Mineralocorticoid-induced Hypertension Research Articles

Abstract Mo064: Na + leak channel NALCN plays an essential role in mineralocorticoid-induced hypertension through nonrenal mechanisms.

In human and animal hyperaldosteronism-related hypertension, the increased blood volume has been regarded as a primary contributor to hypertension generation. However, increases in arterial contractility (and thus peripheral resistance) are also frequently reported in various hypertension models, including the mineralocorticoid-induced hypertensions such as DOCA-salt hypertension. Moreover, non-renal mechanisms (i.e., direct regulation on the cardiovascular ion channels) of the mineralocorticoid-induced hypertension are reportedly important. Na + -leak channel (NALCN) was first cloned as Na + /Ca 2+ channel family in 1999. However, its role in providing background cation conductance and contributing to normal neuronal excitability has been uncovered relatively recently and little is known about the roles of NALCN in cardiovascular system and pathogenesis of hypertension. Here, we show that aldosterone directly upregulates NALCN expression in arterial smooth muscle independent of kidney and contribute to the increases in arterial contractility, thereby contributing to the development of hypertension. Remarkably, mere the transient knockdown of arterial NALCN greatly ameliorated the development of hypertension along with arterial hypercontractility. Moreover, it is very interesting that our findings suggest that NALCN is activated by oxidative stimuli and this activation can be prevented by -gliflozin series SGLT2 inhibitors. From these, we propose that NALCN is a very promising and potent target for the treatment of various hypertensions including mineralocorticoid-related one.

Large animal models of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and multiple comorbidities. The number of patients is continuously increasing, with no improvement in its unfavorable prognosis, and there is a strong need for novel treatments. New devices and drugs are difficult to assess at the translational preclinical step due to the lack of high-fidelity large animal models of HFpEF. In this review, we describe the summary of historical and evolving techniques for developing large animal models. The representative methods are pressure overload models, including (1) aortic banding, (2) aortic stent, (3) renal hypertension, and (4) mineralocorticoid-induced hypertension. Diet-induced metabolic syndromes are also used. A new technique with an inflatable balloon inside the left ventricle can be used during acute/chronic in vivo surgeries to simulate HFpEF-like hemodynamics for pump-based therapies. Canines and porcine are most widely used, but other non-rodent animals (sheep, non-human primates, felines, or calves) have been used. Feline models present the most well-simulated HFpEF pathology, but small size is a concern, and the information is still very limited. The rapid and reliable establishment of large animal models for HFpEF, and novel methodology based on the past experimental attempts with large animals, are needed.

Mycophenolate Improves Brain–Gut Axis Inducing Remodeling of Gut Microbiota in DOCA-Salt Hypertensive Rats

Microbiota is involved in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzed whether MMF improves dysbiosis in mineralocorticoid-induced hypertension. Male Wistar rats were assigned to three groups: untreated (CTR), deoxycorticosterone acetate (DOCA)-salt, and DOCA treated with MMF for 4 weeks. MMF treatment reduced systolic BP, improved endothelial dysfunction, and reduced oxidative stress and inflammation in aorta. A clear separation in the gut bacterial community between CTR and DOCA groups was found, whereas the cluster belonging to DOCA-MMF group was found to be intermixed. No changes were found at the phylum level among all experimental groups. MMF restored the elevation in lactate-producing bacteria found in DOCA-salt joined to an increase in the acetate-producing bacteria. MMF restored the percentage of anaerobic bacteria in the DOCA-salt group to values similar to control rats. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. This study demonstrates for the first time that MMF reduces gut dysbiosis in DOCA-salt hypertension models. This effect seems to be related to its capacity to improve gut integrity due to reduced sympathetic drive in the gut associated with reduced brain neuroinflammation.

Mineralocorticoid receptor associates with pro-inflammatory bias in the hippocampus of spontaneously hypertensive rats.

