Three GABAB agonists, baclofen, 3-aminopropylphosphinic acid (3-APPA) and 3-aminopropyl(methyl)phosphinic acid (SK&F 97541), depressed excitatory postsynaptic potentials (e.p.s.ps) mediated by glutamate in the striatum, and hyperpolarized neurones in the substantia nigra. The ability of 3-aminopropyl(diethyoxymethyl)phosphinic acid (CGP 35348), 3-aminopropyl (hexyl)phosphinic acid (3-APHPA) and phaclofen to antagonize these responses was assessed. 2. Striatal e.p.s.ps, studied in the presence of bicuculline (30 microns), were reduced in amplitude by 92% with 6,7-dinitroquinoxaline-2,3-dione (DNQX; 30 microns). These e.p.s.ps were depressed by up to 95% by SK&F 97541 and baclofen with EC50s of 0.092 microns and 1.25 microns respectively. The maximal effect of 3-APPA was 67% with an EC50 of 0.83 microns. Agonist concentration-effect data fitted a single-site logistic model. GABAB agonists were without effect on striatal neurone membrane potential, input resistance or depolarizations induced by applied glutamate. 3. The depression of striatal e.p.s.ps by SK&F 97541 was reversibly antagonized by CGP 35348, 3-APHPA and phaclofen with estimated equilibrium dissociation constants (KB) of 11.2 +/- 1.7 microns (n = 4), 13.3 +/- 0.4 microM (n = 3) and 405 +/- 43 microM (n = 3) respectively. CGP 35348 and 3-APHPA appeared to act competitively (Schild plot slopes of 0.99 and 1.01 respectively). 4. Nigral neurones were hyperpolarized by up to 25 mV by SK&F 97541 and baclofen with EC50s of 0.15 microns and 3.6 microns respectively. The maximum hyperpolarization by 3-APPA was only 84% that of the other agonists, with an EC50 of 9.0 microM. Agonist concentration-effect data fitted a single-site logistic model. 5. The SK&F 97541-induced hyperpolarization was reversibly antagonized by CGP 35348, 3-APHPA and phaclofen with estimated KBS of 17.6 + 4.4 (n = 3), 14.0 + 1.5 (n = 4), and >400 microM (n = 1) respectively. CGP 35348 appeared competitive (Schild plot slope of 0.99). Antagonists were also tested with baclofen as agonist, yielding similar KB estimates as for SK&F 97541. 6. It is concluded that at both the presynaptic and postsynaptic sites examined, SK&F 97541 was about 10 fold more potent than baclofen or 3-APPA. The antagonists CGP 35348 and 3-APHPA (KB 1O-20 microM) were about 20 fold more potent than phaclofen. The similarities in relative agonist potency and estimated antagonist affinity between these two functionally distinct GABAB receptors renders them pharmacologically indistinguishable at present.

Animals↗
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

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↗
PubMed1988

Design and synthesis of a series of combined vasodilator/beta-adrenoceptor antagonists based on 6-arylpyridazinones.

A series of new 6-[4-[[(aryloxy)acyl]amino]phenyl]-4,5-dihydropyridazinones have been synthesized and evaluated as combined vasodilator/beta-adrenoceptor antagonists and potential antihypertensive agents. Many of the early compounds displayed an unacceptably high level of intrinsic sympathomimetic activity (ISA) and a relatively short duration of action. Disubstitution in the 2,3-positions or in the 4-position of the aryloxy ring gave compounds with low ISA levels and, in some instances, improved duration of action. All of the compounds were vasodilators, but the 5-methylpyridazinone derivatives showed consistently greater antihypertensive activity than their 5-H lower homologues. Further detailed pharmacological investigations led to the selection of 6-[4-[3-[[2-hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]propionamido] phenyl]- 5-methyl-4,5-dihydro-3(2H)-pyridazinone (4t) (SK&F 95018) as a development candidate.

