Biomedical subjects

R J Summers

Publications and source records attributed to R J Summers.

At least 127 records · Page 7Linked to original sources

PubMed1984

Response of nasal blood flow to neurohormones as measured by laser-Doppler velocimetry.

Laser-Doppler velocimetry (LDV) has been adapted to measure nasal blood flow (NBF) in the mucosa of human volunteers. Resting NBF was 42.4 +/- 2.1 ml X 100 g-1 X min-1 in 19 nonatopic subjects and 37.9 +/- 1.7 ml X 100 g-1 X min-1 in 24 atopic subjects. Topical saline, but not water, reduced ipsilateral NBF by 15.4 +/- 6.6% (n = 22) without affecting contralateral NBF. Administration of 60 microgram of oxymetazoline reduced NBF by 26.5% (n = 28), whereas 120 microgram resulted in a 54.3% reduction. Phenylephrine produced a dose-related reduction in NBF with an ID50 (dose producing 50% reduction) of 1,456 microgram. Methacholine (0.006 to 12 mg) had no significant effect on NBF when studied alone or after oxymetazoline pretreatment. Therefore, LDV can be employed to monitor NBF, which has been found to be sensitive to alpha-adrenergic, but not cholinergic, stimulation.

Adolescent↗

PubMed1984

Time course of sympathetic denervation of the rat ovary after freezing its nerve supply.

Brief freezing of the ovarian vascular pedicle in rats reduced ovarian noradrenaline concentration, measured with HPLC, by 67% (P less than 0.01). Freezing of the ovarian suspensory ligament caused a 22% reduction (P less than 0.01) and 33% reduction (P less than 0.05) in 2 experiments. The numbers of adrenergic nerve terminals detected by fluorescence microscopy after these procedures were similarly reduced (P less than 0.01). Freezing of both the pedicle and the ligament produced complete sympathetic denervation in about 50% of the ovaries. From Days 2 to 10 after operation no noradrenaline or nerve terminals were detected in 14 out of 27 ovaries. Nerve terminals were also eliminated from the oviduct. Reinnervation of the ovary began between Days 12 and 30. It is concluded that the adrenergic innervation of the ovary is predominantly through nerves that accompany the vascular supply to the ovary and the ovarian suspensory ligament. Freezing of these routes is a simple and relatively atraumatic means of denervating the ovary for experimental studies.

Animals↗

PubMed1984

Age related changes of catecholamines and their metabolites in central nervous system regions of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats.

Adrenaline (A), dopamine (DA), noradrenaline (NA) the NA metabolite 3,4-dihydroxyphenylethylene-glycol (DHPG) and the DA metabolite 3,4 dihydroxyphenylacetic acid (DOPAC) were assayed in brain regions of male and female WKY and SHR at 6, 14, 28 and 36-40 weeks. Age related differences in catecholamine levels between the two strains were only seen with NA measurements. DOPAC levels were elevated in the striatum of SHR compared to WKY rats at all ages studied which might reflect the known hyperactivity of SHR strain. In the SHR NA but not DHPG levels in several regions, DA and DOPAC levels in midbrain and DA levels in lower brainstem were elevated at 6 weeks of age. These changes may represent a generalized alteration in central catecholamine metabolism in SHR during the early development of hypertension or merely reflect strain differences. It is emphasised that further genetic studies of F2 backcross rats are required to establish an aetiological association between these differences in catechol levels and differences in blood pressure between SHR and WKY rats.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Renal alpha adrenoceptors.

The alpha adrenoceptors modulate renal blood flow, electrolyte balance, and metabolism. In most species both alpha 1 and alpha 2 subtypes are present. The alpha 1 adrenoceptors control blood flow and increase sodium reabsorption and gluconeogenesis. Radioligand studies indicate that the majority of alpha 1 adrenoceptors are located on proximal tubules. The alpha 2 adrenoceptors inhibit adenylate cyclase, and their density varies among species as do the molecular characteristics. In rat but not guinea pig some alpha 2 adrenoceptors are associated with glomeruli, but in both species most receptors are found on proximal tubules.

Adenylyl Cyclase Inhibitors↗

PubMed1983

Effects of yohimbine stereoisomers on contractions of rat aortic strips produced by agonists with different selectivity for alpha 1- and alpha 2-adrenoceptors.