Damage observed in the hippocampus of the adult spontaneously hypertensive rat (SHR) resembles the neuropathology of mineralocorticoid-induced hypertension, supporting a similar endocrine dysfunction in both entities. In the present study, we tested the hypothesis that increased expression of the hippocampal mineralocorticoid receptor (MR) in SHR animals is associated with a prevalent expression of pro-inflammatory over anti-inflammatory factors. Accordingly, in the hippocampus, we measured mRNA expression and immunoreactivity of the MR and glucocorticoid receptor (GR) using a quantitative polymerase chain reaction and histochemistry. We also measured serum-glucocorticoid-activated kinase 1 (Sgk1 mRNA), the number and phenotype of Iba1+ microglia, as well as mRNA expression levels of the pro-inflammatory factors cyclo-oxygenase 2 (Cox2), Nlrp3 inflammasome and tumour necrosis factor α (Tnfα). Expression of anti-inflammatory transforming growth factor (Tgf)β mRNA and the NADPH-diaphorase activity of nitric oxide synthase (NOS) were also determined. The results showed that, in the hippocampus of SHR rats, expression of MR and the number of immunoreactive MR/GR co-expressing cells were increased compared to Wistar-Kyoto control animals. Expression of Sgk1, Cox2, Nlrp3 and the number of ramified glia cells positive for Iba1+ were also increased, whereas Tgfβ mRNA expression and the NADPH-diaphorase activity of NOS were decreased. We propose that, in the SHR hippocampus, increased MR expression causes a bias towards a pro-inflammatory phenotype characteristic for hypertensive encephalopathy.

Protective effects of MCR-1329, a dual α1 and angII receptor antagonist, in mineralocorticoid-induced hypertension.

With the prototypical structures of losartan and prazosin as the axis of our research, MCR-1329 emerged as a potential designed multiple ligand from a series of compounds designed to possess dual antagonistic activity on the α1 and AT1 receptor. After confirming the activity of MCR-1329 in in vitro and acute in vivo models, the present study was undertaken to determine the efficacy of MCR-1329 in a mammalian test system. A rat model of deoxycorticosterone acetate (DOCA)-salt induced renal hypertension following unilateral nephrectomy was utilized to determine the effect of MCR-1329. For mechanistic evaluations, MCR-1329 was evaluated on rat aortic strips in vitro and on rat aortic smooth muscle cells to determine the role of MCR-1329 on phosphoinositide 3 kinase (PI3K) signaling. Results of the study showed that MCR-1329 prevents development of arterial hypertension. It was also observed that MCR-1329 upheld the intimal structures of major arteries like the thoracic aorta. Acetylcholine (Ach)-mediated relaxation remained intact in arteries from MCR-1329 treated animals. It was observed that MCR-1329 partially prevents Thr-308 phosphorylation of Akt following ligand-mediated receptor stimulation in vascular smooth muscle cells. Addition of LY294002 to the reaction medium caused a near-complete inhibition of Akt-phosphorylation. This suggested that MCR-1329 elicits its antihypertensive role by blocking activation of receptor-mediated PI3K-Akt downstream signaling as well as through preservation of arterial integrity. MCR-1329 has the potential to be evaluated further for clinical development as a potential antihypertensive agent with multiple mechanisms of action.

Vascular and Central Activation of Peroxisome Proliferator-Activated Receptor-β Attenuates Angiotensin II-Induced Hypertension: Role of RGS-5.

