[Complex right cervical aortic arch repair: less is more]. / Riparazione di arco aortico cervicale destroposto: "less is more".

Cervical aortic arch is a rare malformation that often has anatomical abnormalities of the supra-aortic trunks and may also be associated with aortic stenosis, aneurysms, or cardiac malformations. To correct them, symptomatic patients undergo surgery, which usually consists of a prosthetic graft repair, aortoplasty patch, or an end-to-end anastomosis. In addition, circulatory arrest and deep hypothermia are often required, as in aortic arch surgery. We report the case of a 13-year-old patient who underwent correction of a right cervical aortic arch stenosis with a post-stenotic aneurysm between the origin of the right carotid artery and the right subclavian artery. The anatomy of the aortic branches was abnormal. The surgical procedure consisted of an extensive resection with direct end-to-end anastomosis, without the use of a prosthetic graft, using moderate hypothermic cardiopulmonary bypass and without circulatory arrest.

Rostafuroxin protects from podocyte injury and proteinuria induced by adducin genetic variants and ouabain.

Glomerulopathies are important causes of morbidity and mortality. Selective therapies that address the underlying mechanisms are still lacking. Recently, two mechanisms, mutant ß-adducin and ouabain, have been found to be involved in glomerular podocytopathies and proteinuria through nephrin downregulation. The main purpose of the present study was to investigate whether rostafuroxin, a novel antihypertensive agent developed as a selective inhibitor of Src-SH2 interaction with mutant adducin- and ouabain-activated Na,K-ATPase, may protect podocytes from adducin- and ouabain-induced effects, thus representing a novel pharmacologic approach for the therapy of podocytopathies and proteinuria caused by the aforementioned mechanisms. To study the effect of rostafuroxin on podocyte protein changes and proteinuria, mice carrying mutant ß-adducin and ouabain hypertensive rats were orally treated with 100 µg/kg per day rostafuroxin. Primary podocytes from congenic rats carrying mutant α-adducin or ß-adducin (NB) from Milan hypertensive rats and normal rat podocytes incubated with 10(-9) M ouabain were cultured with 10(-9) M rostafuroxin. The results indicated that mutant ß-adducin and ouabain caused podocyte nephrin loss and proteinuria in animal models. These alterations were reproduced in primary podocytes from NB rats and normal rats incubated with ouabain. Treatment of animals, or incubation of cultured podocytes with rostafuroxin, reverted mutant ß-adducin- and ouabain-induced effects on nephrin protein expression and proteinuria. We conclude that rostafuroxin prevented podocyte lesions and proteinuria due to mutant ß-adducin and ouabain in animal models. This suggests a potential therapeutic effect of rostafuroxin in patients with glomerular disease progression associated with these two mechanisms.

Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 1: experimental studies.

Essential hypertension is a complex, multifactorial disease associated with a high cardiovascular risk and whose genetic-molecular basis is heterogeneous and largely unknown. Although multiple antihypertensive therapies are available, the large individual variability in drug response results in only a modest reduction of the cardiovascular risk and unsatisfactory control of blood pressure in the hypertensive population as a whole. Two mechanisms, among others, are associated with essential hypertension and related organ damage: mutant α-adducin variants and high concentrations of endogenous ouabain. An antihypertensive agent, rostafuroxin, selectively inhibits these mechanisms in rodents. We investigated the molecular and functional effects of mutant α-adducin, ouabain, and rostafuroxin in hypertensive rats, human cells, and cell-free systems and demonstrated that both mutant α-adducin variants and the ouabain-Na,K-ATPase (Na(+)- and K(+)-dependent adenosine triphosphatase) complex can interact with the Src-SH2 (Src homology 2) domain, increasing Src activity and the Src-dependent Na,K-ATPase phosphorylation and activity. Wild-type α-adducin or Na,K-ATPase in the absence of ouabain showed no interaction with the Src-SH2 domain. Rostafuroxin disrupted the interactions between the Src-SH2 domain and mutant α-adducin or the ouabain-Na,K-ATPase complex and blunted Src activation and Na,K-ATPase phosphorylation, resulting in blood pressure normalization in the hypertensive rats. We have also shown the translatability of these data to humans in a pharmacogenomic clinical trial, as described in the companion paper.

Organ hypertrophic signaling within caveolae membrane subdomains triggered by ouabain and antagonized by PST 2238.

