Diverse Effects of Stress and Additional Adrenocorticotropic Hormone on Digitalis‐Like Compounds in Normal and Nude Mice

Abstract

Digitalis-like compounds (DLC) are steroidal hormones that are synthesized in, and released from, the adrenal gland, whose regulation may be directed by the hypothalamic-pituitary-adrenal (HPA) axis. Increasing evidence points to antitumour properties of these compounds and we hypothesized that the establishment of tumours in athymic nude mice may be facilitated by an abnormal synthesis or secretion of DLC. To explore this hypothesis, DLC concentrations were determined in the plasma, and in adrenal and hypothalamic tissues of nude compared to normal mice under basal conditions, and 30 min after a stress stimulus (i.p. injection of 100 micro l saline) with or without additional adrenocorticotropic hormone (ACTH) 1 micro g/per animal. Simultaneously, plasma corticosterone and serum adrenocorticotropic hormone (ACTH) concentrations were analysed. The basal DLC concentrations were similar in the plasma and the hypothalamus of both strains, whereas the basal adrenal DLC concentration was significantly lower in the nude mice compared to normal mice. The stress stimulus induced in normal mice a significant increase in DLC concentrations in the adrenal gland, the plasma and the hypothalamus. However, in nude mice, it caused an increase only in the adrenal gland and the hypothalamus, whereas the plasma DLC concentration was not affected. In both strains, the administration of ACTH in addition to injection stress did not provoke a further increase in DLC concentrations while inducing a significant increase in plasma corticosterone concentration. Regardless of the applied stimulus, the nude mice expressed significant lower DLC concentrations in the adrenal gland and the plasma compared to normal mice. The low basal adrenal DLC concentration in nude mice and their impaired DLC response towards stress- and ACTH stimulation both support an involvement of DLC in tumorigenesis.

Endogenous Cardiotonic Steroids: Physiology, Pharmacology, and Novel Therapeutic Targets

“…These observations demonstrate that very dramatic effects of EO may be transient. This finding seems to be in agreement with reports demonstrating that EO can be implicated in behavioral stress (Goto et al, 1995, Weidemann et al, 2004) and via activation of hypothalamic-pituitary-adrenocortical axis contributes to the onset of NaCl-sensitive hypertension, which was discussed previously (Fedorova et al, 2005a). …”

“…It is noteworthy that CTS may also be involved in cancer development. In a group of 84 patients with breast cancer, 73.6% had plasma levels of digitalis-immunoreactive CTS that were 3 times lower than those seen in control subjects, whereas 10.8% of these patients with cancer exhibited extremely high CTS levels (Weidemann et al, 2004; Weidemann, 2005). Therapeutic strategies involving either addition of or antagonism of CTS are currently under development (Mijatovic et al, 2007).…”

The neural substrates of rapid-onset Dystonia-Parkinsonism

“…Endo-ouabain is produced by adrenal cortex and the hypothalamus and is indistinguishable from ouabain 45 . Interestingly, stress and exercise increase endo-ouabain levels by as much as 18 fold 46,47 . As delineated earlier we found that perfusion of higher concentrations of ouabain into the cerebellum and basal ganglia precipitate the symptoms seen in RDP in the absence of stress.…”

The digitalis-like steroid hormones: New mechanisms of action and biological significance

“…It was demonstrated that in tissue culture, adrenal cortical cells release DLC in response to angiotensin II (Laredo et al, 1994;Laredo et al, 1997) and ACTH (Laredo et al, 1994). Furthermore, DLC release in vivo has been shown to be stimulated by physical exercise in humans and dogs (Bauer et al, 2005), hypoxia (De Angelis and Haupert, 1998) and behavioral stress (Fedorova et al, 2001;Weidemann et al, 2004) in rodents, and chronic high salt intake in man (Manunta et al, 2006). DLC were also shown to be released from the rat brain, the process stimulated by ANP (Crabos et al, 1988) and hypoxia (De Angelis and Haupert, 1998).…”