High salt intake in modern societies is associated with hypertension, cardiovascular and renal in... more High salt intake in modern societies is associated with hypertension, cardiovascular and renal injuries, including proteinuria and renal fibrosis with progression to chronic kidney disease (CKD). It has been suggested that renal parenchymal hypoxia, which plays a role in accelerated CKD via hypoxia inducible factor (HIF)-mediated pro-fibrotic processes, is intensified by dietary salt and protein excess via enhanced glomerular filtration rate (GFR) and tubular transport in remnant nephrons. Thus, salt restriction is a principal factor in controlling hypertension and its related co-morbidities. Yet concern has been raised regarding a possible J-curve pattern of renal and systemic adverse outcomes with very low sodium intake, related to activation of the renin-angiotensin-aldosterone (RAAS) axis, leading to renal hypoxia. The study by Patinha et al. (2020) published in this issue of The Journal of Physiology addresses RAAS-mediated adaptive changes to a 10-fold salt restriction, involving the renal microcirculation, tubular sodium handling and oxygen expenditure, providing novel perspectives on the control of renal oxygenation. Renal parenchymal PO2 reflects the balance between blood and oxygen supply and the extent of tissue consumption, mostly for tubular transport. An abundant renal blood and oxygen supply, by far exceeding all other organs, enables the filtration process. Yet medullary blood flow, delivered through vasa recta, is limited, being 10% only of total renal blood flow, a necessity for the generation of medullary hypertonicity and urine concentration. However, oxygen expenditure for tubular transport, predominantly for sodium reclamation, takes place along the various nephron segments, and quantitatively is most prominent in the cortex and outer medulla, via proximal tubules (PTs) and medullary thick ascending limbs (mTALS), respectively. The renal oxygenation profile is, therefore, heterogeneous, with renal parenchymal PO2 declining at the cortico-medullary junction to levels as low as 30 mmHg under normal physiological conditions. While the cortex receives a huge blood supply with a low oxygen extraction fraction, indicating sufficient reserves, a physiological outer medullary ‘anginal syndrome’ exists, where limited regional oxygen supply barely meets oxygen requirements for sodium reabsorption by mTALs (Brezis & Rosen, 1995). Therefore, it is anticipated that while cortical PO2 will be mostly affected by changes in regional blood flow and oxygen supply, the impact of changes in tubular transport activity on ambient oxygenation may be most pronounced in the outer medulla. Indeed, controlled hypotension, for example, leads to cortical hypoxia and reversal of medullary hypoxaemia, the former via reduced cortical blood flow, and the later through preserved blood flow but reduced transport activity by mTALs (the consequence of diminished GFR and increased urine transit time and PT solute reabsorption, collectively leading to diminished solute delivery for transport at distal nephron segments) (Brezis et al. 1994). Other examples of the impact of tubular transport on renal regional oxygenation are the reversal of medullary hypoxia by loop diuretics, which block sodium transport by mTALs (Brezis & Rosen, 1995), or the impact of sodium glucose cotransporter (SGLT) inhibition on renal oxygenation, with improved cortical PO2 but declining medullary oxygenation, reflecting translocation of sodium reabsorption from PTs to mTALs (Darawshi et al. 2020). Patinha et al. (2020) report that extreme salt depletion in normotensive rats reduces cortical oxygenation and increases sodium retention, oxygen consumption and extraction with decreased transport work efficacy. Assessing the role of activated RAAS in these changes, they found that candesartan infused into the renal artery did not affect blood pressure and GFR but restored cortical oxygenation, principally by increasing renal blood flow and oxygen delivery. By contrast, mineralocorticoid inhibition normalized enhanced oxygen consumption and extraction by reducing sodium reabsorption without an overt impact on renal oxygenation. Thus, substantial salt restriction leads to an undesirable RAAS-dependent decline in cortical oxygenation, secondary to both a reduction in regional oxygen supply and enhancement of low efficacy tubular transport. Over 30 years ago we included salt depletion in models of hypoxic acute kidney injury (AKI) in rats with selective outer medullary injury (Brezis & Rosen, 1995), anticipating reduced medullary blood flow and oxygenation via stimulation of RAAS. Unexpectedly, we later found that medullary blood flow is hardly affected, probably thanks to angiotensin-AT2-receptor-mediated preserved vasa recta flow. Furthermore, as now also confirmed by Patinha et al. 2020, salt restriction led to an inverted profile of renal parenchymal oxygenation, with reduced cortical PO2 and increased medullary oxygenation (Stillman et al. 1994).…
Objective: Rho-dependent kinases serve as downstream effectors of several vasoconstrictor systems... more Objective: Rho-dependent kinases serve as downstream effectors of several vasoconstrictor systems, whose activities are upregulated in congestive heart failure.
Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac... more Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (ϩ34%) in total renal blood flow and a sustained decrease (Ϫ33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (Ϫ12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure. (Hypertension. 1998;32:746-752.)
Altered gap junctional coupling of ventricular myocytes plays an important role in arrhythmogenes... more Altered gap junctional coupling of ventricular myocytes plays an important role in arrhythmogenesis in ischemic heart disease. Since hypoxia is a major component of ischemia, we tested the hypothesis that hypoxia causes gap junctional remodeling accompanied by conduction disturbances.
Endothelin-1 (ET-1) is an important contributor to ventricular hypertrophy and failure, which are... more Endothelin-1 (ET-1) is an important contributor to ventricular hypertrophy and failure, which are associated with arrhythmogenesis and sudden death. To elucidate the mechanism(s) underlying the arrhythmogenic effects of ET-1 we tested the hypothesis that long-term (24 hrs) exposure to ET-1 impairs impulse conduction in cultures of neonatal rat ventricular myocytes (NRVM). NRVM were seeded on micro-electrode-arrays (MEAs, Multi Channel Systems, Reutlingen, Germany) and exposed to 50 nM ET-1 for 24 hrs. Hypertrophy was assessed by morphological and molecular methods. Consecutive recordings of paced activation times from the same cultures were conducted at baseline and after 3, 6 and 24 hrs, and activation maps for each time period constructed. Gap junctional Cx43 expression was assessed using Western blot and confocal microscopy of immunofluorescence staining using anti-Cx43 antibodies. ET-1 caused hypertrophy as indicated by a 70% increase in mRNA for atrial natriuretic peptide (P < 0.05), and increased cell areas (P < 0.05) compared to control. ET-1 also caused a time-dependent decrease in conduction velocity that was evident after 3 hrs of exposure to ET-1, and was augmented at 24 hrs, compared to controls (P < 0.01). ET-1 increased total Cx43 protein by ~40% (P < 0.05) without affecting non-phosphorylated Cx43 (NP-Cx43) protein expression. Quantitative confocal microscopy showed a ~30% decrease in the Cx43 immunofluorescence per field in the ET-1 group (P < 0.05) and a reduced field stain intensity (P < 0.05), compared to controls. ET-1-induced hypertrophy was accompanied by reduction in conduction velocity and gap junctional remodelling. The reduction in conduction velocity may play a role in ET-1 induced susceptibility to arrhythmogenesis.
Hyperhomocysteinemia is a well-recognized risk factor for accelerated atherosclerosis in hemodial... more Hyperhomocysteinemia is a well-recognized risk factor for accelerated atherosclerosis in hemodialysis patients. To examine the effects of two doses of vitamins B6 and B12 and folic acid on homocysteine levels in hemodialysis patients and assess the functional impact of the methylenetetrahydrofolate reductase genotype on the response to treatment. In a randomized prospective study, we assessed the effects of folic acid and two doses of B-vitamins in 50 hemodialysis patients with hyperhomocysteinemia. Patients were divided into two groups: 26 patients (group A) who received 25 mg of vitamin B6 daily and one monthly injection of 200 microg vitamin B12, and 24 patients (group B) who received 100 mg of vitamin B6 daily and one monthly injection of 1,000 microg vitamin B12. In addition, both groups received 15 mg folic acid daily. Patients were evaluated for homocysteine levels as well as for coagulation and a thorough lipid profile. Baseline Hcy levels were determined after at least 4 we...
