Index Of Norepinephrine Turnover Research Articles

Noradrenergic hyperactivity after partial fornix section: role in cholinergic dependent memory performance

Rats with unilateral or bilateral partial section of the fornix were impaired on an eight arm radial maze task. Neurochemical analysis of hippocampal tissue four weeks after the lesions revealed a 50% reduction of choline acetyltransferase (ChAT) activity. The cholinergic marker was correlated negatively with the number of errors in the maze; the lower the ChAT activity, the higher the error score. The fornix lesion also induced a 50% reduction in norepinephrine (NE), but no change in the noradrenergic metabolite methylhydroxyphenylglycol (MHPG), suggesting a net increase in turnover of NE in these animals. Additional lesion of the noradrenergic system with the neurotoxin DSP4 reduced both MHPG and NE levels by more than 90%, compared to nonlesioned controls, and reversed the behavioral deficit. This treatment had no further effect on cholinergic markers. There was a significant negative correlation between ChAT activity and the index of NE turnover, suggesting that hyperactivity in the noradrenergic system after fornix section inhibits the spared cholinergic function and thus exacerbates the cognitive deficit. The pattern of neurochemical results bear a striking resemblance to those seen in some Alzheimer's patients and suggest that an equilibrium among neurotransmitters is important to cognitive function.

Central noradrenergic activity in intact and sinoaortic denervated Dahl rats.

Lesions in forebrain areas richly innervated by noradrenergic terminals and involved in cardiovascular function reduce or prevent hypertension in the Dahl salt-sensitive (S) rats fed a high (H) salt diet. This led us to examine two questions. (1) Is the noradrenergic activity altered in discrete forebrain and brainstem areas of SH rats? (2) Are these changes in noradrenergic activity eliminated by sinoaortic denervation (SAD)? Studies were done in 10-week-old female SH and Dahl salt-resistant (RH) rats. Half of the rats in each group had SAD surgery 1 week prior to study. An index of norepinephrine (NE) turnover was determined by measuring the decline in tissue NE concentration 8 h after administering alpha-methyl-p-tyrosine, a NE synthesis blocker, to animals from each of four groups: sham-RH, SAD-RH, sham-SH, and SAD-SH (n = 18-20 per group). Various discrete brain areas were obtained using the "punch technique." In SH rats the index of NE turnover was increased in the median preoptic nucleus and decreased in the paraventricular nucleus compared with RH rats regardless of SAD. In contrast, in SH rats the index of NE turnover was increased in the supraoptic nucleus and locus ceruleus compared with RH rats; however, SAD-RH had greater turnover of NE at these sites than SAD-SH. In summary, changes in noradrenergic activity in the median preoptic nucleus and the paraventricular nucleus may be related to genetic predisposition to hypertension in SH rats. In contrast, changes in the locus ceruleus and the supraoptic nucleus of SH rats may be related to impaired baroreflexes and thereby contribute to hypertension.

Parallel development of noradrenergic innervation and cellular compartmentation in the rat spleen

By combining neurochemical measurement of norepinephrine (NE) with double-label immunocytochemistry for tyrosine hydroxylase-positive (TH +) noradrenergic nerves and specific lymphoid markers, we have examined the developmental compartmentation of noradrenergic nerves in the rat spleen. TH + nerve fibers were present in the white pulp of the spleen at birth, among surface IgM-positive (sIgM +) B lymphocytes at the outer border of the periarteriolar lymphatic sheath (PALS), distant from the central artery. During the first 7 days, noradrenergic innervation developed rapidly, forming plexuses of nerve fibers along the central artery and its branches, among T and B lymphocytes of the PALS, and along the developing marginal sinus where ED3 + macrophages accumulate. The splenic concentration of NE (per mg wet wt.) and 3-methoxy-4-hydroxy-phenetheleneglycol (MHPG), a NE metabolite, increased rapidly during this period, suggesting that NE is available and released from these nerves. From 7–14 days, the white pulp expanded to include an inner PALS, outer PALS, marginal sinus, and marginal zone; during this period, TH + fibers arborized principally among T lymphocytes of the inner PALS and adjacent to macrophages along the marginal sinus. By 14 days of age, NE concentration reached adult levels, although the MHPG/NE ratio (an index of NE turnover) remained higher throughout development than in adulthood. Finally, from 14–28 days, the outer PALS expanded to include follicles containing sIgM + B lymphocytes. At the earliest stages of follicular development, a parafollicular rim of noradrenergic fibers was present, providing occasional branches which arborized within the follicle. No further changes were observed in either noradrenergic innervation or cellular compartmentation after 28 days of age. These findings suggest that noradrenergic fibers are present in developing compartments of the spleen at the earliest stages of their development, providing norepinephrine for interaction with a variety of adrenoceptor-bearing lymphoid and nonlymphoid cells.

Effect of renal denervation on arterial pressure in rats with aortic nerve transection.

