Glucocorticoid treatment--effect on adrenal medullary catecholamine production

Abstract

Glucocorticoid and epinephrine are important stress hormones secreted from the adrenal gland during critical illness. Adrenal glucocorticoid stimulates phenylethanolamine N-methyltransferase (PNMT) to convert norepinephrine to epinephrine in the adrenal medulla. Glucocorticoid is sometimes used in catecholamine-resistant septic shock in critically ill patients. By suppressing adrenal glucocorticoid production, glucocorticoid therapy might also reduce the secretion of epinephrine during stress. To investigate this, we used a mouse model subjected to glucocorticoid therapy under basal conditions (experiment 1) and during stress (experiment 2). In experiment 1, pellets containing 0% to 8% dexamethasone were implanted subcutaneously in mice for 4 weeks. In experiment 2, animals received 14 days of intraperitoneal injections of normal saline, low- or high-dose dexamethasone, followed by 2 h of restraint. We found that in experiment 1, adrenal corticosterone did not differ with dexamethasone treatment. Phenylethanolamine N-methyltransferase messenger RNA levels and adrenal catecholamines were highest in the 8% dexamethasone group. Compared with experiment 1, restrained control mice in experiment 2 had high adrenal corticosterone, which decreased with dexamethasone. Phenylethanolamine N-methyltransferase messenger RNA content doubled with restraint but decreased with dexamethasone treatment. As in experiment 1, adrenal catecholamine content increased significantly with dexamethasone treatment. We conclude that without stress, when adrenocorticotropic hormone is low, high doses of exogenous dexamethasone stimulate PNMT and catecholamine synthesis, likely independently of adrenal corticosterone concentration. After stress, adrenocorticotropic hormone levels are elevated, and exogenous dexamethasone suppresses endogenous corticosterone and PNMT production. Nonetheless, catecholamines increase, possibly due to direct neural stimulation, which may override the hormonal regulation of epinephrine synthesis during stress.

Fig. 1. Adrenal corticosterone and PNMT mRNA in unstressed mice receiving increasing concentrations of subcutaneous dexamethasone (Dex) pellets

A, Adrenal corticosterone levels. There was no statistical difference between the adrenal corticosterone levels with increasing dose of pellet Dex (n = 2–4 animals/group). B, Adrenal PNMT/actin mRNA ratio normalized for total RNA content. There are significantly higher levels of PNMT mRNA with increasing dose of Dex supplementation compared with placebo (P = 0.02 by ANOVA for Dex dose, n = 2–4 animals/group).

Fig. 2. Adrenal and plasma catecholamines in unstressed mice receiving increasing concentrations of subcutaneous Dex

A, Adrenal norepinephrine level normalized to protein content. There was a statistically significant increase in adrenal norepinephrine levels with increasing dose of exogenous Dex (P = 0.02 by ANOVA for Dex dose, n = 3–4 animals/group). B, Adrenal epinephrine levels among the different groups. There was a tendency toward a rise in adrenal epinephrine concentration with increasing dose of exogenous Dex (n = 3–4 animals/group). C, Plasma concentration of norepinephrine among the different groups. There was no significant difference between the plasma levels of norepinephrine with increasing dose of exogenous Dex (n = 3–4 animals/group). D, Plasma concentration of epinephrine. There was no significant difference between the plasma epinephrine concentrations of the different groups with increasing dose of exogenous Dex (n = 3–4 animals/group).

Fig. 3. Adrenal and plasma corticosterone and adrenal PNMT mRNA in restraint-stressed mice receiving increasing concentrations of intraperitoneal Dex

A, Adrenal concentration of corticosterone. There was a statistically significant decrease in adrenal corticosterone levels with increasing exogenous dose of Dex (P = 0.04 by ANOVA for Dex dose, n = 2–4 animals/group). B, Plasma corticosterone levels in the three stressed groups. There was a statistically significant decrease in plasma corticosterone levels with increasing dose of exogenous Dex (P = 0.04 by ANOVA for Dex dose, n = 2–4 animals/group). C, Adrenal PNMT/actin mRNA ratio normalized for total RNA content. There was a tendency for decreasing levels of PNMT mRNA levels with increasing Dex dose (n = 2–3 animals/group).

Fig. 4. Adrenal and plasma catecholamines in restraint-stressed mice receiving increasing concentrations of intraperitoneal Dex

A, Adrenal levels of norepinephrine among the three stressed groups. There was a statistically significant increase of the adrenal norepinephrine levels with exogenous Dex administration (P = 0.012 by ANOVA for Dex dose, n = 2–4 animals/group). B, Adrenal levels of epinephrine in the three stressed groups. There was a statistically significant increase of the adrenal epinephrine levels with exogenous dexamethasone administration (P = 0.02 by ANOVA for Dex dose, n = 2–4 animals/group). C, Plasma norepinephrine levels in the three stressed groups. There was no significant difference in plasma levels of norepinephrine between the control and Dex groups (n = 2–4 animals/group). D, Plasma epinephrine levels in the three stressed groups. There is a significant increase in plasma epinephrine level between the sham and the low-dose Dex group (P < 0.05). Although there is a tendency for plasma epinephrine to fall with high-dose Dex, this was not significant (n = 2–4 animals/group).