Active alveolar fluid clearance is important in keeping airspaces free of edema. Angiotensin II p... more Active alveolar fluid clearance is important in keeping airspaces free of edema. Angiotensin II plays a role in the pathogenesis of hypertension, heart failure and others. However, little is known about its contribution to alveolar fluid clearance. Angiotensin II effects are mediated by two specific receptors; AT 1 and AT 2 . The localization of these two receptors in the lung, specifically in alveolar epithelial cells type II, was recently reported. We hypothesize that Angiotensin II may have a role in the regulation of alveolar fluid clearance. We investigated the effect of Angiotensin II on alveolar fluid clearance in rats using the isolated perfused lung model and isolated rat alveolar epithelial cells. The rate of alveolar fluid clearance in control rats was 8.6% ± 0.1 clearance of the initial volume and decreased by 22.5%, 28.6%, 41.6%, 48.7% and 39% in rats treated with 10 -10 M, 10 -9 M, 10 -8 M, 10 -7 M or 10 -6 M of Ang II respectively (P < 0.003). The inhibitory effect of Angiotensin II was restored in losartan, an AT 1 specific antagonist, pretreated rats, indicating an AT 1 mediated effect of Ang II on alveolar fluid clearance. The expression of Na,K-ATPase proteins and cAMP levels in alveolar epithelial cells were down-regulated following the administration of Angiotensin II; suggesting that cAMP may be involved in AngII-induced reduced Na,K-ATPase expression, though the contribution of additional factors could not be excluded. We herein suggest a novel mechanism of clinical relevance by which angiotensin adversely impairs the ability of the lungs to clear edema.
The incidence of both acute and chronic kidney diseases is persistently increasing and is reachin... more The incidence of both acute and chronic kidney diseases is persistently increasing and is reaching epidemic proportions. Early therapeutic intervention may significantly decrease the morbidity and mortality rates among these patients. However, the lack of early non-invasive biomarkers has hampered our ability to diagnose kidney diseases as early as possible, and subsequently, to initiate timely, effective, and appropriate treatment. Until recently, no biomarker for kidney disease, except for creatinine was available to clinicians in general and nephrologists in particular. Unfortunately, creatinine is an unreliable indicator during acute and chronic changes in kidney function, since serum creatinine concentrations can vary widely with age, gender, muscle mass, muscle metabolism, medications and hydration status. Secondly, serum creatinine concentrations may not change until a significant amount of kidney function (50-60%) has already been lost. In the last few years various specific...
Hypertension is the most common risk factor for cardiovascular disease, constituting the most com... more Hypertension is the most common risk factor for cardiovascular disease, constituting the most common cause of death in industrialized countries. Therefore, the task of blood pressure reduction has significant importance in reducing vascular damage, myocardial infarctions, kidney damage and incidence of cerebrovascular accidents. The renin-angiotensin-aldosterone system (RAAS) plays a central role in control and function of the cardiovascular and renal systems, and is deeply involved in the pathophysiology of diseases of vasculature, heart, kidneys and others. Therefore, blockade of RAAS by angiotensin converting enzyme (ACE) inhibitors and blockers of angiotensin II type AT1 receptors (ARBs) is widely utilized by clinicians. Indeed, it has long been known that ACE inhibitors and ARBs protect different targets of angiotensin II, due to impedance of the negative effects of the hormone and the inhibition of aldosterone production, which contributes both directly and indirectly to the d...
Background—Whereas nitric oxide (NO) has been implicated in the pathophysiology of heart failure ... more Background—Whereas nitric oxide (NO) has been implicated in the pathophysiology of heart failure (HF), the significance and functional role of different NO synthase (NOS) isoforms in this pathology are controversial. Our aim was to study in the myocardium of rats with volume-overload-induced HF the expression, activity, and localization of endothelial (eNOS) and inducible (iNOS) isoforms and the involvement of iNOS
We studied the rat model system of high-vs. low-capacity runner (HCR vs. LCR) rats to question th... more We studied the rat model system of high-vs. low-capacity runner (HCR vs. LCR) rats to question the atherogenic properties (oxidative stress, triglycerides and cholesterol metabolism) in the rat macrophages, serum, liver and heart. Half of the LCR or HCR rats consumed pomegranate juice (PJ; 15 μmol of gallic acid equivalents/rat/day) for 3 weeks and were compared to placebo-treated rats. At the end of the study blood samples, peritoneal macrophages (RPM), livers, and hearts were harvested from the rats. RPM harvested from HCR vs. LCR demonstrated reduced cellular oxidation (21%), increased paraoxonase 2 activity (28%) and decreased triglycerides mass (44%). Macrophage uptake rates of fluorescein-isothiocyanate-labeled low-density lipoprotein (LDL) or oxidized LDL were significantly lower, by 37% or by 18%, respectively, in HCR vs. LCR RPM. PJ consumption significantly decreased all the above atherogenic parameters with more substantial beneficial effects observed in the LCR vs. the HCR rats (~80% vs.~40% improvement, respectively). Similar hypo-triglyceridemic pattern was noted in serum from HCR vs. LCR. In contrast to the above results, liver oxidation and triglycerides mass were both minimally increased in HCR vs. LCR rats by 31% and 28%, respectively. In the heart, lipid content was very low, and interestingly, an absence of any significant oxidative stress, along with modest triglyceride accumulation, was observed.
