dinoprost and Hyperaldosteronism

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Water; Dinoprost; Female; Furosemide; Humans; Hyperaldosteronism; Hypertension; Indomethacin; Kallikreins; Kidney; Kinins; Male; Natriuresis; Prostaglandins; Prostaglandins E; Prostaglandins F; Renin; Renin-Angiotensin System; Spironolactone

The congestive heart failure (CHF) syndrome with soft tissue wasting, or cachexia, has its pathophysiologic origins rooted in neurohormonal activation. Mechanical cardiocirculatory assistance reveals the potential for reverse remodeling and recovery from CHF, which has been attributed to device-based hemodynamic unloading whereas the influence of hormonal withdrawal remains uncertain. This study addresses the signaling pathways induced by chronic aldosteronism in normal heart and skeletal muscle at organ, cellular/subcellular, and molecular levels, together with their potential for recovery (Recov) after its withdrawal. Eight-week-old male Sprague-Dawley rats were examined at 4 wk of aldosterone/salt treatment (ALDOST) and following 4-wk Recov. Compared with untreated, age-/sex-/strain-matched controls, ALDOST was accompanied by 1) a failure to gain weight, reduced muscle mass with atrophy, and a heterogeneity in cardiomyocyte size across the ventricles, including hypertrophy and atrophy at sites of microscopic scarring; 2) increased cardiomyocyte and mitochondrial free Ca(2+), coupled to oxidative stress with increased H(2)O(2) production and 8-isoprostane content, and increased opening potential of the mitochondrial permeability transition pore; 3) differentially expressed genes reflecting proinflammatory myocardial and catabolic muscle phenotypes; and 4) reversal to or toward recovery of these responses with 4-wk Recov. Aldosteronism in rats is accompanied by cachexia and leads to an adverse remodeling of the heart and skeletal muscle at organ, cellular/subcellular, and molecular levels. However, evidence presented herein implicates that these tissues retain their inherent potential for recovery after complete hormone withdrawal.

Topics: Animals; Cachexia; Calcium; Cardiomegaly; Dinoprost; Disease Models, Animal; Gene Expression Regulation; Heart Failure; Hydrogen Peroxide; Hyperaldosteronism; Male; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Muscle, Skeletal; Muscular Atrophy; Myocardium; Myocytes, Cardiac; Necrosis; Rats; Rats, Sprague-Dawley; Recovery of Function; Time Factors; Ventricular Remodeling

Chronic aldosterone/salt treatment (ALDOST) is accompanied by an adverse structural remodeling of myocardium that includes multiple foci of microscopic scarring representing morphologic footprints of cardiomyocyte necrosis. Our previous studies suggested that signal-transducer-effector pathway leading to necrotic cell death during ALDOST includes intramitochondrial Ca overloading, together with an induction of oxidative stress and opening of the mitochondrial permeability transition pore (mPTP). To further validate this concept, we hypothesized that mitochondria-targeted interventions will prove to be cardioprotective. Accordingly, 8-week-old male Sprague-Dawley rats receiving 4 weeks ALDOST were cotreated with either quercetin, a flavonoid with mitochondrial antioxidant properties, or cyclosporine A (CsA), an mPTP inhibitor, and compared with ALDOST alone or untreated, age/sex-matched controls. We monitored mitochondrial free Ca and biomarkers of oxidative stress, including 8-isoprostane and H2O2 production; mPTP opening; total Ca in cardiac tissue; and collagen volume fraction to quantify replacement fibrosis, a biomarker of cardiomyocyte necrosis, and employed terminal deoxynucleotidyl transferase dUTP nick end labeling assay to address apoptosis in coronal sections of ventricular myocardium. Compared with controls, at 4 weeks ALDOST we found a marked increase in mitochondrial H2O2 production and 8-isoprostane levels, an increased propensity for mPTP opening, and greater concentrations of mitochondrial free [Ca]m and total tissue Ca, coupled with a 5-fold rise in collagen volume fraction without any terminal deoxynucleotidyl transferase dUTP nick end labeling-based evidence of cardiomyocyte apoptosis. Each of these pathophysiologic responses to ALDOST was prevented by quercetin or cyclosporine A cotreatment. Thus, mitochondria play a central role in initiating the cellular-subcellular mechanisms that lead to necrotic cell death and myocardial scarring. This destructive cycle can be interrupted and myocardium salvaged with its structure preserved by mitochondria-targeted cardioprotective strategies.

