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Biomedical subjects

D R Howlett

Publications and source records attributed to D R Howlett.

At least 37 records · Page 2Linked to original sources
PubMed1988

Antihypertensive and angiotensin converting enzyme inhibitory activities of a novel dihydrobenzofuran analogue.

1. The biochemical and pharmacological profiles of the novel, orally active angiotensin converting enzyme (ACE) inhibitor, N-[N-[[4-(2, 3-dihydro-2-benzofuranyl)-1-(ethoxycarbonyl)]butyl]-(s)-alanyl]- (s)-proline (BRL 36378), have been compared with those of enalapril and captopril. 2. In the conscious sodium deficient spontaneously hypertensive rat, BRL 36378 and enalapril (0.3-10 mg/kg orally) produced comparable falls in blood pressure; at 3 mg/kg orally, captopril was less active than BRL 36378 and enalapril. 3. In the anaesthetised spontaneously hypertensive rat, enalapril was slightly more potent than BRL 36378 as an inhibitor of angiotensin I (AI) pressor responses whilst BRL 36378 was about twice as potent as captopril in this test (i.v. route used). BRL 36378 and enalapril were equipotent as potentiators of bradykinin depressor responses. 4. In the anaesthetised Wistar rat, the maximum inhibition of AI pressor responses by 0.1 microgram/kg i.v. BRL 36378 and captopril was achieved sooner than after the same dose of enalapril. The inhibitory effect of captopril subsided completely by 40-50 min but the maximum effects of BRL 36378 and enalapril persisted for at least 60 min. 5. In the conscious renal hypertensive cat, captopril was slightly more potent than BRL 36378 or enalapril as a blood pressure lowering agent, over 1-10 mg/kg orally. BRL 36378 was more potent than enalapril as an inhibitor of AI induced pressor responses in this model. Captopril possessed similar inhibitory activity to BRL 36378 although minor differences in time course were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1988

Acute and chronic effects of a novel dihydrobenzofuran analogue and enalapril on blood pressure and plasma and tissue angiotensin converting enzyme activity in the sodium deficient normotensive rat.

1. Changes occurring in plasma and tissue angiotensin converting enzyme (ACE) activity have been examined in relation to blood pressure response following acute and chronic administration of N-[N-[[4-(2,3-dihydro-2-benzofuranyl)-1- (ethoxycarbonyl)]-butyl]-(s)-alanyl]-(s)-proline (BRL 36378) and enalapril in the sodium deficient normotensive rat. 2. Both BRL 36378 and enalapril produced a reduction in blood pressure which was evident at 2 and 24 h after acute administration, or at 24 h after chronic (21 days) administration. This was accompanied by inhibition of ACE activity in both plasma and tissues. 3. The magnitude of ACE inhibition was greater following enalapril administration than achieved after BRL 36378 treatment; this was reflected by the greater fall in blood pressure evoked by enalapril. 4. Removal of the respective ACE inhibitors revealed an apparent increase in total enzyme in the plasma of animals dosed chronically with BRL 36378 and enalapril. The onset of this increase in total enzyme was rapid, as it was apparent in plasma at 24 h after a single oral dose of BRL 36378 and enalapril. 5. The increase in total enzyme in plasma may be related to the degree of ACE inhibition, since the increase in total enzyme was of greater magnitude after 21 days treatment with enalapril than following corresponding dosing with BRL 36378. 6. No consistent effects on total enzyme were observed in tissues following acute and chronic administration with the ACE inhibitors. 7. Stimulation of drinking behaviour was observed throughout the periods of chronic (7 and 21 days) administration with both BRL 36378 and enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Specificity of action of the novel antihypertensive agent, BRL 34915, as a potassium channel activator. Comparison with nicorandil.

