Nature of the stimulation of biogenesis of cholesterol in the liver by noradrenaline

1.Administration of noradrenaline increased the incorporation of [1-14C]acetate into hepatic sterols and the activity of liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase. 2. The stimulation was observed at short time-intervals with a maximum at 4h and was progressive with increasing concentrations of noradrenaline. 3. Protein synthesis de novo was a necessary factor for the effect. 4. The stimulatory effect was not mediated through the adrenergic receptors, but appears to involve a direct action of the hormone within the hepatocyte.

Nature of the inhibition by noradrenaline of induction by cortisol of hepatic tryptophan pyrrolase

Administration of noradrenaline inhibited the induction of hepatic trytophan pyrrolase by Cortisol but not by tryptophan. The selective inhibition of pyrrolase was specific to noradrenaline, whereas adrenaline and rat growth hormone also inhibited tyrosine aminotransferase. None of those three hormones had any effect on the incorporation of [32P]-orthophosphate into RNA, stimulated by cortisol. Other biogenic amines, polypeptide hormones and steroid analogues were not inhibitory to the induction of tryptophan pyrrolase by cortisol. The α-adrenergic agonist, phenylephrine, potentiated the noradrenaline inhibition whereas Image -threo-3,4-dihydroxyphenylserine, its precursor, together with pargyline had no effect on the induction process of pyrrolase. These results support the view that noradrenaline exerts its inhibitory action at the cell membrane via the α-receptor, and is not mediated directly by an intracellular mechanism.

In situ UV-vis and CD thin-layer spectroelectrochemistry study of the electrochemical behavior of L-noradrenaline in alkaline solution

Electrochemical redox behavior of noradrenaline in alkaline solution on a glassy carbon electrode has been investigated by in situ UV-vis and CD spectroelectrochemistry by using a long optical path thin-layer cell. The experimental data were processed by using a double logarithmic method of analysis together with nonlinear regression which confirmed that the first step in both the oxidation of noradrenaline and reduction of noradrenochrome is a two-electron irreversible process governed by an EE mechanism. The kinetic parameters of the electrode reactions, i.e., charge transfer coefficient and the number of electrons transferred, alpha(1)n(1) = 0.11 and alpha(2)n(2) = 0.23, formal potentials modified with kinetics, E-1(0') = 0.65 (+/- 0.01) V and E-2(0') = 0.72V and standard rate cnstants, k(1)(0) = 7.0(+/-0.5)x10(-5) cm s(-1), for the first and second steps in the oxidation process of noradrenaline, and similarly, alpha(1)n(1) = 0.33, alpha(2)n(2) = 0.58, E-1(0') = 0.37(+/-0.01) V, E-0' = -0.25 (+/-0.01) V and k(1)(0) approximate to k(2)(0) = 1.06 (+/-0.05)x10(-4) cm s(-1) for the first and second steps in the reduction process of noradrenochrome were also determined.

The balance between the pro-inflammatory effect of plasma noradrenaline and the anti-inflammatory effect of neuronal noradrenaline determines the peripheral effect of noradrenaline

Perfusion experiments on an isolated, canine lateral saphenous vein segment preparation have shown that noradrenaline causes potent, flow dependent effects, at a threshold concentration comparable to that of plasma noradrenaline, when it stimulates the segment by diffusion from its microcirculation (vasa vasorum). The effects caused are opposite to those neuronal noradrenaline causes in vivo and that, in the light of the principle that all information is transmitted in patterns that need contrast to be detected – star patterns need darkness, sound patterns, quietness – has generated the hypothesis that plasma noradrenaline provides the obligatory contrast tissues need to detect and respond to the regulatory information encrypted in the diffusion pattern of neuronal noradrenaline. Based on the implications of that hypothesis, the controlled variable of the peripheral noradrenergic system is believed to be the maintenance of a set point balance between the contrasting effects of plasma and neuronal noradrenaline on a tissue. The hypothalamic sympathetic centres are believed to monitor that balance through the level of afferent sympathetic traffic they receive from a tissue and to correct any deviation it detects in the balance by adjusting the level of efferent sympathetic input it projects to the tissue. The failure of the centres to maintain the correct balance, for reasons intrinsic or extrinsic to themselves, is believed to be responsible for degenerative and genetic disorders. When the failure causes the balance to be polarised in favour of the effect of plasma noradrenaline that is believed to cause inflammatory diseases like dilator cardiac failure, renal hypertension, varicose veins and aneurysms; when it causes it to be polarised in favour of the effect of neuronal noradrenaline that is believed to cause genetic diseases like hypertrophic cardiopathy, pulmonary hypertension and stenoses and when, in pregnancy, a factor causes the polarity to favour plasma noradrenaline in all the maternal tissues except the uterus and conceptus, where it favours neuronal noradrenaline, that is believed to cause preeclampsia.

The effect of chronic captopril therapy on adrenergic receptors, plasma noradrenaline and the vascular responses to infused noradrenaline

Adrenergic receptors (alpha 2, beta 2), plasma noradrenaline, heart rate and the pressor responsiveness to infused noradrenaline were examined in ten healthy male volunteers before and after 2 weeks of placebo or captopril therapy in a double blind cross-over study. No significant differences in these measurements were observed between the captopril and placebo treated groups. The study shows that in sodium replete normotensive subjects, long-term angiotensin converting enzyme inhibition does not lead to changes in adrenoceptor density. There is also no alteration in plasma noradrenaline levels nor in the pressor responsiveness to infused noradrenaline. These data suggest that the known interaction between the renin-angiotensin system and the sympathetic nervous system observed in animals is probably of little significance in man.

Gamma Irradiation and Targeted Radionuclides Enhance the Expression of the Noradrenaline Transporter Transgene Controlled by the Radio-Inducible p21(WAF1/CIP1) Promoter

The use of radiation-inducible promoters to drive transgene expression offers the possibility of temporal and spatial regulation of gene activation. This study assessed the potential of one such promoter element, p21(WAF1/CIP1) (WAF1), to drive expression of the noradrenaline transporter (NAT) gene, which conveys sensitivity to radioiodinated meta-iodobenzylguanidine (MIBG). An expression vector containing NAT under the control of the radiation-inducible WAF1 promoter (pWAF/NAT) was produced. The non-NAT expressing cell lines UVW (glioma) and HCT116 (colorectal cancer) were transfected with this construct to assess radiation-controlled WAF1 activation of the NAT gene. Transfection of UVW and HCT cells with pWAF/NAT conferred upon them the ability to accumulate [(131)I]MIBG, which led to increased sensitivity to the radiopharmaceutical. Pretreatment of transfected cells with ? radiation or the radiopharmaceuticals [(123)I]MIBG or [(131)I]MIBG induced dose- and time-dependent increases in subsequent [(131)I]MIBG uptake and led to enhanced efficacy of [(131)I]MIBG-mediated cell kill. Gene therapy using WAF1-driven expression of NAT has the potential to expand the use of this therapeutic modality to tumors that lack a radio-targetable feature.