Activation of peroxisome proliferator-activated receptor-β/δ (PPARβ) lowers blood pressure in genetic and mineralocorticoid-induced hypertension. Regulator of G-protein-coupled receptor signaling 5 (RGS5) protein, which interferes in angiotensin II (AngII) signaling, is a target gene to PPARβ The aim of the present study was to examine whether PPARβ activation in resistance arteries and brain tissues prevents the elevated blood pressure in AngII-induced hypertension and evaluate the role of RGS5 in this effect. C57BL/6J male mice were divided into five groups (control mice, PPARβ agonist [4-[[[2-[3-Fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742)-treated mice AngII-infused mice, GW0742-treated AngII-infused mice, and AngII-infused mice treated with GW0742 plus PPARβ antagonist 3-[[[2-Methoxy-4-(phenylamino)phenyl]amino]sulfonyl]-2-thiophenecarboxylic acid methyl ester (GSK0660)) and were followed for 3 weeks. GW0742 prevented the increase in both arterial blood pressure and plasma noradrenaline levels and the higher reduction of blood pressure after ganglionic blockade, whereas it reduced the mesenteric arterial remodeling and the hyper-responsiveness to vasoconstrictors (AngII and endothelin-1) in AngII-infused mice. These effects were accompanied by an inhibition of NADPH oxidase expression and activity in the brain. Gene expression profiling revealed a marked loss of brainstem and vascular RGS5 in AngII-infused mice, which was restored by GW0742. GW0742-induced effects were abolished by GSK0660. Small interfering RNA targeting RGS5 caused augmented contractile response to AngII in resistance mesenteric arteries and blunted the inhibitory effect of GW0742 on this response. In conclusion, GW0742 exerted antihypertensive effects, restoring sympathetic tone and vascular structure and function in AngII-infused mice by PPARβ activation in brain and vessels inhibiting AngII signaling as a result of RGS5 upregulation.

Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats.

Inflammation contributes to ANG II-associated impairment of renal autoregulation and microvascular P2X1 receptor signaling, but its role in renal autoregulation in mineralocorticoid-induced hypertension is unknown. Autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. Hypertension was induced in uninephrectomized control rats (UNx) by subcutaneous implantation of a DOCA pellet plus administration of 1% NaCl in the drinking water (DOCA-salt) for 3 wk. DOCA-salt rats developed hypertension that was unaltered by anti-inflammatory treatment with pentosan polysulfate (DOCA-salt+PPS) but was suppressed with "triple therapy" (hydrochlorothiazide, hydralazine, and reserpine; DOCA-salt+TTx). Baseline arteriolar diameters were similar across all groups. UNx rats exhibited pressure-dependent vasoconstriction with diameters declining to 69 ± 2% of control at 170 mmHg, indicating intact autoregulation. DOCA-salt treatment significantly blunted this pressure-mediated vasoconstriction. Diameters remained between 91 ± 4 and 98 ± 3% of control over 65-170 mmHg, indicating impaired autoregulation. In contrast, pressure-mediated vasoconstriction was preserved in DOCA-salt+PPS and DOCA-salt+TTx rats, reaching 77 ± 7 and 75 ± 3% of control at 170 mmHg, respectively. ATP is required for autoregulation via P2X1 receptor activation. ATP- and β,γ-methylene ATP (P2X1 receptor agonist)-mediated vasoconstriction were markedly attenuated in DOCA-salt rats compared with UNx (P < 0.05), but significantly improved by PPS or TTx (P < 0.05 vs. DOCA-salt) treatment. Arteriolar responses to adenosine and UTP (P2Y2 receptor agonist) were unaffected by DOCA-salt treatment. PPS and TTx significantly reduced MCP-1 and protein excretion in DOCA-salt rats. These results support the hypothesis that hypertension triggers inflammatory cascades but anti-inflammatory treatment preserves renal autoregulation in DOCA-salt rats, most likely by normalizing renal microvascular reactivity to P2X1 receptor activation.

Heme Arginate Therapy Enhanced Adiponectin and Atrial Natriuretic Peptide, but Abated Endothelin-1 with Attenuation of Kidney Histopathological Lesions in Mineralocorticoid-Induced Hypertension

