Mode of action of α-methylnoradrenaline on temperature and oxygen consumption in young chickens

1. Temperature, oxygen consumption, electromyographic activity, plasma non-esterified fatty acids and blood sugar were estimated in conscious unrestrained young chickens under conditions of thermoneutrality (31 degrees C) and below thermoneutrality (16 degrees C). In some chickens carotid arterial pressure was also recorded.2. At thermoneutrality, alpha-methylnoradrenaline lowered temperature and oxygen consumption in intact or chronically vagotomized chicks. alpha-Methylnoradrenaline was ineffective on temperature in chicks with transection of the brain-stem posterior to the hypothalamus but anterior to the respiratory centre. Hypothermia due to alpha-methylnoradrenaline was associated with a significant reduction of plasma non-esterified fatty acids but blood sugar was not significantly altered. Lowering of temperature by alpha-methylnoradrenaline occurred despite vasoconstriction which would hinder heat loss.3. Temperature and oxygen consumption were reduced by alpha-methylnoradrenaline in chronically thyroidectomized chicks to the same extent as in intact chicks but recovery did not occur unless the chicks were taken from the metabolism chamber and warmed artificially. In contrast, chronically thyroidectomized chicks given replacement thyroxine were relatively resistant to alpha-methylnoradrenaline.4. Oxygen consumption of tissue slices from different parts of the chick's brain, including the diencephalon, was not altered by alpha-methylnoradrenaline over an extensive dose range. The effects of alpha-methylnoradrenaline on temperature and oxygen consumption in intact chickens were unlikely, therefore, to be due to depressed metabolism of neurones.5. In an environment below thermoneutrality (16 degrees C) temperature was considerably reduced and carotid arterial pressure fell 40-50 mmHg. In contrast, electromyographic activity, oxygen consumption and plasma non-esterified fatty acids were markedly raised whereas blood sugar was insignificantly elevated.6. In experiments at 16 degrees C, alpha-methylnoradrenaline markedly reduced oxygen consumption although values were still higher than those at thermoneutrality. Temperature fell further, but whereas the reductions in oxygen consumption and temperature were long-lasting, electromyographic activity (shivering) was only transiently diminished. Plasma non-esterified fatty acids were reduced after alpha-methylnoradrenaline but not significantly so; blood sugar was not significantly altered. The time-course for recovery of oxygen consumption following a-methylnoradrenaline paralleled recovery from its blood pressure effects but the effect on oxygen consumption was not a consequence of the blood pressure changes. The effects of a-methylnoradrenaline on temperature, oxygen consumption and electromyographic activity were similar to those of another central depressant, pentobarbitone.     

Temperature modulation of α- and β-adrenoceptors in the isolated frog heart

1. The effects of adrenaline on the isolated frog's heart at 27 degrees C are not antagonized by phentolamine (1.5 x 10(-6)M) but are abolished at 7 degrees C.2. At 27 degrees C isoprenaline was more potent than noradrenaline, but at 7 degrees C noradrenaline was more potent than isoprenaline.3. Phenoxybenzamine (1.5 x 10(-5)M) or dibenamine (1.5 x 10(-5)M) at 7 degrees C abolished the work output induced by adrenaline. When the temperature was raised to 24 degrees C, adrenaline caused an increase in work output.4. It is concluded that in the isolated frog heart there are at least two pools of adrenoceptors, the availability of which can be governed by temperature.     

Autoradiography of 3H-α-Fluoromethyl Histidine in Mice: Correlation with the Kidney Histidine Decarboxylase Activity

Tritium-α-fluoromethyl histidine (³H-α-FMH), designed as a k_cat-inhibitor of mammalian histidine decarboxylase (EC 4.1.1.22), was administered intravenously in male and pregnant female mice of the NMRI strain and the distribution of tritium in the body recorded by whole-body and microautoradiography. The results showed penetration of radioactivity into most tissues within 5 min. after the injection. After 4 hrs the highest levels of radioactivity were present in the intestinal content and in the kidneys. In the pregnant animal there was also a high labelling of the foetal tissues. When whole-body sections were washed in TCA prior to the autoradiographic exposure to retain only protein-bound radioactivity, a distinct labelling pattern was seen in the kidneys of the pregnant female mice but not in those of the male mice. Microautoradiography of the kidneys showed that the cells involved were located within the proximal convoluted tubuli. In several mouse strains, including the NMRI, the activity of kidney histidine decarboxylase is low in the males but high in females during a transient period of pregnancy. Incorporation of tritium into kidney protein after treatment with ³H-α-FMH, was correlated to a loss in histidine decarboxylase activity. The isotopic labelling was confined mainly to a component which cofractionated with histidine decarboxylase in polyacrylamidegel electrophoresis (PAGE) under non-denaturing conditions. Our data indicate that the cells described above represent the location of kidney histidine decarboxylase.     