In addition to inhibition of the Na-K ATPase, ouabain activates a signal transduction function, triggering growth and proliferation of cultured cells even at nanomolar concentrations. An isomer of ouabain (EO) circulates in mammalians at subnanomolar concentrations, and increased levels are associated with cardiac hypertrophy and hypertension. We present here a study of cardiac and renal hypertrophy induced by ouabain infused into rats for prolonged periods and relate this effect to the recently described ouabain-induced activation of the Src-EGFr-ERK signaling pathway. Ouabain infusion into rats (15 microg/kg/day for 18 weeks) doubled plasma ouabain levels from 0.3 to 0.7 nm and increased blood pressure by 20 mm Hg (p < 0.001), cardiac left ventricle (+11%, p < 0.05), and kidney weight (+9%, p < 0.01). These effects in vivo are associated with a significant enrichment of alpha1, beta1, gammaa Na-K ATPase subunits together with Src and EGFr in isolated renal caveolae membranes and activation of ERK1/2. In caveolae, direct Na-K ATPase/Src interactions can be demonstrated by co-immunoprecipitation. The interaction is amplified by ouabain, at a high affinity binding site, detectable in caveolae but not in total rat renal membranes. The high affinity site for ouabain is associated with Src-dependent tyrosine phosphorylation of rat alpha1 Na-K ATPase. The antihypertensive compound, PST 2238, antagonized all ouabain-induced effects at 10 microg/kg/day in vivo or 10(-10)-10(-8) m in vitro. These findings provide a molecular mechanism for the in vivo pro-hypertrophic and hypertensinogenic activity of ouabain, or by analogy those of EO in humans. They also explain the pharmacological basis for PST 2238 treatment.

PST 2238: a new antihypertensive compound that modulates renal Na-K pump function without diuretic activity in Milan hypertensive rats.

PST 2238 is a new antihypertensive compound that is able to correct the molecular and functional alterations of the renal Na-K pump and the pressor effect associated with either alpha-adducin mutations or high circulating levels of endogenous ouabain (EO) in genetic and experimental rat models. Due to the close relationship between renal Na-K pump function and tubular Na reabsorption, PST 2238 was investigated to determine whether it is endowed with diuretic activity and consequently might trigger alterations of the renin-aldosterone system and the carbohydrate and lipid metabolism often associated with chronic diuretic therapy. In Milan hypertensive (MHS) rats, in which hypertension is genetically associated with alpha-adducin mutation, increased tubular Na reabsorption, and hyperactivation of the renal Na-K pump. PST 2238 reduced blood pressure and normalized the renal Na-K pump activity at oral doses of micro g/kg, but did not induce, either acutely or chronically, any diuretic activity or hormonal or metabolic alterations. In contrast, HCTZ, given to MHS rats orally at 40 mg/kg, although it displayed diuretic activity and reduced the renal Na-K pump activity, did not lower blood pressure and caused hyperactivation of the renin-aldosterone system, hypokaliemia, and hyperglycemia. The findings lead to the conclusion that PST 2238 is a new antihypertensive compound that normalizes the altered function of the renal Na-K pump associated with hypertension in rat models, but that it is devoid of diuretic activity and does not induce the diuretic-associated side effects.

Synthesis and inotropic activity of 1-(O-aminoalkyloximes) of perhydroindene derivatives as simplified digitalis-like compounds acting on the Na(+),K(+)-ATPase.

A series of 5-substituted (3aS,7aR)-7a-methylperhydroinden-3a-ol derivatives bearing a 1(S)-(omega-aminoalkoxy)iminoalkyl or -alkenyl substituent was synthesized, starting from the Hajos-Parrish ketol 47, as simplified analogues of very potent 17beta-aminoalkyloximes with digitalis skeleton, previously reported. The target compounds were evaluated in vitro for displacement of the specific [3H]ouabain binding from the dog kidney Na(+),K(+)-ATPase receptor. Some of them revealed IC(50) values in the micromolar range. The most active compounds possess a cyclohexyl group in the 5(S) position and in position 1(S) the same aminoalkyloxime groups already reported for the digitoxigenin-like series in position 17beta. Although the ring conformation of these derivatives was comparable to that of uzarigenin, the binding affinities of the most active ones were 4/8-fold lower in comparison to that standard. Three compounds among those with the highest affinities were assayed in vitro for their inotropic activity on an electrically driven guinea pig left atrium and were found to be less potent than both digoxin, the most widely used inotropic agent, and the corresponding digitalis 17beta-aminoalkyloximes.