Adrenergic beta-Antagonists↗
PubMed1988

Synthesis and biological activity of the four stereoisomers of 6-[4-[3-[[2-hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]-propionamido] phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, a combined vasodilator and beta-adrenoceptor antagonist.

6-[4-[3-[[2-Hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]propionamido] phenyl]- 5-methyl-4,5-dihydro-3(2H)-pyridazinone (3) consists of a mixture of four stereoisomers, i.e., two racemates, as a consequence of the two asymmetric centers contained in the structure. An approximately equimolar mixture of these two racemates exhibits a novel combination of vasodilation and beta-adrenergic antagonist activity. This paper describes the synthesis of each of the four possible stereoisomers of 3 and provides clear evidence for the different pharmacological profile of each of the stereoisomers. The RA,SB isomer 3a has an overall profile slightly better than the complete mixture; the other three isomers all show reduced activity as vasodilators and/or beta-adrenergic antagonists.

Adrenergic beta-Antagonists↗
PubMed1987

SK & F 95018, a vasodilator/beta-adrenoceptor antagonist.

The pharmacological properties of a novel vasodilator/beta-adrenoceptor antagonist, SK & F 95018 6-[4-[3-(3-[4-(2-Cyclopropylmethoxyethyl)phenoxy]-2- hydroxypropylamino)propionamido]phenyl]-4,5-dihydro-5-met hylpyridazin- 3(2H)-one methanesulphonate] are described. SK & F 95018 lowered blood pressure and increased hindquarters blood flow in anaesthetised rats over the same dose range 1-5 mumol kg-1. Over a similar dose range SK & F 95018 inhibited isoprenaline-induced tachycardia in ganglion-blocked, anaesthetized cats. SK & F 95018 had minimal effect on bronchial beta 2-adrenoceptors, while simultaneously antagonizing cardiac beta 1-adrenoceptors in anaesthetized guinea-pigs. SK & F 95018 was demonstrated to be a potent antihypertensive agent in conscious spontaneously hypertensive rats over the dose range of 1.6-13 mumol kg-1 i.v. and 13-103 mumol kg-1 p.o. A marked and persistent hypotension was observed in conscious cats at a dose of 7.5 mumol kg-1 i.v. and 19 mumol kg-1 p.o., without reflex tachycardia. In anaesthetized cats, the hypotensive response to the compound was found to be via a reduction in total peripheral resistance with a maintained cardiac output. Vasodilatation and beta-adrenoceptor antagonism have been demonstrated in the same molecule (SK & F 95018) in a combination which would be suitable for effective treatment of hypertension.

Adrenergic beta-Antagonists↗
PubMed1983

Simplified liquid-chromotographic analysis for cyclosporin A, and comparison with radioimmunoassay.

We describe a simplified isocratic "high-performance" liquid-chromatographic method for measuring a new immunosuppressive drug, cyclosporin A, in biological fluids with use of its analogs cyclosporin C and cyclosporin D as internal standards. The method is reproducible and accurate and appears to be specific for cyclosporin A; the detection limit is 31 micrograms/L. The chromatographic measurements of the concentration of cyclosporin A in serum of patients receiving the drug were invariably lower than those by radioimmunoassay and the difference became more pronounced the greater the period of time after dosing. Because measurements of cyclosporin A in serum standards were almost identical with both techniques, the differences between the two sets of results for patients' samples suggests that the radioimmunoassay is nonspecific and measures metabolites of cyclosporin A.

Adult↗
PubMed1981

Immunological and pharmacological monitoring in the clinical use of cyclosporin A.

Immunological reactivity to donor antigens and serum concentrations of cyclosporin A were monitored in six patients after renal transplantation. At concentrations of 0.1--1.0 microgram/ml cyclosporin A prevented both donor-specific immune reactivity and clinical rejection during the early post-transplant course. Measurement of cyclosporin A levels and immunological indices allowed individual adjustment of the dosage so as to give excellent early graft function with few adverse effects.

Cyclosporins↗