Three stereoisomers of yohimbine (corynanthine, rauwolscine and yohimbine) have been used to characterize alpha-adrenoceptors in rat aortic strips. pA2 values for each antagonist were calculated using 3 different agonists ((-)-noradrenaline, (-)-phenylephrine and guanfacine) which possess varying affinities for alpha 1 and alpha 2 receptors. Mean pA2 values were not significantly different irrespective of the agonist used and the order of the potency was corynanthine greater than yohimbine greater than rauwolscine. The results are consistent with the presence of alpha 1-adrenoceptors in rat aorta.

Adrenergic alpha-Agonists↗

PubMed1983

The characteristics of adrenoceptors in homogenates of human cerebral cortex labelled by (3H)-rauwolscine.

The alpha-2-adrenoceptor antagonist (3H)-rauwolscine has been used to label adrenoceptors in membranes from human cerebral cortex. The radioligand binds with high affinity (KD 2.08 nM) to a single population of sites with a density of 135 fmoles/mg protein. Adrenoceptor antagonists displaced binding in a simple monomolecular fashion with an order of affinity rauwolscine greater than yohimbine greater than phentolamine greater than corynanthine greater than prazosin indicating binding to alpha-2-adrenoceptors. Agonists displaced with an order of affinity clonidine greater than (-) adrenaline greater than (-) noradrenaline greater than dopamine greater than (-) isoprenaline but all displayed apparent Hill coefficients less than unity indicating heterogeneity of binding. The relatively high affinity of the alpha-1 antagonist prazosin for (3H)-rauwolscine binding sites in rat cerebral cortex was not observed in the human tissue which had pharmacological properties similar to those described previously in human platelet.

Adrenergic alpha-Agonists↗

PubMed1983

The simultaneous determination of 3,4-dihydroxyphenyl-ethylene glycol, 3,4-dihydroxyphenylacetic acid and catecholamines in brain tissue by high performance liquid chromatography with electrochemical detection.

An assay is described for the simultaneous determination of the deaminated metabolites 3,4-dihydroxyphenylethylene glycol (DHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC), together with noradrenaline, dopamine and adrenaline in brain using high performance liquid chromatography with electrochemical detection. The procedure is simple, specific, and has a limit of detection for each catechol of 5 pg. It offers the advantage of measuring the major monoamine oxidase metabolites of both noradrenaline (i.e. DHPG) and dopamine (i.e. DOPAC), which in some circumstances may reflect neuronal activity, simultaneously with their catecholamine neurotransmitter precursors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1983

Autoradiographic localization of beta-adrenoceptors in rat kidney.

The beta-adrenoceptor antagonist radioligand [125I]cyanopindolol (CYP) has been used to localize beta-adrenoceptors in rat kidney sections. [125I]CYP bound with high affinity to sites in rat kidney sections having the recognition characteristics of beta-adrenoceptors. Autoradiographic studies combined with histochemical techniques demonstrated that the beta-adrenoceptors were primarily located on renal glomeruli, distal and cortical collecting tubules rather than on proximal tubules or vascular elements.

Animals↗

PubMed1983

Evidence from binding studies for beta 1-adrenoceptors associated with glomeruli isolated from rat kidney.

The beta adrenoceptor antagonist radioligand [3H] dihydroalprenolol (DHA) has been used to characterise beta adrenoceptors in membranes prepared from rat renal glomeruli. Association of the ligand was rapid and had reached equilibrium within 10 mins at 37 degrees C. Dissociation occurred in two distinct phases, a rapidly dissociating phase (low affinity site) and a slowly dissociating phase (high affinity site). The KD value for the high affinity site calculated from the kinetic experiments was 0.8 nM. Saturation analysis of binding gave comparable values for KD (1.77 nM) and demonstrated that membranes from glomeruli had four times the density of binding sites measured in renal cortex. In all saturation studies Hill coefficients were not significantly different from unity. Binding was stereoselective with respect to the (-) isomers of isoprenaline and propranolol and the potency of the selective displacing agents betaxolol (beta 1 adrenoceptors) and ICI 118,551 (beta 2 adrenoceptors) indicated that the receptors are of the beta 1 subtype.

Adrenergic beta-Antagonists↗

PubMed1983

Evidence from binding studies for alpha 2-adrenoceptors directly associated with glomeruli from rat kidney.

Binding of the alpha 2-adrenoceptor radioligands [3H]clonidine and [3H]rauwolscine but not the alpha 1-adrenoceptor radioligand [3H]prazosin was enhanced in membranes prepared from rat isolated renal glomeruli. [3H]Rauwolscine binding to glomeruli was stereoselective with respect to the (-)-isomer of noradrenaline and the order of potency of a series of antagonists for displacement of binding indicated that the alpha 2-adrenoceptors in this preparation differ somewhat from those in some other species and tissues. Chemical sympathectomy produced no significant change in the number of sites labelled by [3H]rauwolscine indicating that few of the alpha 2-adrenoceptors in glomerular membranes are associated with sympathetic nerve terminals.

