Corticoides : 60 años después, una asignatura pendiente

El objetivo de este artículo es hacer una breve recopilación de la fisiología del eje hipotálamo-hipofisiario-suprarrenal, para comprender el papel de los corticoides exógenos como herramientas terapéuticas en innumerables patologías, que, utilizados de manera inapropiada, pueden causar efectos deletéreos importantes. La historia de los corticoides empezó hace 164 años, en 1843, cuando Thomas Addison describió los síntomas de la insuficiencia suprarrenal. Casi 100 años después, el 21 de septiembre de 1948, marcó un hito en la historia de la medicina, cuando, en la Clínica Mayo, el Dr. Hench inyectó 100 g de cortisona por primera vez en un paciente con artritis reumatoidea. En 1950, Hench, Kendall y Reichstein recibieron el Premio Nobel de Medicina y Fisiología. En la corteza de las glándulas suprarrenales se sintetizan, a partir del colesterol, tres hormonas diferentes con diversos efectos sobre la homeostasis. Los glucocorticoides sintéticos se clasifican por su potencia antiinflamatoria, vida media y efecto mineralocorticoide; operan en casi todas las células por medio de mecanismos de acción genómicos y no genómicos, lo que genera diferentes respuestas, de ahí su amplio efecto terapéutico en esclerosis múltiple, rechazo de trasplantes, enfermedades respiratorias, como asma y Epoc, entre otras.

Corticoides: 60 años después, una asignatura pendiente

El objetivo de este artículo es hacer una breve recopilación de la fisiología del eje hipotálamo-hipofisiario-suprarrenal, para comprender el papelde los corticoides exógenos como herramientas terapéuticas en innumerables patologías,que, utilizados de manera inapropiada, pueden causar efectos deletéreos importantes. La historia de los corticoides empezó hace 164 años, en 1843, cuando Thomas Addison describió los síntomas de la insuficiencia suprarrenal. Casi 100 años después, el 21 de septiembre de 1948, marcó un hito en la historia de la medicina, cuando, en la Clínica Mayo, el Dr. Hench inyectó 100 g de cortisona por primera vez en un paciente con artritis reumatoidea. En 1950, Hench, Kendall y Reichstein recibieron el Premio Nobel de Medicina y Fisiología. En la corteza de las glándulas suprarrenales se sintetizan, a partir del colesterol, tres hormonas diferentes con diversos efectos sobre la homeostasis. Los glucocorticoides sintéticos se clasifican por su potencia antiinflamatoria, vida media y efecto mineralocorticoide; operan en casi todas las células por medio de mecanismos de acción genómicos y no genómicos, lo que genera diferentes respuestas, de ahí su amplio efecto terapéutico en esclerosis múltiple, rechazo de trasplantes, enfermedades respiratorias, como asma y Epoc, entre otras.

Genomic and nongenomic stimulatory effect of aldosterone on H(+)-ATPase in proximal S3 segments

Leite-Dellova DC, Malnic G, Mello-Aires M. Genomic and non-genomic stimulatory effect of aldosterone on H(+)-ATPase in proximal S3 segments. Am J Physiol Renal Physiol 300: F682-F691, 2011. First published December 29, 2010; doi:10.1152/ajprenal.00172.2010.-The genomic and nongenomic effects of aldosterone on the intracellular pH recovery rate (pHirr) via H(-)(+)ATPase and on cytosolic free calcium concentration ([Ca(2+)](i)) were investigated in isolated proximal S3 segments of rats during superfusion with an Na(+)-free solution, by using the fluorescent probes BCECF-AM and FLUO-4-AM, respectively. The pHirr, after cellular acidification with a NH(4)Cl pulse, was 0.064 +/- 0.003 pH units/min (n = 17/74) and was abolished with concanamycin. Aldosterone (10(-12), 10(-10),10(-8), or 10(-6) M with 1-h or 15- or 2-min preincubation) increased the pHirr. The baseline [Ca(2+)](i) was 103 +/- 2 nM (n = 58). After 1 min of aldosterone preincubation, there was a transient and dose-dependent increase in [Ca(2+)](i) and after 6-min preincubation there was a new increase in [Ca(2+)](i) that persisted after 1 h. Spironolactone [mineralocorticoid (MR) antagonist], actinomycin D, or cycloheximide did not affect the effects of aldosterone (15- or 2-min preincubation) on pHirr and on [Ca(2+)](i) but inhibited the effects of aldosterone (1-h preincubation) on these parameters. RU 486 [glucocorticoid (GR) antagonist] and dimethyl-BAPTA (Ca(2+) chelator) prevented the effect of aldosterone on both parameters. The data indicate a genomic (1 h, via MR) and a nongenomic action (15 or 2 min, probably via GR) on the H(+)-ATPase and on [Ca(2+)](i). The results are compatible with stimulation of the H(+)-ATPase by increases in [Ca(2+)](i) (at 10(-12)-10(-6) M aldosterone) and inhibition of the H(+)-ATPase by decreases in [Ca(2+)](i) (at 10(-12) or 10(-6) M aldosterone plus RU 486).