The role of renal nerves in influencing the control of arterial pressure was studied in Wistar rats with aortic depressor nerve (ADN) transection. Renal denervation prevented or reversed the normal increase in arterial pressure seen after ADN transection. This effect was not due to an effect on the renin-angiotensin system, as the elevated arterial pressure after ADN section in rats with renal nerves intact was shown to be due to increased alpha-adrenergic activity. Food and water intake and urine output decreased significantly in both renal-denervated and sham-denervated rats after ADN section, suggesting that a pressure diuresis mechanism was not responsible for preventing the rise in pressure in renal-denervated rats. In another study, the concentration of norepinephrine in skeletal muscle and hypothalamus at 0 and 8 hours after inhibition of tyrosine hydroxylase with alpha-methyltyrosine was used as an index of norepinephrine turnover. Norepinephrine turnover in skeletal muscle was increased significantly over control values by ADN transection in sham renal-denervated rats, but was not significantly different from controls in renal-denervated rats with ADN section. In the hypothalamus, there was a significant difference between the turnover of norepinephrine in the two groups of ADN-sectioned rats. The results taken together suggest that renal denervation prevents the arterial pressure response to ADN transection by altering the central mechanisms governing sympathetic outflow. It is suggested that this effect may be due to elimination of information carried by afferent renal fibers.

Dopamine accumulation after dopamine β-hydroxylase inhibition in rat heart as an index of norepinephrine turnover

Dopamine concentration in rat heart is normally very low, only a few percent of the concentration of norepinephrine. After treatment of rats with a dopamine β-hydroxylase inhibitor, l-cyclohexyl-2-mercapto-imidazole (CHMI), there was a rapid increase in dopamine concentration even before norepinephrine concentration had decreased perceptibly. This accumulation of dopamine was readily measured by liquid chromatography with electrochemical detection. Since the percentage change in dopamine was much greater than the percentage change in norepinephrine, especially at early times, measurement of dopamine accumulation rather than norepinephrine decline was considered as a useful measure of norepinephrine turnover. Drugs that act on noradrenergic receptors and are known to alter norepinephrine turnover were found to alter the rate of dopamine accumulation. Clonidine and guanabenz decreased dopamine accumulation after CHMI, whereas piperoxan (but not prazosin) increased dopamine accumulation after CHMI. Pergolide, a dopamine agonist whose lowering of blood pressure and cardiac rate has been suggested to be due to suppression of neurogenic release of norepinephrine, also decreased dopamine accumulation after CHMI. The results suggest that measuring dopamine accumulation may have advantages over measuring norepinephrine disappearance after dopamine β-hydroxylase inhibition as an indicator of norepinephrine turnover in heart.

Noradrenergic mechanisms in brain and peripheral organs after aortic nerve transection.

Noradrenergic mechanisms were studied in the hypothalamus, midbrain, medulla, kidney, duodenum, and skeletal muscle of Wistar rats at 3 or 13 days after either bilateral transection of the aortic depressor nerve (ADN) or a sham operation. The rate of decline of tissue norepinephrine (NE) concentration after inhibition of tyrosine hydroxylase with alpha-methyltyrosine was used as an index of NE turnover. Three days after ADN transection, arterial pressure and heart rate were elevated significantly, and NE turnover was increased in all three brain areas, kidney, and skeletal muscle but not in duodenum. The largest change occurred in skeletal muscle, where the time required for tissue NE concentration to decline to 50% of control decreased from 9.0 to 2.5 h. In rats 13 days after ADN transection, arterial pressure was significantly higher than in sham-operated controls, but heart rate was similar to control values. NE turnover was slightly increased in hypothalamus but was not significantly different in muscle and kidney when compared to sham-operated controls. These results suggest that 3 days after ADN transection in the rat, arterial pressure is elevated as a result of increased activity of noradrenergic neurons in the hypothalamus and brain stem, which is translated into increased sympathetic nerve activity to peripheral organs, particularly skeletal muscle. The normal turnover of NE in peripheral organs 13 days after ADN transection suggests that mechanisms other than increased sympathetic activity are responsible for maintaining the elevated arterial pressure.

New inhibitors of dopamine β-hydroxylase

A32390A, 1,6-di-O-(2-isocyano-3-methylcrotonyl)- d-mannitol, obtained from fermentation broths of a species of Pyrenochaeta, inhibited DBH in vitro and lowered heart norepinephrine levels in vivo in rats. A32390A had less effect on adrenal catecholamine levels and did not lower brain norepinephrine levels. Associated with the inhibition of norepinephrine synthesis in vivo was a reduction of blood pressure by A32390A in DOCA hypertensive rats. Although A32390A was effective when given by either intraperitoneal or subcutaneous injection, it did not lower norepinephrine levels or blood pressure when given orally. CHMI (1-cyclohexyl-2-mercapto-imidazole) was the most active among several methimazole derivatives studied as a DBH inhibitor that reduced norepinephrine levels preferentially in brain. The initial decline in brain norepinephrine levels following CHMI injection could be used as an index of norepinephrine turnover. Lowering of brain norepinephrine levels by CHMI on the second day of proestrus in female rats prevented the surge of plasma LH levels that normally occurred on the afternoon of proestrus.