Aldosterone plays an important role in the pathophysiology of congestive heart failure (CHF), and... more Aldosterone plays an important role in the pathophysiology of congestive heart failure (CHF), and spironolac- tone improves cardiovascular function and survival rates in patients with CHF. We hypothesized that the mineralocor- ticoid receptor blockade (MRB) exerted its beneficial effects by reducing oxidative stress and changing the balance between the counter-acting enzymes angiotensin-converting enzyme (ACE) and ACE2. Monocyte-derived macrophages were obtained
PPSA to 5⅐10 Ϫ7 M Ach was also reduced [Ϫ9Ϯ3 % vs. Ϫ23Ϯ2 % in C-C group, pϽ0.05]. This impairment... more PPSA to 5⅐10 Ϫ7 M Ach was also reduced [Ϫ9Ϯ3 % vs. Ϫ23Ϯ2 % in C-C group, pϽ0.05]. This impairment of relaxant responses was prevented by AG treatment in cases of decrease of PPPA to 5⅐10 Ϫ8 M Ach [Ϫ69Ϯ13 % in MCT-AG group vs. MCT-C group, pϽ0.05], to 1⅐10 Ϫ8 M FPTO [Ϫ64Ϯ10% in MCT-AG group didn't differ from Ϫ78Ϯ28% in C-AG group] and PPSA to 5⅐10 Ϫ7 M Ach [Ϫ54Ϯ10 % in MCT-AG group vs. MCT-C group, pϽ0.05].
The Israel Medical Association journal : IMAJ, 2007
Inherited forms of proteinuria constitute a rare and heterogeneous group of diseases, the most pr... more Inherited forms of proteinuria constitute a rare and heterogeneous group of diseases, the most prominent of which is glomerular dysfunction, which leads to proteinuria. Investigation of the genetic background underlying these diseases has provided significant data on the normal operation of the glomerular filter. Among the different components of the glomerulus, the podocyte slit diaphragm is considered the main source for genetically derived protein alteration, which leads in turn to proteinuria. Investigation of the different proteins revealed that the lack of nephrin and podocin is the leading cause of several inherited forms of proteinuria. It was also proposed that the lack of podocin is linked to cardiac anomalies. This review suggests that the absence of slit diaphragm proteins and the open zipper phenomenon are associated with cardiac anomalies.
News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society, 2001
The kidney is both a source of endothelin (ET) generation and an important target organ of this p... more The kidney is both a source of endothelin (ET) generation and an important target organ of this peptide. The highest concentrations of ET-1 in the body exist in the renal medulla, where it mediates natriuretic and diuretic effects through the ET(B) receptor subtype. It is proposed that aberrations in the renal ET system may lead to sodium and water retention and subsequently to the development of hypertension.
Visualization of the intramuscular microcirculation during and after compartmental syndrome was s... more Visualization of the intramuscular microcirculation during and after compartmental syndrome was studied by microangiograms and histologic cross sections. A marked reduction in the circulation of the endomysial capillary network was found during compartment tamponade, whereas the perimysium arteriolar system was patent. Revascularization took place by formation of distorted blood vessels accompanied by intramuscular hematomas in muscles 7 and 14 days after the compartment insult. The cross sections show massive fibroblastic activity around blood vessels that caused concealed intramuscular pressure-ischemic contracture resulting in the foci of myofibrillar necrosis seen within normal muscle tissue. The muscle located in the tamponaded compartment profusely bleeds when it is touched, even though its viability is in doubt. The explanation for this clinical observation might be the abnormal intramuscular revascularization that was found in this work.
Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic... more Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS) in a mouse model.