We investigated the role of heme oxygenase (HO), adiponectin, and atrial natriuretic peptide (ANP) in uninephrectomized (UnX) deoxycorticosterone-acetate (DOCA)-salt hypertensive rats, a volume-overload model characterized by elevated endothelin-1 (ET-1), mineralocorticoid-induced oxidative/inflammatory insults, fibrosis, hypertrophy, and severe renal histopathological lesions that closely mimic end-stage renal disease (ESRD). HO was enhanced with heme arginate (HA) or blocked with chromium mesoporphyrin (CrMP). Histological, morphological/morphometrical, quantitative reverse transcription-polymerase chain reaction, Western blot, enzyme immunoassay, and spectrophotometric analysis were used. Our experimental design included the following groups of rats: A, controls [surgery-free Sprague-Dawley, UnX-sham, UnX-salt (0.9% NaCl + 0.2% KCl), and UnX-DOCA]; B, UnX-DOCA-salt hypertensive; C, UnX-DOCA-salt + HA; D, UnX-DOCA-salt + HA + CrMP; E, UnX-DOCA-salt + CrMP; F, UnX-DOCA-salt + captopril; G, UnX-DOCA-salt + L-arginine; H, UnX-DOCA-salt + spironolactone; and I, UnX-DOCA-salt + vehicle. HA lowered blood pressure and abated kidney hypertrophy and renal lesions, including glomerulosclerosis, tubular dilation, tubular cast formation, interstitial mononuclear cell infiltration, glomerular hypertrophy, and renal-arteriolar thickening in UnX-DOCA hypertension. Correspondingly, HO activity, adiponectin, adenosine monophosphate-activated protein kinase (AMPK), ANP, cGMP, antioxidants such as bilirubin, ferritin, superoxide dismutase, and catalase, and total antioxidant capacity were increased, whereas ET-1, transforming growth factor beta (TGF-beta), fibronectin, and 8-isoprostane were abated. These were accompanied by reduced proteinuria/albuminuria, but increased creatinine clearance. Interestingly, HA was more renoprotective than sipronolactone, L-arginine, and captopril, whereas the HO blocker CrMP exacerbated oxidative injury, aggravating renal lesions and function. Because 8-isoprostane stimulates ET-1 to potentiate oxidative stress and fibrosis, up-regulating HO-1 enhanced tissue antioxidant status alongside cellular targets such as adiponectin, AMPK, ANP, and cGMP to suppress ET-1, TGF-beta, and fibronectin with a corresponding decline of renal lesions, proteinuria/albuminuria, and thus improved renal function. The potent renoprotection of HA could be explored to combat renal hypertrophy and histopathological lesions characteristic of ESRD.

Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats

Induction of heme-oxygenase (HO) is an important cellular defense mechanism against oxidative and inflammatory insults. We analyzed the effects of the HO inducer, heme-arginate, on the phospholipase C (PLC)/inositol-triphosphate (IP(3)) pathway in the mesenteric arterioles of uninephrectomized (UnX) deoxycorticosterone acetate (DOCA)-salt hypertensive rats, which is a volume-overload model characterized by elevated endothelin (ET-1) and mineralocorticoid-induced oxidative/inflammatory insults. Our study included the following groups: (A) controls [(i) surgery-free Sprague-Dawley (SD) rats, (ii) UnX-Sham, (iii) UnX-Salt (0.9% NaCl+0.2% KCl) and (iv) UnX-DOCA)]; (B) UnX-DOCA-salt hypertensive rats; (C) UnX-DOCA-salt+heme-arginate; (D) UnX-DOCA-salt+heme-arginate+chromium mesoporphyrin (CrMP), the HO inhibitor; (E) UnX-DOCA-salt+CrMP (F); SD+heme-arginate, (G) UnX-DOCA-salt+vehicle dissolving heme-arginate and CrMP and (H) normal-SD+heme-arginate. Quantitative reverse transcriptase PCR, western blot, enzyme immunoassay and spectrophotometric analyses were used. Heme-arginate enhanced mesenteric arteriole HO-1, HO activity, cyclic guanosine monophosphate (cGMP) and anti-oxidants including bilirubin, ferritin, superoxide dismutase with potentiation of the total anti-oxidant capacity. Correspondingly, oxidative/inflammatory mediators such as 8-isoprostane, nuclear-factor kappaB (NF-kappaB) and ET-1 were markedly reduced. Furthermore, heme-arginate suppressed PLC activity, attenuated IP(3) and reduced resting intracellular calcium. The effects of heme-arginate were nullified by the HO inhibitor, with aggravation of oxidative/inflammatory insults. In heme-arginate-treated SD rats, the HO system was potentiated to a lesser magnitude and the suppression of ET-1, PLC, IP(3) and NF-kappaB were less accentuated, suggesting greater selectivity of HO against the ET-1-PLC-IP(3)-NF-kappaB destructive axis in the pathological condition of mineralocorticoid-induced hypertension. Given that ET-1 stimulates PLC and IP(3), which in turn activates NF-kappaB, the concomitant reduction of ET-1, PLC, IP(3) and NF-kappaB alongside the corresponding decline of resting intracellular calcium may account for the reduction of blood pressure and attenuation of oxidative/inflammatory injury by heme-arginate.