Animals↗

PubMed1983

Characterization of postsynaptic alpha-adrenoceptors in rat aortic strips and portal veins.

Postsynaptic alpha-adrenoceptors in rat isolated aortic strips and portal veins have been examined using a number of agonist and antagonist drugs which have varying selectivity for alpha 1- and alpha 2-adrenoceptors. In both tissues (-)-noradrenaline [-)-NA), (-)-adrenaline [-) Adr) (-)-alpha-methyl noradrenaline [-)-alpha-Me-NA) and (-)-phenylephrine [-)-PE) were full agonists, while clonidine, oxymetazoline and (2-(2,6-dichlorophenyl)-5,6-dihydroimidazo(2,1,b) thiazole (44,549) were partial agonists. Guanfacine was a full agonist in aortic strips but only a partial agonist in portal veins. In aortic strips, pA2 values for prazosin and yohimbine were not significantly different using (-)-NA, (-)-PE or guanfacine as the agonist, suggesting a single population of alpha-adrenoceptors. The order of potency of the antagonists, prazosin = 2-(beta-(4-hydroxyphenyl)-ethylaminomethyl)-tetralone (BE2254) greater than phentolamine greater than yohimbine greater than rauwolscine, is indicative of an alpha 1-type of receptor. In portal veins, the order of potency of the antagonists was prazosin greater than BE2254 greater than phentolamine greater than yohimbine greater than rauwolscine, again indicating an alpha 1-type of receptor. The mean pA2 value for yohimbine was not significantly different in either tissue. However, mean pA2 values for prazosin, BE-2254 and phentolamine were approximately one order of magnitude lower in portal veins than in aortic strips, suggesting that the receptors in the two tissues may not be identical.

Adrenergic alpha-Agonists↗

PubMed1983

Age related changes of noradrenaline content in brain regions of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WK) rats.

Noradrenaline (NA) was assayed in brain regions of male and female WK and SHR of 6 to 40 weeks of age, using high performance liquid chromatography with electrochemical detection (HPLC-ECD). The change of levels with age was similar in brain regions of both strains except in brainstem and thoracic spinal cord where levels fell progressively with age in SHR but not in WK rats. The fall in NA content in these two regions is associated with a rise in blood pressure with age in the SHR and suggests a relationship between NA levels and hypertension. The demonstration of different patterns of change in NA levels with age between WK and SHR represents a new approach to resolving the problem of the lack of appropriate control animals for genetic models of disease. However, the data also emphasise that differences in catecholamine metabolism may occur between in-bred strains of rat such as the WK and SHR, and between male and female rats, unrelated to differences in blood pressure.

Age Factors↗

PubMed1983

Characterization of central alpha-adrenoceptors using 3H-clonidine and its derivatives.

alpha-Adrenoceptors in brain can be studied readily by radioligand binding techniques. This provides valuable information not only on the distribution of receptors in brain regions, but also on the regulation of receptors. The usefulness of this technique is dependent in part on a radioligand with high specificity for the receptor under study. Our studies have shown that 3H-clonidine does not bind exclusively to alpha 2-adrenoceptor subtypes, but also interacts with alpha 1-adrenoceptors. In contrast, 3H-guanfacine labels a high affinity alpha 2 subtype with good selectivity, but 3H-lofexidine probably labels with both alpha 2 and alpha 1-adrenoceptor binding sites.

Adrenergic alpha-Agonists↗

PubMed1982

The relationship between alpha 2-adrenoceptor selectivity and anticonvulsant effect in a series of clonidine-like drugs.

Clonidine and the 4 clonidine-like drugs: 44-549, lofexidine, guanfacine, and CP-14,304-18, had anticonvulsant activity against pentylenetetrazole-induced convulsions in rats. The magnitude and dose range over which anticonvulsant effects were observed was related to the selectivity of the compounds for alpha 2 and alpha 1 adrenoceptors. Selective alpha 2 adrenoceptor agonists may form a new group of anticonvulsants.

Animals↗

PubMed1982

Localisation of [3H]clonidine binding to membranes from guinea pig renal tubules.

