MineralocorticoidsFor decades, the role of aldosterone was thought to be limited to salt and water homeostasis control. This traditional view of the action of aldosterone restricted to sodium reabsorption in epithelial tissues must be revisited. Clinical trials have demonstrated the therapeutic benefit of MR blockade in heart failure of various origins. The beneficial effects of MR inhibition in patients with heart diseases emphasize the mineralocorticoids aldosterone of this receptor in cardiovascular tissue. Mineralocorticoids aldosterone progress have been made in understanding the pathological situations in which MR blockade is beneficial mineralocorticlids well as mineralocorticoids aldosterone mechanisms underlying the deleterious effects mineralocorticoids aldosterone MR activation. Experimental anabolic androgenic ratio prohormones indicated that chronic activation of the MR in target tissues induces structural and functional changes in the heart, kidneys and blood vessels.
Mineralocorticoid | definition of mineralocorticoid by Medical dictionary
In Canine and Feline Gastroenterology , Mineralocorticoids aldosterone , glucocorticoids cortisol, corticosterone , and sex steroids androgens, estrogens, progesterone are metabolized by the liver. Changes in the concentrations of total and free cortisol and of the binding capacity of corticosteroid-binding globulin have been reported in canine liver disease. Mineralocorticoids also exert their effects on blood pressure through actions in the brain.
Although mineralocorticoid receptors have been observed in the hippocampus and hypothalamus, their role was difficult to determine until relatively recently. In a series of elegant experiments, Elise Gomez-Sanchez demonstrated that infusion of minute quantities of aldosterone into the ventricles of the brain induces hypertension in animals after 14 days. The hypertension could be blocked by the intraventricular infusion of either a mineralocorticoid receptor antagonist or by amiloride.
The observed increase in blood pressure in this model could be enhanced with sodium loading but was not dependent on it.
This central form of hypertension appears to be mediated by a generalized increase in sympathetic tone with an accompanying rise in vascular resistance. Thus concentrations of aldosterone, which would produce no visible systemic effect, can produce hypertension when placed directly into the brain.
Portman 2 , in Endocrinology of the Heart in Health and Disease , Mineralocorticoids are a class of steroid hormones that influence salt and water balance. The primary mineralocorticoid is aldosterone, but other endogenous hormones such as progesterone and deoxycorticosterone have mineralocorticoid function.
Aldosterone, produced in the adrenal gland cortex, is induced primarily by angiotensin II see Chapter 9, Renin Angiotensin Aldosterone System and Heart Function and is regulated by adrenocorticotrophin hormone ACTH and potassium levels. The mineralocorticoid receptor MR is a NR found in the cytosol that crosses the lipid bilayer of the cell with equal affinity for mineralocorticoids and glucocorticoids e. The MR consists of three domains: In the absence of ligand, the MR interacts with heat shock proteins to prevent the transcription of these target genes.
MRs are expressed in many different tissues and cell types, including cardiomyocytes, vascular smooth muscle and coronary endothelial cells, fibroblasts, and inflammatory cells. This is surprising since plasma concentrations of cortisol are to fold higher than aldosterone. Mineralocorticoids increase absorption of sodium and secretion of potassium in the kidney, sweat glands, salivary glands, and intestinal epithelial cells.
Thus aldosterone is critical in conserving body salt. The main site of action in the kidneys is the distal nephron principal cells of the connecting segment and collecting tubules where aldosterone promotes tubular resorption of sodium and chloride and excretion of potassium Rose, In the connecting segment and cortical collecting tubule, aldosterone increases the number of sodium and potassium channels in the luminal membrane and increases the activity of the sodium-potassium adenosine triphosphatase ATPase pump in the basolateral membrane.
Chloride is passively absorbed via the paracellular pathway. Potassium is exchanged for sodium by the sodium-potassium ATPase pump and then secreted from the cell into the lumen. Aldosterone also enhances sodium reabsorption but not potassium secretion in the papillary collecting tubules and causes secretion of hydrogen ions in exchange for sodium in the intercalated cells of the cortical collecting tubules.
Thus a deficiency of aldosterone causes a mild metabolic acidosis. Aldosterone also reduces the concentration of sodium and raises the concentration of potassium in sweat, saliva, and colonic secretions. Volume 3 Sixth Edition , Mineralocorticoids are adrenal steroids that have their principal effects on ion transport by epithelial cells, resulting in a loss of potassium and conservation of sodium. The most potent and important naturally occurring mineralocorticoid is aldosterone.