The mammalian mineralocorticoid receptor: tying down a promiscuous receptor.

The mineralocorticoid receptor (MR) has been called a promiscuous receptor because its intrinsic affinity for aldosterone, cortisol and corticosterone is similar. Since glucocorticoids circulate in concentrations 100- to 1000-fold those of aldosterone, stoichiometry dictates that MR should be activated by glucocorticoids, not aldosterone, yet MRs are expressed in many tissues and regulate diverse functions, many of them under the regulation of the renin-angiotensin-aldosterone system. A relatively small number of brain MRs are aldosterone selective and modulate blood pressure. Evidence for possible mechanisms conferring ligand specificity in the context of mineralocorticoid-induced hypertension and the brain are discussed. These include factors (or mechanisms) intrinsic to the receptor, such as alternative splice variants and translation start sites, and extrinsic to the MR, including differential access through the blood-brain barrier, differential recruitment of co-regulators and scaffolding proteins, 11beta-steroid dehydrogenase activity, synthesis of potent acylated aldosterone derivatives and the synthesis of relevant amounts of aldosterone in areas of the brain that modulate blood pressure.

Adrenal corticosteroid effects in the central nervous system on long-term control of blood pressure

Adrenal corticosteroid effects in the central nervous system on long-term control of blood pressure

Pendrin as a regulator of ECF and blood pressure

Abnormal renal sodium handling plays a pivotal role in the pathophysiology of arterial hypertension. Though sodium is present in the diet as a chloride salt, most studies have focused on the renal mechanisms of sodium transport and their regulation, and very few have investigated the impact of chloride. However, strong evidence indicates that chloride may play a very important role in the 'prohypertensive' effects of sodium. Several observations indicate that sodium has to be administered as NaCl and not as NaHCO3 to raise arterial blood pressure. Recently, genetic studies have pointed out the critical role of the most distal parts of the nephron in regulating sodium balance and blood pressure. Interestingly, in those segments, the transport of Na+ and Cl- proceeds separately, through different molecules. Recent evidence has demonstrated that an apical Cl-/HCO3- exchanger called pendrin is an absolute requirement for chloride reabsorption in the collecting system, indicating that chloride absorption is not passive and paracellular but is mediated by the intercalated cells. Importantly, pendrin disruption protects mice against mineralocorticoid-induced hypertension and impairs renal adaptation to a low NaCl diet. Moreover, recent findings suggest several mechanisms by which chloride transport might affect NaCl balance and blood pressure. Pendrin-mediated chloride transport through intercalated cells appears to be an independent and important determinant of renal NaCl handling and therefore might represent a new target for blood pressure control.

Six Cases of Congenital Adrenal Hyperplasia That Were Due to 17α-hydroxylase/17,20-lyase Deficiency

α-hydroxylase/17,20-lyase deficiency is a rare phenotype of congenital adrenal hyperplasia (CAH), and this is characterized by hyporeninemic hypertension, primary amenorrhea and abnormality of the secondary sexual characteristics (pseudohermaphroditism in men). This typ e of CAH is usually misdiagnosed at first as mineralocorticoid induced hypertension with primary aldosteroni sm, but primary amenorrhea with deficient sex hormone is a clue for making the correct diagnosis. The authors experienced 6 cases of 17α -hydroxylase/17,20-lyase deficiency in patients who ranged from 15 to 42 years of age. 4 cases were diagnosed according to the investigation of their mineralocorticoid-induced hypertension and 2 cases their primary amenorrhea and sexual infantilism. All of them had hypokalemia, hyporeninemic hypertension and an atrophied uterus and ovaries. In the genotypic male (46 XY), the testicles were atrophied in the abdominal cavity. The levels of cortisol, estrogen and dehydroepiandroste rone sulfate (DHEAS) were low, but the levels of progesterone and 11-deoxycorticosterone were high. Therefore, the diagnosis of 17α-hydroxylase/17,20-lyase deficiency should be considered in female patients who present with both sexual infantilism and mineralocorticoid hypertension. We report on these cases with a brief review of the literature. (J Korean

