Adrenal adrenaline- and noradrenaline-containing cells and celiac sympathetic ganglia are differentially controlled by centrally administered corticotropin-releasing factor and arginine–vasopressin in rats

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Abstract

The adrenal glands and sympathetic celiac ganglia are innervated mainly by the greater splanchnic nerves, which contain preganglionic sympathetic nerves that originated from the thoracic spinal cord. The adrenal medulla has two separate populations of chromaffin cells, adrenaline-containing cells (A-cells) and noradrenaline-containing cells (NA-cells), which have been shown to be differentially innervated by separate groups of the preganglionic sympathetic neurons. The present study was designed to characterize the centrally activating mechanisms of the adrenal A-cells, NA-cells and celiac sympathetic ganglia with expression of cFos (a marker for neural excitation), in regard to the brain prostanoids, in anesthetized rats. Intracerebroventricularly (i.c.v.) administered corticotropin-releasing factor (CRF) induced cFos expression in the adrenal A-cells, but not NA-cells, and celiac ganglia. On the other hand, i.c.v. administered arginine–vasopressin (AVP) resulted in cFos induction in both A-cells and NA-cells in the adrenal medulla, but not in the celiac ganglia. Intracerebroventricular pretreatment with indomethacin (an inhibitor of cyclooxygenase) abolished the CRF- and AVP-induced cFos expression in all regions described above. On the other hand, intracerebroventricular pretreatment with furegrelate (an inhibitor of thromboxane A2 synthase) abolished the CRF-induced cFos expression in the adrenal A-cells, but not in the celiac ganglia, and also abolished the AVP-induced cFos expression in both A-cells and NA-cells in the adrenal medulla. These results suggest that centrally administered CRF activates adrenal A-cells and celiac sympathetic ganglia by brain thromboxane A2-mediated and other prostanoid than thromboxane A2 (probably prostaglandin E2)-mediated mechanisms, respectively. On the other hand, centrally administered AVP activates adrenal A-cells and NA-cells by brain thromboxane A2-mediated mechanisms in rats.

Introduction

The relative importance of the adrenal medulla and sympathetic nervous system in various pathophysiological conditions has generally been inferred from measurement of plasma adrenaline and noradrenaline, since plasma adrenaline and noradrenaline have been shown to reflect the activity of adrenal medulla and sympathetic nervous system, respectively. Hypoglycemia causes the elevation of plasma adrenaline (Young et al., 1984, Fujino and Fujii, 1995, Vollmer et al., 1997), while hypotension elevates both catecholamines (noradrenaline > adrenaline) (Brown and Fisher, 1984, Vollmer et al., 2000). Immobilization stress elicits a robust increase in the plasma adrenaline and noradrenaline (Kvetnansky and Mikulaj, 1970, Jezova et al., 1999, Dronjak et al., 2004), while cold stress triggers a robust increase in plasma noradrenaline (Dronjak et al., 2004). Likewise, centrally administered neuropeptides such as corticotropin-releasing factor (CRF), arginine–vasopressin (AVP), bombesin, thyrotropin-releasing hormone, and α-calcitonin gene-related peptide also produce differential changes in the plasma catecholamines (Brown et al., 1979, Brown et al., 1985, Fisher et al., 1983, Brown and Fisher, 1984, Feuerstein et al., 1984, Hasegawa et al., 1993, Okuma et al., 1996, Yokotani et al., 2001, Okada et al., 2002).

In the adrenal medulla of both humans and rats, adrenaline and noradrenaline are localized in separate populations of cells with the number of adrenaline-containing cells (A-cells) about 4-fold greater than that of noradrenaline-containing cells (NA-cells) (Verhofstad et al., 1985, Suzuki and Kachi, 1996). Despite the constancy of the stored amounts of adrenaline and noradrenaline, the proportion of each catecholamine secreted seems to vary depending on the strength and type of stimulus, suggesting a differential control of A-cells and NA-cells (Vollmer, 1996). Recently, adrenal A- and NA-cells have been shown to be innervated by separate groups of preganglionic sympathetic neurons located in the spinal cord (Edwards et al., 1996, Vollmer et al., 2000). Adrenaline secreted into circulation is almost produced within the adrenal A-cells (Axelrod, 1962, Wurtman, 2002), while plasma noradrenaline seems to reflect the secretion from adrenal NA-cells in addition to the release from sympathetic nerves (Folkow and von Euler, 1954, Vollmer et al., 1997, Yokotani et al., 2001, Yokotani et al., 2005, Okada et al., 2003a). However, little is known about centrally controlling mechanisms of adrenal A-cells, NA-cells and sympathetic nerves.