Direct action of aldosterone on bicarbonate reabsorption in in vivo cortical proximal tubule

Pergher PS, Leite-Dellova D, de Mello-Aires M. Direct action of aldosterone on bicarbonate reabsorption in in vivo cortical proximal tubule. Am J Physiol Renal Physiol 296: F1185-F1193, 2009. First published February 18, 2009; doi:10.1152/ajprenal.90217.2008.-The direct action of aldosterone (10(-12) M) on net bicarbonate reabsorption (J(HCO3)(-)) was evaluated by stationary microperfusion of an in vivo middle proximal tubule (S2) of rat kidney, using H ion-sensitive microelectrodes. Aldosterone in luminally perfused tubules caused a significant increase in J(HCO3)(-) from a mean control value of 2.84 +/- 0.08 [49/19 (n degrees of measurements/n degrees of tubules)] to 4.20 +/- 0.15 nmol.cm(-2).s(-1) (58/10). Aldosterone perfused into peritubular capillaries also increased J(HCO3)(-), compared with basal levels during intact capillary perfusion with blood. In addition, in isolated perfused tubules aldosterone causes a transient increase of cytosolic free calcium ([Ca(2+)](i)), monitored fluorometrically. In the presence of ethanol ( in similar concentration used to prepare the hormonal solution), spironolactone (10(-6) M, a mineralocorticoid receptor antagonist), actinomycin D (10(-6) M, an inhibitor of gene transcription), or cycloheximide (40 mM, an inhibitor of protein synthesis), the J(HCO3)(-) and the [Ca(2+)](i) were not different from the control value; these drugs also did not prevent the stimulatory effect of aldosterone on J(HCO3)(-) and on [Ca(2+)](i). However, in the presence of RU 486 alone [10(-6) M, a classic glucocorticoid receptor (GR) antagonist], a significant decrease on J(HCO3)(-) and on [Ca(2+)](i) was observed; this antagonist also inhibited the stimulatory effect of aldosterone on J(HCO3)(-) and on [Ca(2+)](i). These studies indicate that luminal or peritubular aldosterone (10(-12) M) has a direct nongenomic stimulatory effect on J(HCO3)(-) and on [Ca(2+)](i) in proximal tubule and that probably GR participates in this process. The data also indicate that endogenous aldosterone stimulates J(HCO3)(-) in middle proximal tubule.

Genomic and nongenomic dose-dependent biphasic effect of aldosterone on Na(+)/H(+) exchanger in proximal S3 segment: role of cytosolic calcium

