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Query: UNIPROT:P06889 (Mol)
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The effect of beta- and alpha-adrenergic stimulation on cardiovascular function and development of cardiac hypertrophy was studied in rats by measuring the heart weight/body weight and cardiac RNA/DNA ratios. Beta-receptor stimulation with isoproterenol over 3 days induced an increase in the biosynthesis of cardiac adenine nucleotides, myocardial protein synthesis, and the heart weight/body weight ratio. The isoproterenol-induced metabolic effects were prevented by simultaneous beta-adrenergic blockade with propranolol. Alpha-adrenergic stimulation with norfenephrine for 3 days induced an increase in heart rate, total peripheral resistance, the myocardial RNA/DNA, and left ventricular weight/body weight ratio. The calcium antagonist verapamil prevented the hemodynamic changes but did not influence the development of cardiac hypertrophy. The alpha-adrenergic blocker prazosin reversed the norfenephrine-induced functional changes and prevented cardiac hypertrophy. Norepinephrine was infused into isolated perfused working rat hearts to elucidate some molecular biological changes that precede the development of cardiac hypertrophy. It increased transiently and sequentially the mRNA of c-fos and c-myc. This enhancement occurred at about the same time as that induced by elevation of pre- and afterload but was more pronounced. These findings were compared with those obtained in other studies assessing the effects of catecholamines on proto-oncogene expression. Combination of norepinephrine with pre- and afterload elevation induced the c-fos mRNA signal to appear earlier, to be more pronounced, and to persist for a longer period of time. Similar results were obtained in regard to the c-myc mRNA. These findings indicate that the combination of two hypertrophy-inducing stimuli which may cause a higher degree of cardiac hypertrophy in vivo induce an earlier, more pronounced, and longer lasting expression of the proto-oncogenes c-fos and c-myc.
J Mol Med (Berl)
PMID:Catecholamine-induced cardiac hypertrophy: significance of proto-oncogene expression. 942 17

Developmental changes in the functional properties of thoracic aorta were examined in neonatal and adult guinea-pigs. Norepinephrine-induced contractions of the neonatal aortic rings were markedly enhanced by removal of the endothelium, whereas those of the adult rings were only slightly enhanced. Carbachol induced endothelium-dependent relaxation to a similar extent in both neonatal and adult aortic rings precontracted with 30 microM norepinephrine. A23187 induced endothelium-dependent relaxation in the adult aortic rings precontracted with 30 microM norepinephrine, whereas it failed to induce the relaxation in the neonatal aortic ring. Sodium nitropurusside induced endothelium-independent relaxation to a similar extent in both neonatal and adult aortic rings precontracted with 30 microM norepinephrine. The endothelium-dependent relaxation induced by carbachol and by A23187 were inhibited either by NG-nitro-L-arginine or by methylene blue, but not by indomethacin, indicating that both the relaxations were mediated by nitric oxide, but not by prostacyclin. These results suggest that, although the neonatal endothelium of the guinea-pig aorta is capable of releasing nitric oxide, the mechanisms underlying the synthesis and/or release of nitric oxide may be different between the neonatal and adult endothelium.
Res Commun Mol Pathol Pharmacol 1997 Oct
PMID:Difference in the endothelium mediated effects of A23187 on thoracic aorta between neonatal and adult guinea pigs. 943 15