Arachidonic acid is metabolized rapidly to oxygenated products, such as prostaglandin E2 and thromboxane A2, by several distinct enzymes including cyclooxygenase, prostaglandin E synthase and thromboxane A synthase (Flower and Blackwell, 1976, Irvine, 1982, Axelrod, 1990). Previously, we reported that centrally administered prostaglandin E2 evokes noradrenaline release from sympathetic nerves by activation of the brain prostanoid EP3 receptors (Yokotani et al., 1995, Yokotani et al., 2005). Recently we also reported that centrally administered CRF evokes the brain thromboxane A2-mediated adrenal adrenaline secretion and the other prostanoid (probably prostaglandin E2)-mediated sympathetic noradrenaline release, while centrally administered AVP, bombesin and histamine evoke the brain thromboxane A2-mediated adrenal secretion of both adrenaline and noradrenaline in rats (Yokotani et al., 2001, Yokotani et al., 2005, Okada et al., 2003a, Shimizu et al., 2006).

Since the greater splanchnic nerve, which contains sympathetic preganglionic nerves originated from spinal cord, ramifies into the adrenal gland and celiac sympathetic ganglia (Yokotani et al., 1983), these regions are very useful to identify the centrally activated adrenal A-, NA-cells and celiac sympathetic ganglia with nuclear expression of cFos, immediate early gene product (Sagar et al., 1988, Herrera and Robertson, 1996). In the present study, therefore, we examined the effects of centrally administered CRF and AVP on the cFos expression in these regions, in regard to the brain arachidonic acid cascade, to further clarify the presence of differential activating mechanisms for sympathetic nerves and adrenal medulla.

Section snippets

Animals

Male Wistar rats weighing about 350 g were maintained in an air-conditioned room at 22–24 °C under a constant day–night rhythm for more than 2 weeks and given food (laboratory chow, CE-2; Clea Japan, Hamamatsu, Japan) and water ad libitum. All efforts were made to minimize animal suffering and the number of animals used. All rats were treated in accordance with the Guiding Principles for the Care and Use of laboratory animals approved by the Graduate School of Medicine, Kochi University.

Experimental design

Under

CRF- and AVP-induced cFos expression in the adrenal medulla and celiac ganglia

In the adrenal medulla, A-cells (PNMT-staining cells in the total chromaffin cells) were 74.2 ± 5.9% and NA-cells (PNMT-negative cells in the total chromaffin cells) were 25.8 ± 5.9% (n = 44).

Administration of CRF (1.5 and 3.0 nmol/animal, i.c.v.) effectively increased cFos expression in the adrenal A-cells and noradrenergic neurons in the celiac ganglia, and these responses obtained with CRF (1.5 nmol/animal, i.c.v.) was greater than those obtained with CRF (3.0 nmol/animal, i.c.v.) (Fig. 1A, B, C,

Discussion

In many mammalian species, adrenomedullary chromaffin cells consist of A-cells and NA-cells. The former cells contain the enzyme PNMT, which converts noradrenaline to adrenaline. Previous studies with immunohistochemical staining for PNMT show that A-cells occupied large areas in the adrenal medulla, and NA-cells were scattered among A-cell regions (Edwards et al., 1996, Suzuki and Kachi, 1996, Phillips et al., 2001). In the present experiment, the number of A-cells is about 3-fold greater than

Acknowledgements

This work was supported in part by a grant from The Smoking Research Foundation in Japan and The Dean Research Fund of the Kochi University.

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