Hemin therapy attenuates kidney injury in deoxycorticosterone acetate-salt hypertensive rats

Upregulating the heme oxygenase (HO) system removes the prooxidant heme, and thus is cytoprotective. Additionally, the products from the HO pathway including, carbon monoxide, bilirubin, and biliverdin, scavenge reactive oxygen species, inhibit lipid peroxidation, and suppress tissue inflammation, while the iron formed enhances the synthesis of the antioxidant ferritin. Deoxycorticosterone acetate (DOCA)-salt hypertension, a model of human primary aldosteronism, causes oxidative stress and impairs renal function by stimulating inflammatory/oxidative transcription factors such as NF-kappaB and activating protein (AP-1). The effect of the HO system in end-organ damage in mineralocorticoid-induced hypertension has not been fully characterized. In this study, the administration of the HO inducer hemin lowered blood pressure (191 vs. 135 mmHg; n = 22, P < 0.01), increased creatinine clearance, and reduced kidney hypertrophy proteinuria, albuminuria, and histopathological lesions, including glomerular hypertrophy, glomerulosclerosis, tubular dilation, tubular cast formation, and interstitial mononuclear cell infiltration in nephrectomy/DOCA-high-salt-hypertension. The renoprotection was accompanied by reduced levels of NF-kappaB, AP-1, fibronectin, transforming growth factor (TGF)-beta, and 8-isoprostane, a marker of oxidative stress. Correspondingly, a robust increase in total antioxidant capacity, HO activity, cGMP, and an antioxidant like ferritin was observed in hemin-treated animals. Our findings suggest that suppression of oxidative/inflammatory insults alongside the corresponding decline of fibronectin and TGF-beta, an activator of extracellular matrix proteins, may account for the attenuation of renal histopathological lesions and the antihypertrophic effects of hemin. The multifaceted interaction among the HO system, TGF-beta, fibronectin, AP-1, and NF-kappaB may be explored to design new drugs against end-stage-organ damage.

The Flame That Lights the Fire

Low-grade inflammation has acquired progressive recognition over the past few years as a mechanism for cardiovascular and renal damage. In hypertension, the activation of inflammatory mediators has been demonstrated in blood vessels, the heart, and the kidney in angiotensin (Ang) II–dependent models of hypertension, such as human angiotensinogen/human renin double transgenic rats1 and rats infused with Ang II,2 or in mineralocorticoid-induced hypertension.3 Both Ang II and endothelin-1 trigger an inflammatory process that participates in the mechanisms of hypertension. In a mouse model deficient in macrophages, the osteopetrotic mouse, Ang II- and endothelin-1–dependent hypertension were blunted together with oxidative stress generation, inflammatory mediator expression, vascular remodeling, and endothelial dysfunction.4,5 In human hypertension, inflammatory biomarkers, specifically C-reactive protein but also others, predict incident hypertension.6 Ang II exerts proinflammatory effects by stimulating redox-sensitive signaling cascades leading to mitogen-activated protein kinase activation, more specifically, p38 mitogen-activated protein kinase. Oxidative stress then stimulates inflammatory mediators, including nuclear factor κB and activator protein-1. These, in turn, trigger production of chemokines, such as monocyte chemoattractant peptide-1, involved in macrophage recruitment, and activation of proinflammatory and prothrombotic agents, such as plasminogen activator inhibitor-1, and adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1.7 These inflammatory actions may require …