Worsening renal function (WRF) and congestion are inextricably related pathophysiologically, sugg... more Worsening renal function (WRF) and congestion are inextricably related pathophysiologically, suggesting that WRF occurring in conjunction with persistent congestion would be associated with worse clinical outcome. We studied the interdependence between WRF and persistent congestion in 762 patients with acute decompensated heart failure (HF). WRF was defined as ‡0.3 mg/dl increase in serum creatinine above baseline at any time during hospitalization and persistent congestion as ‡1 sign of congestion at discharge. The primary end point was all-cause mortality with mean follow-up of 15 -9 months. Readmission for HF was a secondary end point. Persistent congestion was more common in patients with WRF than in patients with stable renal function (51.0% vs 26.6%, p <0.0001). Both persistent congestion and persistent WRF were significantly associated with mortality (both p <0.0001). There was a strong interaction (p [ 0.003) between persistent WRF and congestion, such that the increased risk for mortality occurred predominantly with both WRF and persistent congestion. The adjusted hazard ratio for mortality in patients with persistent congestion as compared with those without was 4.16 (95% confidence interval [CI] 2.20 to 7.86) in patients with WRF and 1.50 (95% CI 1.16 to 1.93) in patients without WRF. In conclusion, persisted congestion is frequently associated with WRF. We have identified a substantial interaction between persistent congestion and WRF such that congestion portends increased mortality particularly when associated with WRF. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;115:932e937)
High salt intake in modern societies is associated with hypertension, cardiovascular and renal in... more High salt intake in modern societies is associated with hypertension, cardiovascular and renal injuries, including proteinuria and renal fibrosis with progression to chronic kidney disease (CKD). It has been suggested that renal parenchymal hypoxia, which plays a role in accelerated CKD via hypoxia inducible factor (HIF)-mediated pro-fibrotic processes, is intensified by dietary salt and protein excess via enhanced glomerular filtration rate (GFR) and tubular transport in remnant nephrons. Thus, salt restriction is a principal factor in controlling hypertension and its related co-morbidities. Yet concern has been raised regarding a possible J-curve pattern of renal and systemic adverse outcomes with very low sodium intake, related to activation of the renin-angiotensin-aldosterone (RAAS) axis, leading to renal hypoxia. The study by Patinha et al. (2020) published in this issue of The Journal of Physiology addresses RAAS-mediated adaptive changes to a 10-fold salt restriction, involving the renal microcirculation, tubular sodium handling and oxygen expenditure, providing novel perspectives on the control of renal oxygenation. Renal parenchymal PO2 reflects the balance between blood and oxygen supply and the extent of tissue consumption, mostly for tubular transport. An abundant renal blood and oxygen supply, by far exceeding all other organs, enables the filtration process. Yet medullary blood flow, delivered through vasa recta, is limited, being 10% only of total renal blood flow, a necessity for the generation of medullary hypertonicity and urine concentration. However, oxygen expenditure for tubular transport, predominantly for sodium reclamation, takes place along the various nephron segments, and quantitatively is most prominent in the cortex and outer medulla, via proximal tubules (PTs) and medullary thick ascending limbs (mTALS), respectively. The renal oxygenation profile is, therefore, heterogeneous, with renal parenchymal PO2 declining at the cortico-medullary junction to levels as low as 30 mmHg under normal physiological conditions. While the cortex receives a huge blood supply with a low oxygen extraction fraction, indicating sufficient reserves, a physiological outer medullary ‘anginal syndrome’ exists, where limited regional oxygen supply barely meets oxygen requirements for sodium reabsorption by mTALs (Brezis & Rosen, 1995). Therefore, it is anticipated that while cortical PO2 will be mostly affected by changes in regional blood flow and oxygen supply, the impact of changes in tubular transport activity on ambient oxygenation may be most pronounced in the outer medulla. Indeed, controlled hypotension, for example, leads to cortical hypoxia and reversal of medullary hypoxaemia, the former via reduced cortical blood flow, and the later through preserved blood flow but reduced transport activity by mTALs (the consequence of diminished GFR and increased urine transit time and PT solute reabsorption, collectively leading to diminished solute