N-octanoyl dopamine, a non-hemodyanic dopamine derivative, for cell protection during hypothermic organ preservation.

BACKGROUND: Although donor dopamine treatment reduces the requirement for post transplantation dialysis in renal transplant recipients, implementation of dopamine in donor management is hampered by its hemodynamic side-effects. Therefore novel dopamine derivatives lacking any hemodynamic actions and yet are more efficacious in protecting tissue from cold preservation injury are warranted. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects. METHODOLOGY/PRINCIPAL FINDINGS: To this end, we assessed protection against cold preservation injury in HUVEC by the attenuation of lactate dehydrogenase (LDH) release. Modification of dopamine by an alkanoyl group increased cellular uptake and significantly improved efficacy of protection. Further variation revealed that only compounds bearing two hydroxy groups in ortho or para position at the benzene nucleus, i.e. strong reductants, were protective. However, other reducing agents like N-acetyl cysteine and ascorbate, or NADPH oxidase inhibition did not prevent cellular injury following cold storage. Unlike dopamine, a prototypic novel compound caused no hemodynamic side-effects. CONCLUSIONS/SIGNIFICANCE: In conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity. The novel dopamine derivatives might be of clinical relevance in donor pre-conditioning as they are completely devoid of hemodynamic action, their increased cellular uptake would reduce time of treatment and therefore also may have a potential use for non-heart beating donors.

Progesterone receptor membrane component 1--many tasks for a versatile protein.

The protein now called Progesterone Receptor Membrane Component 1 (PGRMC1) has been described independently by many groups in different cellular contexts. As a result it has been given an impressive diversity of names. While this protein was initially described on the basis of a singular property, e.g. expression or steroid binding, its possible physiological roles have only recently been reported. Current evidence supports the perception that PGRMC1 may be involved in sterol metabolism or homeostasis and cell survival. Here, we summarize a few sometimes neglected pieces of evidence from the literature along with unpublished findings on the properties and functions of PGRMC1.

Classic versus non-classic receptors for nongenomic mineralocorticoid responses: emerging evidence.

Mineralocorticoids, which are synthesized locally in the central nervous system in addition to their adrenal production, trigger both genomic and nongenomic responses. Several functions of mineralocorticoids in the CNS are known to date, which are reviewed along with nongenomic responses in other tissues. A controversy regarding the identity of receptors that mediate nongenomic, transcription-independent cellular responses to steroids is presently attracting considerable scientific interest. While there is strong evidence for classic receptors belonging to the nuclear receptor superfamily to mediate nongenomic steroid effects in some cases, it does not exist for others. Recent findings on new and unexpected properties of classic receptors have partially withdrawn the interest from novel, non-classic membrane receptors, which are being progressively identified at present. This has been facilitated by the robust and elaborate toolkit for classic receptor studies in contrast to the comparably immature research tools for alternative receptors. To know the nature of receptors involved may be the key to beneficial medical translation of specific and targeted steroid responses.

Mineralocorticoid receptor antagonists do not block rapid ERK activation by aldosterone.

Aldosterone can elicit rapid nongenomic effects both in vivo and in vitro, often mediated by signal transduction cascades. However, it is not understood how these rapid effects are initiated. In this study we show that aldosterone leads to rapid activation of mitogen activated protein kinases ERK1/2 in the cortical collecting duct cell line M-1. Inhibitors of transcription and translation could not block this activation, which suggests an extranuclear (nongenomic) mechanism. Although it is known that M-1 cells do not contain a transcriptionally functional MR, it is not known whether a closely related protein still could mediate the effects, or an unrelated nonclassic receptor. To test this hypothesis, the effects of four classical mineralocorticoid receptor antagonists were studied. None of the compounds could block the response to aldosterone. Altogether, the data suggest that rapid aldosterone effects in M-1 cells are initiated by a receptor different from the classical mineralocorticoid receptor.

Nongenomic steroid action: controversies, questions, and answers.

Steroids may exert their action in living cells by several ways: 1). the well-known genomic pathway, involving hormone binding to cytosolic (classic) receptors and subsequent modulation of gene expression followed by protein synthesis. 2). Alternatively, pathways are operating that do not act on the genome, therefore indicating nongenomic action. Although it is comparatively easy to confirm the nongenomic nature of a particular phenomenon observed, e.g., by using inhibitors of transcription or translation, considerable controversy exists about the identity of receptors that mediate these responses. Many different approaches have been employed to answer this question, including pharmacology, knock-out animals, and numerous biochemical studies. Evidence is presented for and against both the participation of classic receptors, or proteins closely related to them, as well as for the involvement of yet poorly understood, novel membrane steroid receptors. In addition, clinical implications for a wide array of nongenomic steroid actions are outlined.

Nongenomic effects of aldosterone: cellular aspects and clinical implications.

Nongenomic action of aldosterone has been observed in many cell types which often are different from the classic target tissues for mineralocorticoid action, such as vascular cells. As judged from their time scale and insensitivity toward inhibitors of protein synthesis, effects are not mediated by the classic mineralocorticoid receptor pathway. Here we summarize studies on rapid in vitro aldosterone effects, e.g. ion fluxes, and second messengers involved therein. Furthermore, several clinical studies on in vivo aldosterone action have shown rapid effects on cardiovascular parameters, among them baroreflex and vascular resistance. Taken together with the beneficial effect of aldosterone antagonism in heart failure patients that was demonstrated in the Randomized Aldactone Evaluation Study (RALES), aldosterone may be an equally important factor of the renin-angiotensin-aldosterone system in cardiovascular pathogenesis.