In the quail preoptic area (POA) anatomical and pharmacological data suggest that catecholamines may be implicated in the control of testosterone (T) aromatization into estrogens. The biochemical mechanism(s) mediating this control of the enzyme activity is (are) however unexplored. The present studies were carried out to investigate whether the catecholamines, dopamine (DA) and norepinephrine (NE) are able to directly affect aromatase activity (AA) measured during in vitro incubations of POA homogenates. AA was quantified in the POA-hypothalamus of adult male Japanese quail by measuring the tritiated water production from [1beta-3H]-androstenedione. Enzyme activity was linear as a function of the incubation time and of the protein content of homogenates. It exhibited a typical Michaelis-Menten kinetics, with an apparent Km of 2.8 nM and a Vmax of 266.6 fmol h(-1) mg wet weight(-1). AA was then measured at a substrate concentration of 25 nM in the presence of catecholamines and some of their receptor agonists or antagonists, at two concentrations, 10(-3) and 10(-6) M. Norepinephrine and prazosin (alpha1-adrenergic antagonist) had no or very limited effects on AA at both concentrations. In contrast, DA and some D1 and/or D2 receptor agonists (apomorphine[D1/D2], SKF-38393 [D1] and RU-24213 [D2]) depressed AA by 40 to 70% at the 10(-3) M concentration. One D2 receptor antagonist also produced a major inhibition of AA (sulpiride) while other antagonists either had no significant effect or only produced moderate decreases in enzyme activity (SCH-23390 [D1], spiperone [D2], pimozide [D2]) as did two DA indirect agonists, amfonelic acid and nomifensine. The inhibitory effect of the agonists was not antagonized by the less active antagonists, SCH-23390 [D1] or spiperone [D2]. Taken together these results suggest that the inhibitory effects do not involve specific binding of DA or its agonists/antagonists to dopaminergic receptors mediating changes in cAMP concentration. This conclusion is also supported by the observation that addition of dibutyryl cAMP did not change brain AA. It appears more likely that DA and dopaminergic drugs inhibit AA by a direct effect on the enzyme, as suggested by the competitive nature of DA and SKF-38393 inhibition of AA (Ki's of 59 and 84 microM, respectively). The functional significance of this effect should still be demonstrated but this mechanism may represent an important physiological pathway through which neurotransmitters could rapidly affect steroid-dependent processes such as the neural synthesis of estrogens. This would provide a mean by which environmental stimuli could affect reproductive behavior and physiology.
J Steroid Biochem Mol Biol
PMID:A direct dopaminergic control of aromatase activity in the quail preoptic area. 944 11

We have examined the ryanodine receptor, Ca(2+)-ATPase, calsequestrin and phospholamban mRNA levels in the left ventricles of pacing-induced heart failure and norepinephrine infusion dogs. The heart failure dogs showed a decrease in the levels of ryanodine receptor and Ca(2+)-ATPase mRNAs. Norepinephrine infusion caused a reduction of Ca(2+)-ATPase mRNA but no change in ryanodine receptor mRNA. There was a corresponding reduction of the immunoreactive Ca(2+)-ATPase protein levels in both heart failure and norepinephrine infusion animals compared to controls. In contrast, the mRNAs of calsequestrin and phospholamban were unchanged in dogs with either congestive heart failure or norepinephrine infusion. Thus, since norepinephrine infusion and congestive heart failure produced similar reductions of Ca(2+)-ATPase mRNA and protein, we postulate that the down-regulation of Ca(2+)-ATPase in congestive heart failure may be caused, at least in part, by sympathetic stimulation that occurs in heart failure.
J Mol Cell Cardiol 1998 Jan
PMID:Altered sarcoplasmic reticulum Ca2+ ATPase gene expression in congestive heart failure: effect of chronic norepinephrine infusion. 950 Aug 74

The metabolism of glucose in porcine carotid artery was tracked by isotopic methods during sustained isometric contraction induced by 100 microM norepinephrine (NE). In resting muscles, 74 and 18% of glucose taken up was accounted for by glycolysis and glycogen synthesis, respectively. Lactate production accounted for 69%, pyruvate production for 12%, and glucose oxidation accounted for 14% of glycolytic flux. The oxidation of glucose accounted for 57% of the consumption of O2 and thus constituted the primary oxidative substrate. During contraction by NE, glucose-uptake declined modestly below the resting basal rate. Glycolysis of external glucose and lactate production decreased and then increased with sustained contraction. Norepinephrine stimulated simultaneous glycogenolysis and glycogen synthesis, with net glycogen synthesis prevailing over 90 min of isometric contraction. Furthermore, NE modified the distribution of glucosyl units throughout the glycogen pool. The steady state rate of oxidation of glucose did not increase during NE contraction, even though O2-consumption increased. In contrast, increased glucose oxidation was demonstrable during contraction induced by 80 mm KCl. Furthermore, oxidation of exogenous fatty acid could be demonstrated during NE-induced contraction. Thus, NE exerts multiple effects on glucose and glycogen metabolism in smooth muscle, but it does not stimulate glucose oxidation.
J Mol Cell Cardiol 1998 Mar
PMID:Metabolic fate of glucose in vascular smooth muscle during contraction induced by norepinephrine. 951 45