Experiments have been performed to investigate the specificity of the mechanism of action of the novel antihypertensive agent, BRL 34915. BRL 34915 (0.5-100 microM) and nicorandil (10-500 microM) stimulated the efflux of rubidium from preloaded rabbit isolated mesenteric arteries. BRL 34915 also caused an increase in the rubidium efflux rate constant in other vascular smooth muscles. Tetraethylammonium (0.1-30 mM) inhibited BRL 34915 (10 microM), nicorandil (100 microM) and potassium (30 mM) induced stimulations of rubidium efflux, but had no effect on noradrenaline (30 microM) induced efflux. Only noradrenaline induced efflux was inhibited by apamin (3-100 nM). Examination of other second messenger systems demonstrated that BRL 34915 (at concentrations up to 100 microM) did not have any appreciable effect on cGMP accumulation in rabbit mesenteric artery, cAMP or cGMP phosphodiesterase in rat heart, or cAMP and inositol phosphate accumulation in rat brain slices. Nicorandil (100 microM) caused a small increase in cGMP accumulation in rabbit mesenteric artery. Radioligand binding studies showed that BRL 34915 did not interact with dihydropyridine, 5-hydroxytryptamine, dopamine, alpha 1, alpha 2 or beta adrenoceptor binding sites. [3H]-BRL 34915 did not bind specifically to any site in any tissue studied, either in vitro or ex vivo. Thus we have been unable to demonstrate an effect of BRL 34915 other than of increasing potassium efflux in rabbit vascular smooth muscle. This lends support to other evidence suggesting that BRL 34915 relaxes vascular smooth muscle (and hence lowers blood pressure) by a novel, and specific, mechanism involving hyperpolarisation of the smooth muscle cell membrane.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1986

Angiotensin-converting enzyme responses following enalapril in the sodium deficient rat.

The relationship between blood pressure lowering activity and inhibition of plasma and tissue angiotensin-converting enzyme (ACE) has been studied in the sodium deficient normotensive rat at 24, 48 and 96 h after the administration for 21 days of enalapril (MK-421, 10 mg/kg per day p.o.). Blood pressure was reduced and plasma ACE activity inhibited at 24 and 48, but not 96 h, after cessation of dosing. Tissue ACE activity (aorta, lung, mesenteric bed) was inhibited up to 96 h post dose when blood pressure had returned to control values. ACE production (activity following removal of inhibitor) was increased in plasma at 24, 48 and 96 h post dose but in tissues (adrenal glands, renal arteries and mesenteric bed) only at 48 h post dose. There was no tendency for ACE production to increase in the lung, the largest source of the enzyme in the rat. Thus it appears that inhibition of ACE activity in both plasma and tissue contributes to the blood pressure lowering activity of enalapril in the sodium deficient normotensive rat.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Effects of idazoxan on catecholamine systems in rat brain.

Experiments have been performed to assess the potency of idazoxan (RX 781094) at alpha and beta-adrenoceptors and dopamine receptors and on catecholamine uptake processes in rat brain. The effects of idazoxan on the turnover rates of noradrenaline and dopamine have been determined. Radioligand binding studies with cerebral cortex membranes have demonstrated that idazoxan exhibits 46-fold selectivity for alpha 2-adrenoceptors labelled by (3H)-idazoxan (Mean Ki +/- S.E.M. = 3.1 +/- 0.4 nM) compared with alpha 1-adrenoceptors labelled by (3H)-prazosin (Mean Ki +/- S.E.M. = 142 +/- 27 nM). Under the same conditions, yohimbine showed 6-fold selectivity for alpha 2-adrenoceptors. Idazoxan had low affinity for beta-adrenoceptors labelled by (3H)-dihydroalprenolol (IC50 value greater than 10 microM), for dopamine receptors labelled by (3H)-domperidone (IC50 value greater than 20 microM), for the (3H)-noradrenaline uptake site in rat hypothalamus (IC50 = 31 microM) and for the (3H)-dopamine uptake site in rat striatum (IC50 value approximately 800 microM). In rats treated with alpha-methyl-p-tyrosine, idazoxan (10-80 mg/kg, po) produced a marked increase (63% at 10, 217% at 20 mg/kg, po) in the apparent rate of turnover of noradrenaline in rat cortex/striatum, without affecting the rate of turnover of dopamine. This was in contrast to yohimbine (5-20 mg/kg, po) which increased the turnover rates of both catecholamines. In the absence of alpha-methyl-p-tyrosine, idazoxan (5-40 mg/kg, po) produced a dose related increase in the MHPG concentration and a small (20-30%) reduction in the steady state concentration of NA; the duration of the reduction was dose-related. DA steady state concentrations were unaffected. Idazoxan is a new selective alpha 2-adrenoceptor antagonist which should prove a valuable investigative tool in neurochemical studies and which may be a useful clinical agent in the management of the affective disorders.