In the distal convoluted tubule of the mammalian nephron, a cation exchange mechanism exists for the resorption of sodium from the glomerular filtrate and secretion of potassium into the lumen. These reactions are accelerated by mineralocorticoids and proceed at a slower rate in their absence. A lack of secretion of mineralocorticoids such as in idiopathic adrenal atrophy of dogs may result in a lethal retention of potassium and loss of sodium.
Glucocorticoid hormones secreted by the adrenal cortex are involved with the intermediary metabolism of glucose. Cortisol and lesser amounts of corticosterone are the most important naturally occurring glucocorticoids secreted by the adrenal gland in domestic animals.
In general, the actions of glucocorticoids on carbohydrate, protein, and lipid metabolism result in sparing of glucose and a tendency to hyperglycemia and increased glucose production. The acute effects of glucocorticoids are observed minutes before the compensatory effects of insulin become prominent. There is a decrease in glucose uptake in adipose tissue, skin, fibroblasts, and lymphoid tissue, followed shortly by increased catabolism in these tissues and muscle.
This provides amino acids for gluconeogenesis, which is increased mainly in the liver. In addition, glucocorticoids decrease lipogenesis and increase lipolysis in adipose tissue, which results in release of glycerol and free fatty acids. Glucocorticoids also function to suppress inflammatory and immunologic responses and thereby attenuate the associated tissue destruction and fibroplasia. However, under the influence of high levels of glucocorticoids, there is enhancement of the spread of infections and reduced resistance to a number of bacterial, viral, and fungal diseases.
Glucocorticoids may impair the immunologic response at any stage from the initial interaction and processing of antigens through the induction and proliferation of immunocompetent lymphocytes and subsequent antibody production. Inhibition of a number of lymphoid cell functions by glucocorticoids forms part of the basis for suppression of the immunologic response. Glucocorticoids also decrease the initial inflammatory reaction and its classic manifestations of heat, swelling, and pain.
The degree of hyperemia, extravasation, cellular migration, and infiltration at the site of injury is decreased. Especially important are the effects of glucocorticoids on the vascular responses of increased permeability, diapedesis, and extravasation. Capillary blood flow is decreased, and there is less endothelial swelling. In addition, a number of phagocytic mechanisms are inhibited by glucocorticoids, and clearance of particulate substances from the blood and lymph is impaired.
The accumulation of engulfed antigens in macrophages probably is related to the enhanced stability of lysosomal membranes caused by glucocorticoids. There is a diminished capacity of lysosomes to interact with phagocytized material and release hydrolytic enzymes.
Glucocorticoids exert a negative effect on wound healing. Dogs receiving high therapeutic levels of adrenal corticosteroids or animal patients with hyperadrenocorticism may have wound dehiscence following surgery. The basis mechanism involved is inhibition of fibroblast proliferation and collagen synthesis, leading to a decrease in scar tissue formation.
Secretion of adrenal sex hormones by cells of the zona reticularis occurs under normal conditions but in minute amounts that probably are of minor physiologic significance. Secretory cells of the inner zone of the cortex synthesize progesterone, estrogens, and androgens. Under pathologic conditions, excessive secretion of adrenal sex steroids infrequently may occur associated with an adrenocortical neoplasm.
The clinical manifestations of virilism, precocious sexual development, or feminization depend upon which steroid is secreted in excess, the sex of the patient, and the age of onset. The renin-angiotensin system is the major regulator of aldosterone production by the zona glomerulosa of the adrenal cortex. Renin is an enzyme secreted into the circulation by cells of the juxtaglomerular apparatus in the kidney.
It acts to cleave the plasma globulin angiotensinogen, to form angiotensin I. This decapeptide is further hydrolyzed to angiotensin II by a converting enzyme. Angiotensin II is both a potent vasoconstrictor and a trophic hormone for the zona glomerulosa of the adrenal cortex, resulting in the synthesis and secretion of aldosterone.
It is a very labile peptide that is quickly inactivated in plasma and tissues by angiotensinases. A number of factors regulate renin secretion by the kidney. Renin release and eventually aldosterone secretion are increased by conditions that compromise blood flow and pressure to the kidney, severe dehydration that results in decreased intravascular blood volume, and sodium depletion.