delivery for transport at distal nephron segments) (Brezis et al. 1994). Other examples of the impact of tubular transport on renal regional oxygenation are the reversal of medullary hypoxia by loop diuretics, which block sodium transport by mTALs (Brezis & Rosen, 1995), or the impact of sodium glucose cotransporter (SGLT) inhibition on renal oxygenation, with improved cortical PO2 but declining medullary oxygenation, reflecting translocation of sodium reabsorption from PTs to mTALs (Darawshi et al. 2020). Patinha et al. (2020) report that extreme salt depletion in normotensive rats reduces cortical oxygenation and increases sodium retention, oxygen consumption and extraction with decreased transport work efficacy. Assessing the role of activated RAAS in these changes, they found that candesartan infused into the renal artery did not affect blood pressure and GFR but restored cortical oxygenation, principally by increasing renal blood flow and oxygen delivery. By contrast, mineralocorticoid inhibition normalized enhanced oxygen consumption and extraction by reducing sodium reabsorption without an overt impact on renal oxygenation. Thus, substantial salt restriction leads to an undesirable RAAS-dependent decline in cortical oxygenation, secondary to both a reduction in regional oxygen supply and enhancement of low efficacy tubular transport. Over 30 years ago we included salt depletion in models of hypoxic acute kidney injury (AKI) in rats with selective outer medullary injury (Brezis & Rosen, 1995), anticipating reduced medullary blood flow and oxygenation via stimulation of RAAS. Unexpectedly, we later found that medullary blood flow is hardly affected, probably thanks to angiotensin-AT2-receptor-mediated preserved vasa recta flow. Furthermore, as now also confirmed by Patinha et al. 2020, salt restriction led to an inverted profile of renal parenchymal oxygenation, with reduced cortical PO2 and increased medullary oxygenation (Stillman et al. 1994).…
Objective: Rho-dependent kinases serve as downstream effectors of several vasoconstrictor systems... more Objective: Rho-dependent kinases serve as downstream effectors of several vasoconstrictor systems, whose activities are upregulated in congestive heart failure.
Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac... more Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (ϩ34%) in total renal blood flow and a sustained decrease (Ϫ33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (Ϫ12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure. (Hypertension. 1998;32:746-752.)
Altered gap junctional coupling of ventricular myocytes plays an important role in arrhythmogenes... more Altered gap junctional coupling of ventricular myocytes plays an important role in arrhythmogenesis in ischemic heart disease. Since hypoxia is a major component of ischemia, we tested the hypothesis that hypoxia causes gap junctional remodeling accompanied by conduction disturbances.
Endothelin-1 (ET-1) is an important contributor to ventricular hypertrophy and failure, which are... more Endothelin-1 (ET-1) is an important contributor to ventricular hypertrophy and failure, which are associated with arrhythmogenesis and sudden death. To elucidate the mechanism(s) underlying the arrhythmogenic effects of ET-1 we tested the hypothesis that long-term (24 hrs) exposure to ET-1 impairs impulse conduction in cultures of neonatal rat ventricular myocytes (NRVM). NRVM were seeded on micro-electrode-arrays (MEAs, Multi Channel Systems, Reutlingen, Germany) and exposed to 50 nM ET-1 for 24 hrs. Hypertrophy was assessed by morphological and molecular methods. Consecutive recordings of paced activation times from the same cultures were conducted at baseline and after 3, 6 and 24 hrs, and activation maps for each time period constructed. Gap junctional Cx43 expression was assessed using Western blot and confocal microscopy of immunofluorescence staining using anti-Cx43 antibodies. ET-1 caused hypertrophy as indicated by a 70% increase in mRNA for atrial natriuretic peptide (P < 0.05), and increased cell areas (P < 0.05) compared to control. ET-1 also caused a time-dependent decrease in conduction velocity that was evident after 3 hrs of exposure to ET-1, and was augmented at 24 hrs, compared to controls (P < 0.01). ET-1 increased total Cx43 protein by ~40% (P < 0.05) without affecting non-phosphorylated Cx43 (NP-Cx43) protein expression. Quantitative confocal microscopy showed a ~30% decrease in the Cx43 immunofluorescence per field in the ET-1 group (P < 0.05) and a reduced field stain intensity (P < 0.05), compared to controls. ET-1-induced hypertrophy was accompanied by reduction in conduction velocity and gap junctional remodelling. The reduction in conduction velocity may play a role in ET-1 induced susceptibility to arrhythmogenesis.