Leite-Dellova DC, Oliveira-Souza M, Malnic G, Mello-Aires M. Genomic and nongenomic dose-dependent biphasic effect of aldosterone on Na(+)/H(+) exchanger in proximal S3 segment: role of cytosolic calcium. Am J Physiol Renal Physiol 295: F1342-F1352, 2008. First published August 20, 2008; doi:10.1152/ajprenal.00048.2008.-The effects of aldosterone on the intracellular pH recovery rate (pHirr) via Na(+)/H(+) exchanger and on the [Ca(2+)](i) were investigated in isolated rat S3 segment. Aldosterone [10(-12), 10(-10), or 10(-8) M with 1-h, 15- or 2-min preincubation (pi)] caused a dose-dependent increase in the pHirr, but aldosterone (10(-6) M with 1-h, 15- or 2-min pi) decreased it (these effects were prevented by HOE694 but not by S3226). After 1 min of aldosterone pi, there was a transient and dose-dependent increase of the [Ca(2+)](i) and after 6-min pi there was a new increase of [Ca(2+)](i) that persisted after 1 h. Spironolactone, actinomycin D, or cycloheximide did not affect the effects of aldosterone (15 -or 2-min pi) but inhibited the effects of aldosterone (1-h pi) on pHirr and on [Ca(2+)](i). RU 486 prevented the stimulatory effect of aldosterone (10(-12) M, 15 -or 2-min pi) on both parameters and maintained the inhibitory effect of aldosterone (10(-6) M, 15- or 2-min pi) on the pHirr but reversed its stimulatory effect on the [Ca(2+)](i) to an inhibitory effect. The data indicate a genomic (1 h, via MR) and a nongenomic action (15 or 2 min, probably via GR) on [Ca(2+)](i) and on the basolateral NHE1 and are compatible with stimulation of the NHE1 by increases in [Ca(2+)](i) in the lower range (at 10(-12) M aldosterone) and inhibition by increases at high levels (at 10(-6) M aldosterone) or decreases in [Ca(2+)](i) (at 10(-6) M aldosterone plus RU 486).

Extracellular Signal-Regulated Kinase 1/2 Activation, via Downregulation of Mitogen-Activated Protein Kinase Phosphatase 1, Mediates Sex Differences in Desoxycorticosterone Acetate-Salt Hypertension Vascular Reactivity

Extracellular signal-regulated kinase (ERK) 1/2 has been reported to play a role in vascular dysfunction associated with mineralocorticoid hypertension. We hypothesized that, compared with female rats, an upregulation of ERK1/2 signaling in the vasculature of male rats contributes to augmented contractile responses in mineralocorticoid hypertension. Uninephrectomized male and female Sprague-Dawley rats received desoxycorticosterone acetate (DOCA) pellets (200 mg per animal) and saline to drink for 3 weeks. Control uninephrectomized rats received tap water to drink. Blood pressure, measured by telemetry, was significantly higher in male DOCA rats (191 +/- 3 mm Hg) compared with female DOCA rats (172 +/- 7 mm Hg; n=5). DOCA treatment resulted in augmented contractile responses to phenylephrine in aorta (22 +/- 3 mN; n=6) and small mesenteric arteries (13 +/- 2 mN; n=6) from male DOCA rats versus uninephrectomized male rats (16 +/- 3 and 10 +/- 2 mN, respectively; P<0.05) and female DOCA rats (15 +/- 1 and 11 +/- 1 mN, respectively). ERK1/2 inhibition with PD-98059 (10 mu mol/L) abrogated increased contraction to phenylephrine in aorta (14 +/- 2 mN) and small mesenteric arteries (10 +/- 2 mN) from male DOCA rats, without any effects in arteries from male uninephrectomized or female animals. Compared with the other groups, phosphorylated ERK1/2 levels were increased in the aorta from male DOCA rats, whereas mitogen-activated protein kinase phosphatase 1 expression was decreased. Interleukin-10 plasma levels, which positively regulate mitogen-activated protein kinase phosphatase 1 activity, were reduced in male DOCA-salt rats. We speculate that augmented vascular reactivity in male hypertensive rats is mediated via activation of the ERK1/2 pathway. In addition, mitogen-activated protein kinase phosphatase 1 and interleukin 10 play regulatory roles in this process. (Hypertension. 2010; 55: 172-179.)