Adrenergic alpha-Antagonists↗
PubMed1983

A method for dissecting two site receptor interactions in ligand binding studies.

A general model has been developed describing the relationship between the measured (IC50) and absolute affinities (KI), observed in radioligand binding studies when two ligands, one radioactive, interact with two receptors or binding sites. The model shows the dependence of the IC50's upon the concentration of radioligand for any combinations of the absolute affinities of the radioligand (Kd's) and the displacing ligand (KI's). By constraining the affinities of the two ligands for the sites, five special cases of the general model can be described that model all possible 'selectivities' the ligands may have for the sites. The properties of these five cases can be exploited experimentally to probe the nature of the ligand/site interactions by the simple expedient of constructing a number of displacement curves at different radioligand concentrations. The method has been tested experimentally in three situations where two ligand/two site interactions occur, and is shown to be a useful technique to qualitatively examine the underlying binding reactions.

Animals↗
PubMed1979

Loss of beta-adrenoceptor binding sites in rat striatum following kainic acid lesions.

Intrastriatal injection of kainic acid (5 nmoles) to rats led to severe destruction of nerve cell bodies throughout the caudate-putamen complex and an extensive proliferation of glial cells. Lesioned striata displayed a significant 23% loss of beta-adrenoceptor binding sites 21--24 days after injection of kainic acid. Further analysis of these changes revealed that this loss of sites was selectively within the beta 1 receptor population. Although these results do not rule out a partial glial cell localisation for beta-adrenoceptors, they do indicate that at least a proportion of beta 1 receptors are present on striatal perikarya.

Animals↗
PubMed1979

Pharmacological characteristics of beta-adrenoceptor binding sites in intact and sympathectomized rat spleen.

[3H]-(--)-Dihydroalprenolol ([3H]-DHA) binds to rat spleen membranes with a dissociation equilibrium constant (KD) of about 0.7 nM and a maximal number of binding sites of 272 fmoles x mg protein-1. Approximately 90% of the sites labelled by 1 nM [3H]-DHA possess classical properties of beta-adrenoceptors. The labelled ligand is stereospecifically displaced by the isomers of propranolol and the order of potency of agonists is: isoprenaline greater than adrenaline greater than noradrenaline. Highly selective beta 1 antagonists such as practolol and atenolol displaced [3H]-DHA from spleen membranes in a biphasic manner indicating the co-existence of beta 1 and beta 2 sites (30--35% beta 1; 65--70% beta 2) in this tissue. Support for this classification was provided by the binding of the beta 2 agonist procaterol to spleen membranes. This drug possessed high affinity only for those sites that have low affinity for the beta 1 selective agents. Chemical sympathectomy induced by chronic 6-hydroxydopamine administration did not alter the number or the pharmacological properties of beta-adrenoceptor binding sites. The results suggest that both beta 1 and beta 2 adrenoceptors are probably postsynaptic in spleen.

Alprenolol↗
PubMed1977

Fluorescent assay of total serum cholesterol, with use of gas-liquid chromatography to study saponification efficiency.

We describe a fluorescent determination of total cholesterol in serum for which the accuracy and precision are comparable to that for the method of Abell-Kendall, a method of generally accepted accuracy. By the use of quality reagents and the rigorous exclusion of water, the strong fluorophor that develops on reacting concentrated sulfuric acid with cholesterol can be used to quantitatively determine the total cholesterol in serum. We used gas-liquid chromatography to monitor the extent of saponification of the cholesterol esters, because we found them to have fluorescent efficiencies that differed from that of free cholesterol. Sodium methoxide in methanol/methylene chloride (1/3 by vol) was shown by gas-liquid chromatography to very effectively saponify the cholesterol esters in serum.

Cholesterol↗