Reduced α1- and β2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure

1. alpha 1-Adrenoceptor (phenylephrine in the presence of propranolol) and beta 2-adrenoceptor (fenoterol)-mediated positive inotropic effects were investigated in human ventricular preparations isolated from five non-failing (prospective organ donors) and from eight explanted failing hearts with end-stage idiopathic dilative cardiomyopathy (NYHA IV). 2. For comparison, the nonselective beta-adrenoceptor agonist isoprenaline, the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX), the cardiac glycoside dihydroouabain, and calcium were studied. 3. Furthermore, the influence of IBMX on adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDE activity as well as total beta-adrenoceptor density, beta 1- and beta 2-adrenoceptor subtype distribution, and alpha 1-adrenoceptor density were compared in nonfailing and failing human heart preparations. The radioligands (-)-[125I]-iodocyanopindolol for beta-adrenoceptor binding and [3H]-prazosin for alpha 1-adrenoceptor binding were used. 4. The inotropic responses to calcium and dihydroouabain in failing human hearts were unchanged, whereas the maximal alpha 1- and beta 2-adrenoceptor-mediated positive inotropic effects were greatly reduced. The inotropic effects of the other cyclic AMP increasing compounds, i.e. isoprenaline and IBMX, were also reduced to about 60% of the effects observed in nonfailing controls. The potency of these compounds was decreased by factors 4-10. 5. The basal PDE activity and the PDE inhibition by IBMX were similar in nonfailing and failing preparations. 6. The total beta-adrenoceptor density in nonfailing hearts was about 70 fmol mg-1 protein. In failing hearts the total number of beta-adrenoceptors was markedly reduced by about 60%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cold stress on the subcellular distribution of noradrenaline in the rat heart

Rats were exposed to cold (4°) for 2 hr to study the effect of increased sympathetic activities on the subcellular distribution of noradrenaline in the heart. Cold-exposure caused about 30% decrease of total noradrenaline contents in both auricles and ventricles of normal or adrenalectomized rats. This depletion of noradrenaline caused by cold was completely prevented by pretreatment of the rat with hexamethonium chloride. Measurement of the subcellular distribution of noradrenaline revealed that the percentage depletion in particle-bound amine in both auricles and ventricles was greater than in the supernatant noradrenaline. It is suggested that the noradrenaline in the particulate fraction is the functional pool of the amine available for release by nerve impulses.     

Central α- and β-adrenoceptors modifying arterial blood pressure and heart rate in conscious cats

1 In conscious unrestrained cats noradrenaline, alpha-methylnoradrenaline and clonidine, infused into the lateral cerebral ventricles (i.c.v.) caused dose-related falls in blood pressure and heart rate; both effects were abolished after i.c.v. phentolamine.2 In 12 out of 20 cats, i.c.v. isoprenaline and salbutamol when given caused dose-related pressor responses and tachycardias. These effects were abolished after i.c.v. beta-adrenoceptor blocking drugs but were unaffected by alpha-adrenoceptor blocking agents.3 In 5 out of 20 cats, i.c.v. isoprenaline regularly produced dose-related falls in blood pressure with associated tachycardias; both effects were abolished after i.c.v. beta-adrenoceptor blocking agents.4 Intracerebroventricular dopamine produced cardiovascular responses which were qualitatively similar to those produced by i.c.v. isoprenaline.5 Intracerebroventricular adrenaline produced complex responses in untreated animals but typical alpha-effects were obtained after prior i.c.v. treatment with a beta-adrenoceptor blocking agent and typical beta-effects after i.c.v. pretreatment with an alpha-adrenoceptor blocking agent.6 The cardiovascular changes produced by i.c.v. beta-adrenoceptor agonists were abolished after systemic administration of hexamethonium or bethanidine.7 The results are discussed in the light of the mode of action of beta-adrenoceptor stimulants and beta-adrenoceptor blocking agents in the treatment of hypertension.     

An investigation of presynaptic α-adrenoceptor subtypes in the pithed rat heart

1 The presynaptic cardio-inhibitory and postsynaptic pressor responses to the α-adrenoceptor agonists xylazine and cirazoline, and the interaction with the antagonists yohimbine and prazosin, were examined in the pithed rat.

2 Evidence was found to suggest that, as well as the already established pre- and postsynaptic α₂- and postsynaptic α₁-receptors, presynaptic α₁-receptors are present.

     

Effect of cocaine on the affinity of α-adrenoceptors for noradrenaline

1. Doses of cocaine which cause specific or unspecific supersensitivity in cat spleen did not alter the blocking effect of phenoxybenzamine on the responses of isolated cat spleen strips to noradrenaline.2. The same doses of cocaine did not increase the protection of alpha-adrenoceptors given by noradrenaline during a standard exposure to phenoxybenzamine.3. It is concluded that cocaine does not change the affinity of the alpha-adrenoceptor for noradrenaline, and therefore changes in affinity are not responsible for the potentiating action of cocaine.     

Effect of some amphetamine analogues on α-methyl-p-tyrosine-induced catalepsy in rats

A single dose of α-methyl-p-tyrosine induced catalepsy in rats, commencing 6 h after administration. This catalepsy was strongly enhanced by (+)-amphetamine and (-)-ephedrine, but was antagonized by other amphetamine-like drugs. The implication of these findings is briefly discussed.     