Topics: Aldosterone; Animals; Antioxidants; Calcium; Cardiotonic Agents; Cyclosporine; Dinoprost; Hydrogen Peroxide; Hyperaldosteronism; Male; Mitochondria; Mitochondrial Membrane Transport Proteins; Myocardium; Myocytes, Cardiac; Oxidative Stress; Quercetin; Rats; Rats, Sprague-Dawley

Intracellular Ca(2+) overloading, coupled to induction of oxidative stress, is present at 4-wk aldosterone/salt treatment (ALDOST). This prooxidant reaction in cardiac myocytes and mitochondria accounts for necrotic cell death and subsequent myocardial scarring. It is intrinsically linked to increased intracellular zinc concentration ([Zn(2+)](i)) serving as an antioxidant. Herein, we addressed the temporal responses in coupled Ca(2+) and Zn(2+) dyshomeostasis, reflecting the prooxidant-antioxidant equilibrium, by examining preclinical (week 1) and pathological (week 4) stages of ALDOST to determine whether endogenous antioxidant defenses would be ultimately overwhelmed to account for this delay in cardiac remodeling. We compared responses in cardiomyocyte free [Ca(2+)](i) and [Zn(2+)](i) and mitochondrial total [Ca(2+)](m) and [Zn(2+)](m), together with biomarkers of oxidative stress and antioxidant defenses, during 1- and 4-wk ALDOST. At week 1 and compared with controls, we found: 1) elevations in [Ca(2+)](i) and [Ca(2+)](m) were coupled with [Zn(2+)](i) and [Zn(2+)](m); 2) increased mitochondrial H(2)O(2) production, cardiomyocyte xanthine oxidase activity, and cardiac and mitochondrial 8-isoprostane levels, counterbalanced by increased activity of antioxidant proteins, enzymes, and the nonenzymatic antioxidants that can be considered as cumulative antioxidant capacity; some of these enzymes and proteins (e.g., metallothionein-1, Cu/Zn-superoxide, glutathione synthase) are regulated by metal-responsive transcription factor-1; and 3) although these augmented antioxidant defenses were sustained at week 4, they fell short in combating the persistent intracellular Ca(2+) overloading and marked rise in cardiac tissue 8-isoprostane and mitochondrial transition pore opening. Thus a coupled Ca(2+) and Zn(2+) dyshomeostasis occurs early during ALDOST in cardiac myocytes and mitochondria that regulate redox equilibrium until week 4 when ongoing intracellular Ca(2+) overloading and prooxidants overwhelm antioxidant defenses.

Topics: Aldosterone; Animals; Calcium; Dinoprost; Disease Models, Animal; Glutathione Peroxidase; Homeostasis; Hyperaldosteronism; Male; Mitochondria, Heart; Myocytes, Cardiac; Necrosis; Nephrectomy; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sodium Chloride; Zinc

In studies on human skin fibroblasts originating from three patients with Bartter's syndrome and in corresponding age and sex matched controls, the bradykinin stimulated release of PGE2, PGI2, PGF2 alpha and of arachidonic acid was examined. The studies were aimed at demonstrating the possible changes of prostaglandin production under the influence of changing extracellular potassium concentrations (0-12 mmol K/l) in the two study groups. Earlier studies were confirmed and extended by one more pair of fibroblast cultures, showing a decreased bradykinin stimulated PGE2 production in fibroblasts from patients with Bartter's syndrome as compared to control. The difference in bradykinin stimulated PGE2 production was significant, irrespective of the extracellular potassium concentrations, to which the cultures were exposed. The bradykinin stimulated PGE2 and PGF2 alpha-production by control fibroblasts was directly proportional to extracellular potassium concentrations, whereas the PG-production of Bartter's syndrome fibroblasts remained uninfluenced by extracellular potassium. Extra- and intracellular potassium concentrations were directly proportional and there was no difference in this relationship between controls and Bartter's syndrome. The direct proportionality between bradykinin stimulated PGE2 production and potassium concentrations in control fibroblasts is, despite the apparent contradiction, in accordance with findings in the literature. The lack of a comparable proportionality in fibroblasts from patients with Bartter's syndrome is interpreted to correspond to an insensitivity to changes of potassium concentrations and thus to an insensitivity to one of the modulators of AA metabolism.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Bartter Syndrome; Bradykinin; Cells, Cultured; Child; Child, Preschool; Dinoprost; Dinoprostone; Fibroblasts; Humans; Hyperaldosteronism; Kinetics; Male; Potassium; Prostaglandins; Prostaglandins E; Prostaglandins F; Reference Values; Skin