Impaired Vasodilator Activity in Deoxycorticosterone Acetate-Salt Hypertension Is Associated With Increased Protein O-GlcNAcylation

Hyperglycemia, which increases O-linked beta-N-acetylglucosamine (O-GlcNAc) proteins, leads to changes in vascular reactivity. Because vascular dysfunction is a key feature of arterial hypertension, we hypothesized that vessels from deoxycorticosterone acetate and salt (DOCA-salt) rats exhibit increased O-GlcNAc proteins, which is associated with increased reactivity to constrictor stimuli. Aortas from DOCA rats exhibited increased contraction to phenylephrine (E(max) [mN] = 17.6 +/- 4 versus 10.7 +/- 2 control; n = 6) and decreased relaxation to acetylcholine (47.6 +/- 6% versus 73.2 +/- 10% control; n = 8) versus arteries from uninephrectomized rats. O- GlcNAc protein content was increased in aortas from DOCA rats (arbitrary units = 3.8 +/- 0.3 versus 2.3 +/- 0.3 control; n = 5). PugNAc (O- GlcNAcase inhibitor; 100 mu mol/L; 24 hours) increased vascular O- GlcNAc proteins, augmented phenylephrine vascular reactivity (18.2 +/- 2 versus 10.7 +/- 3 vehicle; n = 6), and decreased acetylcholine dilation in uninephrectomized (41.4 +/- 6 versus 73.2 +/- 3 vehicle; n = 6) but not in DOCA rats (phenylephrine, 16.5 +/- 3 versus 18.6 +/- 3 vehicle, n = 6; acetylcholine, 44.7 +/- 8 versus 47.6 +/- 7 vehicle, n = 6). PugNAc did not change total vascular endothelial nitric oxide synthase levels, but reduced endothelial nitric oxide synthase(Ser-1177) and Akt(Ser-473) phosphorylation (P < 0.05). Aortas from DOCA rats also exhibited decreased levels of endothelial nitric oxide synthase(Ser-1177) and Akt(Ser-473) (P < 0.05) but no changes in total endothelial nitric oxide synthase or Akt. Vascular O-GlcNAc-modified endothelial nitric oxide synthase was increased in DOCA rats. Blood glucose was similar in DOCA and uninephrectomized rats. Expression of O- GlcNAc transferase, glutamine: fructose-6-phosphate amidotransferase, and O- GlcNAcase, enzymes that directly modulate O-GlcNAcylation, was decreased in arteries from DOCA rats (P < 0.05). This is the first study showing that O-GlcNAcylation modulates vascular reactivity in normoglycemic conditions and that vascular O- GlcNAc proteins are increased in DOCA-salt hypertension. Modulation of increased vascular O-GlcNAcylation may represent a novel therapeutic approach in mineralocorticoid hypertension. (Hypertension. 2009; 53: 166-174.)

History of hypertension and eplerenone in patients with acute myocardial infarction complicated by heart failure

In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study ( n = 6632), eplerenone- associated reduction in all- cause mortality was significantly greater in those with a history of hypertension ( Hx- HTN). There were 4007 patients with Hx- HTN ( eplerenone: n = 1983) and 2625 patients without Hx- HTN ( eplerenone: n = 1336). Propensity scores for eplerenone use, separately calculated for patients with and without Hx- HTN, were used to assemble matched cohorts of 1838 and 1176 pairs of patients. In patients with Hx- HTN, all- cause mortality occurred in 18% of patients treated with placebo ( rate, 1430/ 10 000 person- years) and 14% of patients treated with eplerenone ( rate, 1058/ 10 000 person- years) during 2350 and 2457 years of follow- up, respectively ( hazard ratio [ HR]: 0.71; 95% CI: 0.59 to 0.85; P < 0.0001). Composite end point of cardiovascular hospitalization or cardiovascular mortality occurred in 33% of placebo-treated patients ( 3029/ 10 000 person- years) and 28% of eplerenone- treated patients (2438/10 000 person- years) with Hx- HTN ( HR: 0.82; 95% CI: 0.72 to 0.94; P = 0.003). In patients without Hx- HTN, eplerenone reduced heart failure hospitalization ( HR: 73; 95% CI: 0.55 to 0.97; P = 0.028) but had no effect on mortality ( HR: 0.91; 95% CI: 0.72 to 1.15; P = 0.435) or on the composite end point ( HR: 0.91; 95% CI: 0.76 to 1.10; P = 0.331). Eplerenone should, therefore, be prescribed to all of the post - acute myocardial infarction patients with reduced left ventricular ejection fraction and heart failure regardless of Hx- HTN.