Influence of gallic acid on α-amylase and α-glucosidase inhibitory properties of acarbose

Acarbose is an antidiabetic drug which acts by inhibiting α-amylase and α-glucosidase activities but with deleterious side effects. Gallic acid (GA) is a phenolic acid that is widespread in plant foods. We therefore investigated the influence of GA on α-amylase and α-glucosidase inhibitory properties of acarbose (in vitro). Aqueous solutions of acarbose and GA were prepared to a final concentration of 25μM each. Thereafter, mixtures of the samples (50% acarbose + 50% GA; 75% acarbose + 25% GA; and 25% acarbose + 75% GA) were prepared. The results revealed that the combination of 50% acarbose and 50% GA showed the highest α-glucosidase inhibitory effect, while 75% acarbose + 25% GA showed the highest α-amylase inhibitory effect. Furthermore, all the samples caused the inhibition of Fe²⁺-induced lipid peroxidation (in vitro) in rat pancreatic tissue homogenate, with the combination of 50% acarbose and 50% GA causing the highest inhibition. All the samples also showed antioxidant properties (reducing property, 2,2′-azino-bis (-3-ethylbenzthiazoline-6-sulphonate [ABTS*] and 1,1-diphenyl-2-picrylhydrazyl [DPPH] free radicals scavenging abilities, and Fe²⁺ chelating ability). Therefore, combinations of GA with acarbose could be employed as antidiabetic therapy, with a possible reduction of side effects of acarbose; nevertheless, the combination of 50% acarbose and 50% GA seems the best.     

Effect of γ-hydroxybutyrate on the release of monoamines from the rat striatum

A simple in vitro system was developed to study the effect of gamma-hydroxybutyrate on nerve cell depolarization-induced release of labelled DA and 5-hydroxytryptamine. The release of (3)H-dopamine formed in rat striatal slices incubated with (3)3H-tyrosine was followed. A three minute exposure to K+ (53.0 mM) caused a thirty-fold increase in the release of newly synthesized (3)H-dopamine. This K + -induced release was antagonized when gamma-hydroxybutyrate (1 mM) was present in the medium. Potassium (53.0 mM) increased (eighteen-fold) the release of (3)H-dopamine from striatal slices initially loaded by preincubation with (3)H-dopamine. The K + -induced release of this pool of DA was, however, not antagonized by gamma-hydroxybutyrate.Potassium (53.0 mM) also increased the release from striatal slices of (3)H-5-hydroxytryptamine (5-HT) newly synthesized from (3)H-tryptophan. This K + -induced release of 5-HT was also not inhibited by gamma-hydroxybutyrate. The ability of gamma-hydroxybutyrate to antagonize only the K + -induced release of newly formed DA may explain why this agent causes a rapid and selective increase in brain dopamine.     

Protective Effects of the Hydroethanolic Extract of Fridericia chica on Undifferentiated Human Neuroblastoma Cells Exposed to α-Zearalenol (α-ZEL) and β-Zearalenol (β-ZEL)

Fridericia chica (Bignoniaceae) is a traditional medicinal plant. The aim of this research was to determine the protective effects of the hydroethanolic extract from the F. chica leaves (HEFc) against the cytotoxicity of zearalenone (α-ZEL) and β-ZEL on SH-SY5Y cells. Free radical scavenging activity of HEFc was evaluated using the DPPH method. The cytotoxicity of both zearalenone metabolites and HEFc was examined using MTT test, as was the cytoprotective effects of the HEFc on cells treated with these mycotoxins. The chemical composition of HEFc was determined using UPLC-QTOF-MS/MS. HEFc elicited good DPPH radical scavenging activity following a concentration-dependent relationship. Cells exposed to α-ZEL exhibited a viability ˂50% after 48 h of treatment (25 and 50 µM), while those exposed to β-ZEL showed viability ˂50% (100 µM) and ˂25% (25-100 µM) after 24 and 48 h of exposure, respectively. HEFc showed a significant increase in cell viability after exposure to α-ZEL (25 and 50 µM) and β-ZEL (6–100 µM) (p < 0.05). UPLC-QTOF-MS/MS analyses allowed the identification of 10 phytochemical components in the HEFc. In short, the hydroethanolic extract of F. chica grown in Colombian Caribbean can protect against the effects of mycotoxins and it is a valuable source of compounds with antioxidant properties.     

Effect of temperature on changes, induced by oestrus, in α- and β-adrenoceptor activities of the rat uterus

The alpha- and beta-adrenoceptor activities of the isolated rat uterus during the oestrous cycle were intluenced greatly by temperature changes. During dioestrus, lowering the bath temperature to 25 degrees C from 40 degrees C increased two-fold the inhibition produced by (-)-adrenaline, (-)-noradrenaline, (-)-phenylephrine and (-)-isoprenaline. During oestrus adrenaline, noradrenaline and phenylephrine produced biphasic responses of contraction followed by inhibition at 40 degrees C and isoprenaline produced only inhibition. At 25 degrees C the contractile alpha-responses either were abolished (phenylephrine) or greatly reduced (adrenaline and noradrenaline), while the inhibitory beta-effects of all four amines were increased.