Adrenocorticotropin ACTH secreted by the adenohypophysis is the principal regulator of adrenal cortical growth and secretory activity, particularly of cells in the zonae fasciculata and reticularis. The adrenal cortex secretes physiologic quantities of cortisol only in response to ACTH stimulation. The zona glomerulosa and its secretion of aldosterone is responsive to ACTH, but at a lower level compared to the zonae fasciculata and reticularis. Cyclic AMP stimulates certain key enzymes e.
Control of the secretion of ACTH by the adenohypophysis is governed by the hypothalamus largely through the secretion of corticotropin-releasing hormone CRH. This peptide is secreted by neurons of the hypothalamus into capillaries that form the hypothalamic-pituitary portal system and convey CRH to corticotrophs of the pituitary.
Arginine-vasopressin produced in neurons of the hypothalamus may also play a role in regulation of secretion of ACTH in some species. Negative feedback control of ACTH secretion is exerted primarily by the circulating level of cortisol acting on secretory cells in the hypothalamus and adenohypophysis.
When plasma cortisol levels are elevated beyond the normal physiologic range as occurs following exogenous administration or with a cortisol-producing adrenal tumor , ACTH secretion is suppressed, secretory cells in the zonae fasciculata and reticularis decrease the rate of synthesis and release of corticosteroid hormones, and the adrenal cortex undergoes trophic atrophy.
Conversely, when cortisol levels are subnormal, there is increased release of ACTH from the pituitary gland in an attempt to increase cortisol secretion and return blood levels toward normal. Mineralocorticoids are by definition adrenal steroids that regulate electrolyte balance; however, in the context of the central nervous system CNS , this has limited relevance except perhaps in the context of the central regulation of sodium balance.
In classical sodium transporting epithelia such as the distal nephron or the distal colon, aldosterone, the primary physiological mineralocorticoid acts via the mineralocorticoid receptor MR to mediate vectorial sodium transport, and indeed to regulate potassium and hydrogen ion homeostasis both indirectly and also directly Fuller and Young, Mineralocorticoid action is arguably synonymous with activation of the MR and this receptor is the focus of this chapter.
The MR is however much more than just a mineralocorticoid receptor. The MR binds aldosterone and the physiological glucocorticoid, cortisol or corticosterone in rodents. Cortisol also binds to the closely related glucocorticoid receptor GR. Indeed, when these receptors were first identified using tritiated ligands in radioreceptor assays, two corticosteroid receptors were identified and designated type 1 and 2 Feldman et al. These are now more usually known as the MR and the GR, respectively.
These receptors are members of the nuclear receptor superfamily which numbers 48 in the human Mangelsdorf et al. They are closely related to the androgen AR and progesterone PR receptors, the homology being less for the estrogen receptor ER Arriza et al. These nuclear receptors, although primarily ligand-dependent transcription factors, can also exhibit nontranscriptional effects and, in the case of the ER, ligand-independent effects Gruber et al.
The basic model of steroid hormone action Figure 1 has the receptor being held in a high affinity but transcriptionally inactive state in the cytoplasm; ligand binding induces a conformational change in the receptor which results in dissociation from the hsp90 complex and translocation to the nucleus where target genes are activated or repressed with corresponding changes in specific mRNAs and hence the encoded proteins which mediate the physiological response Feldman et al.
The MR is expressed in differentiated polarized epithelia, differentiated neurons, and intact blood vessels among other tissues. There is a paucity of in vitro models which adequately reflect the in vivo situation. Where cell lines have been developed, their longevity has generally been limited. That being said, the last decade has seen a significant expansion of our knowledge of the MR. Abdel-Rahman, in Advances in Pharmacology , Mineralocorticoids are physiologically important for the regulation of sodium and water in humans and other species.
This form of production of hypertension has been employed in primates, pigs, dogs, and rodents with much success. With additional salt administration that is absolutely required for development, this form of hypertension has been associated with increased release of vasopressin leading to water retention and vasoconstriction and elevated activity of the RAAS leading to elevated SNS activity. The sustained form of hypertension appears to be low-renin salt dependent and has been used to evaluate the ability of ET antagonists to reduce blood pressure as the ET system is involved in the production of low-renin hypertension van den Meiracker, While the DOCA—salt model is one of the more routinely used forms of endocrine-induced hypertension, recent advances in knowledge regarding the regulation of blood pressure have suggested other interventions that may be important, leading to the development of other models that include chronic administration of AT II using osmotic mini-pumps and the cholinergic agonists, physostigmine, or oxotremorine.