Brain serotonin blockade and paradoxical salt intake in rats

Serotonin antagonism in the lateral parabrachial nucleus (LPBN) enhances sodium appetite induced by hypovolaemia and angiotensin-mineralocorticoid activation, but produces no sodium intake in euhydrated animals. In the present work, male adult rats (n=21) that received bilateral injections of the serotonergic antagonist methysergide (4 mug/ 0.2 mul) into the LPBN combined to intragastric load of 2 M NaCl (2 ml/rat), ingested hypertonic NaCl (ingestion of 4.3+/-1.6 ml/2 h of 0.3 M NaCl versus vehicle into LPBN: 0.2+/-0.2 ml/2 h, P<0.05). Methysergide- and vehicle-treated animals also ingested water (9.5+/-0.7 and 7.2+/-0.5 ml/2 h, respectively, P>0.05) as expected from the state of cell dehydration produced by the load. Ingestion of water (11.0+/-1.2 ml/2 h), and of 0.3 M NaCl (1.1+/-0.7 ml/2 h) were not altered by methysergide in NaCl loaded rats with misplaced LPBN injections (n=15). The ingestion of hypertonic NaCl by rats with serotonergic blockade in the LPBN suggests that the circuits subserving sodium appetite are activated, but at the same time strongly inhibited through the LPBN, during cell dehydration. (C) 2003 IBRO. Published by Elsevier Ltd. All rights reserved.

Central angiotensin II induces sodium bicarbonate intake in the rat

The aim of this work was to test mineral preference in hydrated rats that received a pulse intracerebroventricular (icv(p)) injection of ANG II at a dipsogenic dose (50 ng). The icv(p) ANG II induced a four-fold higher ingestion of 0.15 M NaHCO(3) than of other mineral solutions at palatable concentrations (0.15 M NaCl, 0.05 mM CaCl(2) and 0.01 M KCl) in a five-bottle test with water available in a fifth bottle; water intake was not consistently high in this test. Contrary to what is predicted by the mineralocorticoid/angiotensin II synergy hypothesis, the 0.15 M NaCl intake in the five-bottle test was not enhanced by icvp ANG H preceded by deoxycorticosterone (DOCA) treatment (2.5 mg/day for 3 days); neither was the NaHCO(3) intake. This result contrasted with the vigorous ingestion of both isotonic sodium solutions, but mostly of NaCl, rather than of other fluids, by sodium-depleted (furosemide 10 mg sc + 24 h removal ambient sodium) rats in a sodium appetite test. The results suggest that mineralocorticoid combined to icv(p) ANG II does not simulate the sodium preference shown during sodium appetite. The results also show that a dipsogenic dose of central ANG II induces a reliable ingestion of isotonic sodium bicarbonate in the rat. (C) 2007 Elsevier Ltd. All rights reserved.

Serotonergic receptor blockade in the lateral parabrachial nucleus: Different effects on hypertonic and isotonic NaCl intake

Hypertonic NaCl intake is produced by serotonin receptor antagonism in the lateral parabrachial nucleus (LPBN) of dehydrated rats or in rats pretreated with a mineralocorticoid, for example deoxycorticosterone (DOCA), that receive an intracerebroventricular injection (icv) of angiotensin II (ang II). The objective of the present work was to find out whether these two mechanisms are also involved with isotonic NaCl intake. Serotonin receptor blockade by methysergide in the LPBN (4 mu g/0.2 mu l bilaterally) had no effect on 0.15 M NaCl (methysergide: 19.3 +/- 5.2 ml/60 min; vehicle: 19.3 +/- 4.2 ml/60 min; n=7) or water (methysergide: 3.4 +/- 1.4 ml/ 60 min; vehicle 2.2 +/- 0.6 ml/60 min) intake induced by systemic diuretic furosemide combined with low dose of captopril (Furo/Cap). Methysergide treatment 4 days later in the same animals produced the expected enhancement in the 0.3 M NaCl intake induced by Furo/Cap (methysergide: 16.6 +/- 3.5 ml/60 min; vehicle: 6.6 +/- 1.5 ml/60 min). Similar result was obtained when another group was tested first with 0.3 M NaCl and later with 0.15 M NaCl. Isotonic NaCl intake induced by icv ang II was however enhanced by prior DOCA treatment. A de novo hypertonic NaCl intake was produced in another group by the same combined treatment. The results suggest that a facilitatory mechanism like the mineralocorticoid/ang II synergy may enhance NaCl solution intake at different levels of tonicity, while the action of an inhibitory mechanism, like the LPBN serotonergic system, is restricted to the ingestion at hypertonic levels. (c) 2007 Elsevier B.V. All rights reserved.