Insulin secretion from isolated pancreatic islets of 8- to 12-day-old rats was investigated in a dynamic in vitro (perifusion) system. The aims of the study were (i) to describe a carefully controlled in vitro method to study the mechanism of insulin secretion and to analyse the effects and dynamic interactions of bioactive compounds on isolated rat pancreatic islets, (ii) to validate the method by comparing fundamental data on the functions of the islets obtained with this method to those collected with other techniques; and (iii) to find novel features of the control of insulin secretion. The method was carefully designed to maintain the functional capacity of the explanted cells. A functional standardization system was elaborated consisting of (i) analysis of the changes in the basal hormone secretion of the cells; (ii) evaluating responses to a standard, specific stimuli (50 mM glucose for 3 min); (iii) determining the alteration of the momentary size of the hormone pool with responses to KCl; and (iv) direct determination of the total intracellular hormone content from the extract of the column. The technique provides accurate quantitative data on the dynamic responses to biologically active compounds that act directly on the pancreatic islets. The islets maintained their full responsiveness for up to 7 days, and responses as close as in 1-min intervals could be distinguished. A linear dose-response relationship was found on the glucose-induced insulin release in case of 3-min stimulation with 4 and 500 mM of glucose (lin-log graph). Utilizing this method, we showed that no desensitization to glucose-induced insulin release can be observed if the responsiveness of the cells is properly maintained and the parameters of the stimulation are carefully designed. Exposure of the explanted islets to 10 microM acetylcholine or 30 mM arginine (Arg) induced a transitory elevation of insulin release similar in shape to that experienced after glucose stimulation. Norepinephrine (NE), dopamine (DA) and somatostatin (SS) did not induce any detectable alteration on the basal insulin secretion of the islets. However, 100 nM SS given together with 50 mM glucose, 30 mM Arg or 10 microM acetylcholine significantly reduced the insulin-releasing effect of these substances (by 75.5, 71.5 and 72.5%, respectively). At the same time, SS did not alter the insulin response of the islets to 100 mM elevation of K+ concentration. SS also inhibited glucose-induced insulin release in a dose-dependent way (ED50 = 22 nM). A similar dose-dependent inhibitory effect on glucose-induced insulin release was found with NE (ED50 = 89 nM) and DA (ED50 = 2.2 microM). gamma-Aminobutyric acid (GABA) did not influence insulin release under similar circumstances.
Cell Mol Life Sci 1998 Jul
PMID:Dynamic insulin secretion from perifused rat pancreatic islets. 971 Dec 40

Moderate protein restriction throughout pregnancy in the rat leads to relative hyperlipidaemia and blunted insulin responsiveness of lipid fuel supply, and impairs foetal growth. The present study examined the basis for these changes. Isocaloric 8% (vs 20%) protein diets were provided throughout pregnancy. Rats were sampled at 19-20 days of gestation. Protein restriction enhanced triacylglycerol (TAG) secretion rates (estimated using Triton WR 1339) 1.6-fold (P < 0.05) in the post-absorptive state. Insulin infusion (4.2 mU/kg per min) decreased plasma TAG concentrations by 33% (P < 0.05) and 48% (P < 0.05) in control (C) and protein-restricted (PR) pregnant groups, an effect associated with suppression of TAG secretion by 42% (P < 0.05) and 51% (P < 0.01) respectively, in the C and PR groups. Since TAG concentrations decline more rapidly, while TAG secretion is enhanced, TAG utilisation during hyperinsulinaemia is enhanced in the PR group. We evaluated whether these changes were associated with dysregulation of lipolysis using adipocytes from two abdominal depots (mesenteric and parametrial). Noradrenaline-stimulated glycerol release was enhanced in parametrial adipocytes (by 40%; P < 0.05) from PR pregnant rats. The anti-lipolytic action of insulin at low concentrations (< or = 15 microU/ml) was impaired by protein restriction (adipocytes from both depots). There was no evidence for altered intra-hepatic regulation of fatty acid (FA) disposal at the level of carnitine palmitoyltransferase. Our results demonstrate increased post-absorptive production of non-carbohydrate energy substrates (TAG and FA) as a consequence of mild protein restriction during pregnancy. These adaptations contribute to a homeostatic strategy to reduce the maternal requirement for gluconeogenesis from available amino acids, optimising the foetal protein supply. Protein restriction also enhances TAG turnover during hyperinsulinaemia. This effect is not a consequence of abnormal regulation of hepatic lipid metabolism by insulin.
Mol Cell Endocrinol 1998 Jul 25
PMID:Moderate protein restriction during pregnancy modifies the regulation of triacylglycerol turnover and leads to dysregulation of insulin's anti-lipolytic action. 978 99