The selective radioligand [3H]clonidine has been used to localise alhpa 2 adrenoceptors in guinea pig kidney. Chemical sympathectomy with 6-hydroxydopamine produced no significant change in the number of sites labeled by [3H]clonidine indicating that the majority of binding sites were not located on sympathetic nerve terminals. Binding was enhanced in membranes prepared from renal tubules and considerably reduced in preparations from glomeruli. Subcellular fractions of renal cortex revealed that binding was to plasma membranes and that the greatest binding capacity was present in the fraction rich in basal lateral membranes. It is concluded that the major concentration of renal alpha 2 adrenoceptors are present on renal tubules and that they may be localised to a particular pole of the renal tubule cell.

Animals↗

PubMed1982

Anticonvulsant effects of clonidine mediated through central alpha2-adrenoceptors.

The effects of centrally (0.3-30 ng/kg) and peripherally (0.01 microgram/kg-1.0 mg/kg) administered clonidine on PTZ-induced seizures was studied in rats. At low doses, dose-dependent decreases in the duration of seizures was observed but at higher doses the duration returned to control levels. Anticonvulsant activity was antagonized by yohimbine (100 microgram/kg i.p.) indicating alpha2-adrenoceptor involvement, whereas the second phase of the response was antagonized by prazosin (10 ng/kg i.c.v.) indicating that it involved alpha1-adrenoceptors.

Animals↗

PubMed1982

New developments in alpha-adrenoreceptor drugs for the treatment of hypertension.

The alpha 1- and alpha 2-adrenoreceptor types are defined in terms of the selective binding of radioligands and their displacement from membrane preparations by a range of agonists and antagonists. Their distribution is described in brain, kidney, heart, and peripheral blood vessels. A group of centrally acting clonidine-like drugs are classified in terms of their selectivity for the alpha 2-adrenoreceptors, and it is suggested that differences between alpha-adrenoreceptors in various tissues may allow development of highly selective alpha 2-adrenoreceptor agonists for specific tissue sites such as the juxtaglomerular cells and brainstem nuclei controlling blood pressure. It is further suggested that the aim of treatment with such compounds is to modulate adrenergic activity while retaining normal homeostatic mechanisms. For this purpose, competitive agonists and antagonists are preferable to compounds which bind irreversibly to the receptor.

Adrenergic alpha-Antagonists↗

PubMed1982

[3H]-guanfacine: a radioligand that selectively labels high affinity alpha2-adrenoceptor sites in homogenates of rat brain.

[3H]-guanfacine (N-amidino-2-(2,6-dichloro 3[3H] phenyl) acetamide hydrochloride; 24.2 Ci/mmol) has been used as a radioligand in homogenates of rat cerebral cortex. Specific binding of [3H]-guanfacine was linear with respect to tissue concentration (2.5-15 mg/ml), saturable and not markedly affected in the pH range 6.5-8.0. Analysis of the saturation of [3H]-guanfacine binding using an iterative least squares fitting procedure gave best fits to a single site model. [3H]-guanfacine binding was of high affinity (Kd 1.77 +/- 0.24 nM; n = 8) to a population of non interacting sites (nH 0.99 +/- 0.02; n = 8) with a density of 118.2 +/- 8.4 fmol/mg protein (n = 8). Highest levels of binding were achieved in cerebral cortex followed by thalamus greater than hypothalamus greater than medulla/pons greater than spinal cord greater than striatum greater than cerebellum. Binding was stereoselective with regard to the (-)-isomer of noradrenaline and the order of potency for displacement of [3H]-guanfacine by agonists was naphazoline greater than clonidine greater than (-)-adrenaline greater than (-)-alpha methylnoradrenaline greater than (-)-noradrenaline greater than (+/-)-alpha-methylnoradrenaline greater than (+)-noradrenaline greater than methoxamine greater than (+)-adrenaline greater than phenylephrine and by antagonists was phentolamine greater than dihydroergocryptine greater than piperoxane greater than yohimbine greater than prazosin greater than labetalol greater than indoramin suggested binding to alpha 2-adrenoceptors. The monovalent cations Na+ and K+ and also guanosine 5'-triphosphate (GTP) produced concentration-dependent inhibition whereas the divalent cations Ca2+, Mg2+, and Mn2+ first enhanced, then inhibited [3H]-guanfacine binding. Na+ (150 mM) or GTP (100 microM) produced marked reductions and Mn2+ (5 mM) marked increases in the number of receptor sites labelled by [3H]-guanfacine. 9 It is concluded that [3H]-guanfacine preferentially labels a high affinity state of the alpha 2- adrenoceptor in homogenates of rat cerebral cortex.

Adrenergic alpha-Agonists↗