Mineralocorticoid antagonism and cardiac hypertrophy

Aldosterone provides circulatory support by promoting reabsorption of sodium in exchange for potassium in the kidney. Mineralocorticoid receptors (MRs) are found in nonepithelial (vessel, heart, and brain) and epithelial tissues. Excess aldosterone may exert harmful effects by provoking hypertrophy and fibrosis in the cardiovascular system, thus contributing to reduced vascular compliance and increased ventricular stiffness. Primary aldosteronism is the most common cause of mineralocorticoid-induced hypertension, and MR antagonism offers the best prospect for achieving therapeutic goals. MR blockade also ameliorates pathological changes in the heart in the setting of low-aldosterone hypertension. The beneficial cardiac effects of MR antagonists are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by activation of MRs. MR antagonism thus may have wide therapeutic potential in various cardiovascular diseases, with its benefit not limited to those characterized by aldosterone or salt excess.

Protective effects of estradiol in the brain of rats with genetic or mineralocorticoid-induced hypertension

Abnormalities of hippocampus and hypothalamus are commonly observed in rats with genetic (SHR) or mineralocorticoid/salt-induced hypertension. In the hippocampus, changes include decreased cell proliferation in the dentate gyrus (DG), astrogliosis and decreased neuronal density in the hilus, whereas in the hypothalamus expression of arginine vasopressin (AVP) is markedly elevated. Here, we report that estradiol treatment overturns these abnormalities. We used 16-week-old male SHR with blood pressure (BP) approximately 190 mmHg and their normotensive Wistar-Kyoto (WKY) controls, and male Sprague-Dawley rats made hypertensive by administration of 10mg deoxycorticosterone acetate (DOCA) every other day plus 1% NaCl as drinking fluid for 4 weeks (BP approximately 160 mmHg). Controls received oil vehicle plus 1% NaCl only. Half of the animals in each group were implanted s.c. with a single estradiol benzoate pellet weighing 14 mg for 2 weeks. Estradiol-treated SHR and DOCA-salt rats showed, in comparison to their respective steroid-free groups: (a) enhanced proliferation in the DG measured by bromodeoxyuridine incorporation; (b) decreased number of glial fibrillary acidic protein (GFAP) immunopositive astrocytes; (c) increased density of neurons in the hilus of the DG, and (d) decreased hypothalamic AVP mRNA expression. These results indicate that neuronal and glial alterations of hypertensive models are plastic events reversible by steroid treatment. The estradiol protective effects may be of pharmacological interest to attenuate the consequences of hypertensive encephalopathy.

TNF-α inhibition reduces renal injury in DOCA-salt hypertensive rats

Studies suggest that the inflammatory cytokine TNF-alpha plays a role in the prognosis of end-stage renal diseases. We previously showed that TNF-alpha inhibition slowed the progression of hypertension and renal damage in angiotensin II salt-sensitive hypertension. Thus, we hypothesize that TNF-alpha contributes to renal inflammation in a model of mineralocorticoid-induced hypertension. Four groups of rats (n = 5 or 6) were studied for 3 wk with the following treatments: 1) placebo, 2) placebo + TNF-alpha inhibitor etanercept (1.25 mg.kg(-1).day(-1) sc), 3) deoxycorticosterone acetate + 0.9% NaCl to drink (DOCA-salt), or 4) DOCA-salt + etanercept. Mean arterial blood pressure (MAP) measured by telemetry increased in DOCA-salt rats compared with baseline (177 +/- 4 vs. 107 +/- 3 mmHg; P < 0.05), and TNF-alpha inhibition had no effect in the elevation of MAP in these rats (177 +/- 8 mmHg). Urinary protein excretion significantly increased in DOCA-salt rats compared with placebo (703 +/- 76 vs. 198 +/- 5 mg/day); etanercept lowered the proteinuria (514 +/- 64 mg/day; P < 0.05 vs. DOCA-salt alone). Urinary albumin excretion followed a similar pattern in each group. Urinary monocyte chemoattractant protein (MCP)-1 and endothelin (ET)-1 excretion were also increased in DOCA-salt rats compared with placebo (MCP-1: 939 +/- 104 vs. 43 +/- 7 ng/day, ET-1: 3.30 +/- 0.29 vs. 1.07 +/- 0.03 fmol/day; both P < 0.05); TNF-alpha inhibition significantly decreased both MCP-1 and ET-1 excretion (409 +/- 138 ng/day and 2.42 +/- 0.22 fmol/day, respectively; both P < 0.05 vs. DOCA-salt alone). Renal cortical NF-kappaB activity also increased in DOCA-salt hypertensive rats, and etanercept treatment significantly reduced this effect. These data support the hypothesis that TNF-alpha contributes to the increase in renal inflammation in DOCA-salt rats.