In 2 adult patients with Bartter's syndrome, in whom chloride reabsorption at the diluting segment of the nephron was markedly reduced, serum potassium concentration could be improved with oral administration of a large amount of potassium chloride. In both cases, improvement of serum potassium levels with oral potassium load resulted in an increase in plasma renin activity (PRA) and plasma aldosterone concentration (PAC), a decrease in urinary excretion of prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha), and an improvement of pressor responsiveness to angiotensin II and norepinephrine. Treatment with indomethacin also improved the pressor responsiveness to angiotensin II and norepinephrine, but this occurred in association with a decrease in PRA, PAC and urinary excretion of PGE2 and PGF2 alpha. These results indicated that an event at the renal tubular level leading to potassium depletion is the most proximal pathogenetic defect in Bartter's syndrome, and that this in turn contributes to excessive prostaglandin production leading further to the decreased pressor responsiveness to vasoactive substances.

Topics: Aldosterone; Angiotensin II; Bartter Syndrome; Blood Pressure; Dinoprost; Dinoprostone; Female; Humans; Hyperaldosteronism; Hypokalemia; Indomethacin; Male; Middle Aged; Norepinephrine; Potassium; Potassium Chloride; Prostaglandins E; Prostaglandins F; Renin

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Bartter Syndrome; Child; Child, Preschool; Dinoprost; Epoprostenol; Female; Humans; Hyperaldosteronism; Infant; Kinetics; Male; Prostaglandins; Prostaglandins E; Prostaglandins F; Reference Values; Renin

Basal and bradykinin stimulated release of prostaglandins (6-oxo-PGF1 alpha, PGF2 alpha, PGE2) and of arachidonic acid (C20:4) from skin fibroblast cultures of two patients with Bartter's Syndrome were compared with age and sex matched controls. PG-formation from 14C-C20:4 was studied, and for PGE2 a radioimmunoassay was also employed. The data show that in basal release, Bartter's Syndrome fibroblasts produce significantly less PGE2 than controls. Stimulated release of 6-oxo-PGF1 alpha was higher, that of PGE2 lower and that of C2O:4 higher in Bartter's Syndrome than in controls, all differences being significant. Despite equal culturing conditions the estimated intracellular potassium was higher in the patients fibroblasts than in controls. In skin fibroblasts from patients with Bartter's Syndrome stimulated prostaglandin production from C2O:4 is mostly depressed, with the exeption of prostacyclin which is enhanced. The permeability of cell membranes for potassium might play a pathogenetic role.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Bartter Syndrome; Cells, Cultured; Child; Child, Preschool; Dinoprost; Dinoprostone; Fibroblasts; Humans; Hyperaldosteronism; Male; Potassium; Prostaglandins; Prostaglandins E; Prostaglandins F; Skin

Diagnostic value of plasma and urinary prostaglandins E2 and F2 alpha measurements was compared in 5 patients with Bartter's syndrome and 5 patients with pseudo-Bartter's syndrome. Bartter's syndrome is characterised by constant simultaneous increase of plasma and urinary PGE2; this hypersecretion is insufficiently suppressed by indomethacin treatment. Pseudo-Bartter's syndrome is characterised by normal urinary PGE2 excretion which is considerably decreased by indomethacin treatment at the same dose. The measurement of plasma and urinary prostaglandins helps to distinguish the Bartter's syndrome from pseudo-Bartter's syndrome.

Topics: Adolescent; Adult; Bartter Syndrome; Dinoprost; Dinoprostone; Humans; Hyperaldosteronism; Indomethacin; Male; Prostaglandins; Prostaglandins E; Prostaglandins F