Aldosterone is not Involved in the Ventricular Remodeling Process Induced by Tobacco Smoke Exposure

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Serotonergic mechanisms of the lateral parabrachial nucleus and cholinergic-induced sodium appetite

Central cholinergic mechanisms are suggested to participate in osmoreceptor-induced water intake. Therefore, central injections of the cholinergic agonist carbachol usually produce water intake (i.e., thirst) and are ineffective in inducing the intake of hypertonic saline solutions (i.e., the operational definition of sodium appetite). Recent studies have indicated that bilateral injections of the serotonin receptor antagonist methysergide into the lateral parabrachial nucleus (LPBN) markedly increases salt intake in models involving the activation of the renin-angiotensin system or mineralocorticoid hormones. The present studies investigated whether sodium appetite could be induced by central cholinergic activation with carbachol (an experimental condition where only water is typically ingested) after the blockade of LPBN serotonergic mechanisms with methysergide treatment in rats. When administered intracerebroventricularly in combination with injections of vehicle into both LPBN, carbachol (4 nmol) caused water drinking but insignificant intake of hypertonic saline. In contrast, after bilateral LPBN injections of methysergide (4 mug), intracerebroventricular carbachol induced the intake of 0.3 M NaCl. Water intake stimulated by intracerebroventricular carbachol was not changed by LPBN methysergide injections. The results indicate that central cholinergic activation can induce marked intake of hypertonic NaCl if the inhibitory serotonergic mechanisms of the LPBN are attenuated.

Undernutrition fetal programming: effects on kidney morphology, renal steroid and angiotensin receptors expression and urinary sodium excretion

Maternal undernutrition affects the foetal development, promoting renal alterations and adult hypertension. The present study investigates, in adult male rats, the effect of food restriction in utero on arterial blood pressure changes (AP), and its possible association with the number of nephrons, renal function and angiotensin II (AT1R/AT2R), glucocorticoid (GR) and mineralocorticoid (MCR) receptors expression. The daily food supply to pregnant rats was measured and one group (n=5) received normal quantity of food (NF) while the other group received 50% of that (FR50) (n=5). The AP was measured weekly. At 16 weeks of life, fractionator’s method was used to estimate glomeruli number in histological slices. The renal function was estimate by creatinine and lithium clearances. Blood and urine samples were collected to biochemical determination of creatinine, sodium, potassium and lithium. At 90th and 23rd days of life, kidneys were also processed to AT1R, AT2R, GR and MCR immunolocalization and for western blotting analysis. FR50 offspring shows a significant reduction in BW (FR50: 5.67 ± 0.16 vs. 6.84 ± 0.13g in NF, P<0.001) and increased AP from 6th to 12nd week (6thwk FR50: 149.1 ± 3.4 vs. 125.1 ± 3.2mmHg in NF, P<0.001and, 12ndwk FR50: 164.4 ± 4.9 vs. 144.0 ± 3.3 mmHg in NF, P=0.02). Expression of AT1R and AT2R were significantly decreased in FR50 (AT1, 59080 ± 2709 vs. 77000 ± 3591 in NF, P=0.05; AT2, 27500 ± 95.50 vs. 67870 ± 1509 in NF, P=0.001) while the expression of GR increased in FR50 (36090 ± 781.5 vs. 4446 ± 364.5 in NF, P=0.0007). The expression of MCR did not change significantly. We also verified a pronounced decrease in fractional urinary sodium excretion in FR50 offspring (0.03 ± 0.02 vs. 0.06 ± 0.04 in NF, p=0.03). This occurred despite unchanged creatinine clearance. The study led us to suggest that fetal undernutrition, with increased fetal exposure... (Complete abstract click electronic access below)

Fetal kidney programming by severe food restriction: effects on structure, hormonal receptor expression and urinary sodium excretion in rats

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