Phase I evaluation of abiraterone acetate (CB7630), a 17 alpha hydroxylase C17,20-Lyase inhibitor in androgen-independent prostate cancer (AiPC)

5064 Background: Abiraterone acetate (Ab) is an oral inhibitor of 17 alpha hydroxylase and C17,20-Lyase, which are important in adrenal androgen synthesis. A phase I study was undertaken to define the maximum tolerated dose (MTD) of Ab in patients (pts) with AIPC, the need for corticosteroid replacement (CSR) and the effects of Ab on hormone levels. Methods: Eligible pts had progressive AIPC by consensus criteria and normal organ and adrenal function. Dose escalations both while fasting and with food range from 250 mg to a maximum planned dose of 2,000 mg per day. Single dose pharmacokinetic (pK) analysis was performed prior to the onset of continuous daily dosing. Results: Sixteen pts have been enrolled, 3 with non-metastatic AIPC and 13 with bone/soft tissue metastases. Median PSA and testosterone levels are 26.7 and 7.7 ng/dL, respectively. Fourteen of 16 received prior ketoconazole. CSR has been required during the first month in 1 pt at a dose level of 500 and in 1 pt in month 3. Two pts experienced syncopal events (grade 3) on Ab, one at 250 mg and one at 500 mg, both after starting CSR. Mineralocorticoid-induced hypertension (grade 2) developed in 4 pts and was treated with aldosterone antagonists. Grade 1 edema has occurred in 3 pts. Testosterone became undetectable in 4/9 pts with available data, the mineralocorticoid deoxycorticosterone rose by a median 6.7 fold on therapy (range 1.5–67 fold). PK suggest maximum concentrations of Ab are achieved within 2 hr post dose with a mean t 1/2 of 7.8 hr, and interpatient variability in AUC and Cmax of approximately 2.5 fold. A decline in PSA by &gt;50% occurred in 7 of 14 patients (50%) completing the initial 28 days of treatment. Five of 9 pts with ketoconazole refractory disease experienced a &gt;50% reduction in PSA. Conclusions: Abiraterone appears to have moderate activity in AIPC pts (including significant activity in pts treated previously with ketoconazole) and an acceptable toxicity profile. CSR has not been consistently required. No significant financial relationships to disclose.

A Case of Ectopic ACTH Syndrome Associated with Small Cell Lung Cancer Presented with Hypokalemia

We report a case of a 73-year-old female patient who was diagnosed with ectopic ACTH syndrome caused by small cell lung cancer. We initially presumed that the patient was in a state of mineralocorticoid excess, because she had hypertension and hypokalemic alkalosis. This was however excluded because her plasma renin activity was not suppressed and her plasma aldosterone/plasma renin activity ratio was below 25. Moreover, her 24 hour urine free cortisol level was elevated and her serum cortisol levels after a low dose dexamethasone suppression test, were not suppressed. Furthermore, her basal plasma ACTH and serum cortisol levels increased and her serum cortisol level after a high dose dexamethasone suppression test was not suppressed. We performed studies to identify the source of ectopic ACTH syndrome and found a 3 cm-sized mass in the patient’s right lower lobe of her lung, which was eventually diagnosed as small cell lung cancer following a bronchoscopic biopsy. In conclusion, Cushing’s syndrome, and in particular ectopic ACTH syndrome, must be considered in the differential diagnosis of mineralocorticoid-induced hypertension. The excessive cortisol saturates the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity, which in turn, inactivates the conversion of cortisol to cortisone in the renal tubules. Moreover, excessive cortisol causes binding to the mineralocorticoid receptors, causing mineralocorticoid hypertension, characterized by severe hypercortisolism.