Two closely related genes of thermostable Bac. brevis metalloproteases were cloned and expressed in Bac. subtilis cells. Their restriction maps and directions of transcription were determined. Thermostability and thermal optimum of proteolytic activity of cloned gene products are significantly lower than those of native enzymes. The authors believe that alteration of the enzymes' characteristics may be due to uncorrected folding of thermostable protein in case of its expression in mesophilic bacterial strains.
Mol Gen Mikrobiol Virusol 1998
PMID:[Cloning and expression of thermostable secretory metalloproteinase genes from two Bacillus brevis strains in Bacillus subtilis cells]. 981 25

Effects of phenoxybenzamine on the myogenic contraction in response to quick stretch were examined in the isolated dog cerebral artery. Quick stretch at a rate of 10 cm/sec by 30% of the initial muscle length (= 100%) produced a myogenic contraction in dog basilar artery. Pretreatment of the cerebral artery strips with phenoxybenzamine (10(-4) M) for 30 min inhibited the stretch-induced contraction by 50-60%. By comparison, the treatment with phenoxybenzamine abolished the cerebral artery contractions induced by 5-hydroxytryptamine and histamine. Norepinephrine-induced contraction was also suppressed to about 10% by the treatment with phenoxybenzamine. High KCl (80 mM)-induced depolarizing contraction was nearly completely inhibited by the phenoxybenzamine treatment. These findings suggest that the site(s) of mechanoreception of membrane stretch (quick stretch) leading to myogenic contraction of dog cerebral artery is not susceptible to alkylation by phenoxybenzamine. It seems likely that mechanosensor site(s) responsible for inducing myogenic contraction by quick stretch is distinct from the sites for the reception of chemical stimulations.
Res Commun Mol Pathol Pharmacol 1998 Aug
PMID:Phenoxybenzamine-sensitive sites are not responsible for the mechanoreception of membrane stretch leading to myogenic contraction of dog cerebral artery. 982 Dec 16

Activation of protein kinases is an important intermediate step in signaling pathways of many G protein-coupled receptors including alpha1-adrenergic receptors. The present study was designed to investigate the capacity of the three cloned subtypes of human alpha1-receptors, namely, alpha1A, alpha1B and alpha1D to activate phosphatidylinositol 3-kinase (PI 3-kinase) and p21ras in transfected NIH3T3 cells. Norepinephrine activated PI 3-kinase in cells expressing human alpha1A and alpha1B via pertussis toxin-insensitive G proteins; alpha1D-receptors did not detectably activate this kinase. Transient transfection of NIH 3T3 cells with the alpha-subunit of the G protein transducin (alpha(t)) a scavenger of betagamma-subunits released from activated G proteins, inhibited alpha1B-receptor but not alpha1A-receptor-stimulated PI 3-kinase activity. Stimulation of both alpha1A- and alpha1B-receptors activated p21ras and stimulated guanine nucleotide exchange on Ras protein. Overexpression of a dominant negative mutant of p21ras attenuated alpha1B-receptor but not alpha1A-receptor activation of PI 3-kinase. Overexpression of a dominant negative mutant of PI 3-kinase attenuated alpha1A- but not alpha1B-receptor-stimulated mitogen-activated protein kinase activity. These results demonstrate the capacity for heterologous signaling of the alpha1-adrenergic receptor subtypes in promoting cellular responses in NIH3T3 cells.
Mol Endocrinol 1999 Jan
PMID:Contrasting signaling pathways of alpha1A- and alpha1B-adrenergic receptor subtype activation of phosphatidylinositol 3-kinase and Ras in transfected NIH3T3 cells. 989 8


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