Hyperhomocysteinemia is a well-recognized risk factor for accelerated atherosclerosis in hemodial... more Hyperhomocysteinemia is a well-recognized risk factor for accelerated atherosclerosis in hemodialysis patients. To examine the effects of two doses of vitamins B6 and B12 and folic acid on homocysteine levels in hemodialysis patients and assess the functional impact of the methylenetetrahydrofolate reductase genotype on the response to treatment. In a randomized prospective study, we assessed the effects of folic acid and two doses of B-vitamins in 50 hemodialysis patients with hyperhomocysteinemia. Patients were divided into two groups: 26 patients (group A) who received 25 mg of vitamin B6 daily and one monthly injection of 200 microg vitamin B12, and 24 patients (group B) who received 100 mg of vitamin B6 daily and one monthly injection of 1,000 microg vitamin B12. In addition, both groups received 15 mg folic acid daily. Patients were evaluated for homocysteine levels as well as for coagulation and a thorough lipid profile. Baseline Hcy levels were determined after at least 4 we...
Active alveolar fluid clearance is important in keeping airspaces free of edema. Angiotensin II p... more Active alveolar fluid clearance is important in keeping airspaces free of edema. Angiotensin II plays a role in the pathogenesis of hypertension, heart failure and others. However, little is known about its contribution to alveolar fluid clearance. Angiotensin II effects are mediated by two specific receptors; AT 1 and AT 2 . The localization of these two receptors in the lung, specifically in alveolar epithelial cells type II, was recently reported. We hypothesize that Angiotensin II may have a role in the regulation of alveolar fluid clearance. We investigated the effect of Angiotensin II on alveolar fluid clearance in rats using the isolated perfused lung model and isolated rat alveolar epithelial cells. The rate of alveolar fluid clearance in control rats was 8.6% ± 0.1 clearance of the initial volume and decreased by 22.5%, 28.6%, 41.6%, 48.7% and 39% in rats treated with 10 -10 M, 10 -9 M, 10 -8 M, 10 -7 M or 10 -6 M of Ang II respectively (P < 0.003). The inhibitory effect of Angiotensin II was restored in losartan, an AT 1 specific antagonist, pretreated rats, indicating an AT 1 mediated effect of Ang II on alveolar fluid clearance. The expression of Na,K-ATPase proteins and cAMP levels in alveolar epithelial cells were down-regulated following the administration of Angiotensin II; suggesting that cAMP may be involved in AngII-induced reduced Na,K-ATPase expression, though the contribution of additional factors could not be excluded. We herein suggest a novel mechanism of clinical relevance by which angiotensin adversely impairs the ability of the lungs to clear edema.
The incidence of both acute and chronic kidney diseases is persistently increasing and is reachin... more The incidence of both acute and chronic kidney diseases is persistently increasing and is reaching epidemic proportions. Early therapeutic intervention may significantly decrease the morbidity and mortality rates among these patients. However, the lack of early non-invasive biomarkers has hampered our ability to diagnose kidney diseases as early as possible, and subsequently, to initiate timely, effective, and appropriate treatment. Until recently, no biomarker for kidney disease, except for creatinine was available to clinicians in general and nephrologists in particular. Unfortunately, creatinine is an unreliable indicator during acute and chronic changes in kidney function, since serum creatinine concentrations can vary widely with age, gender, muscle mass, muscle metabolism, medications and hydration status. Secondly, serum creatinine concentrations may not change until a significant amount of kidney function (50-60%) has already been lost. In the last few years various specific...
Hypertension is the most common risk factor for cardiovascular disease, constituting the most com... more Hypertension is the most common risk factor for cardiovascular disease, constituting the most common cause of death in industrialized countries. Therefore, the task of blood pressure reduction has significant importance in reducing vascular damage, myocardial infarctions, kidney damage and incidence of cerebrovascular accidents. The renin-angiotensin-aldosterone system (RAAS) plays a central role in control and function of the cardiovascular and renal systems, and is deeply involved in the pathophysiology of diseases of vasculature, heart, kidneys and others. Therefore, blockade of RAAS by angiotensin converting enzyme (ACE) inhibitors and blockers of angiotensin II type AT1 receptors (ARBs) is widely utilized by clinicians. Indeed, it has long been known that ACE inhibitors and ARBs protect different targets of angiotensin II, due to impedance of the negative effects of the hormone and the inhibition of aldosterone production, which contributes both directly and indirectly to the d...
Background—Whereas nitric oxide (NO) has been implicated in the pathophysiology of heart failure ... more Background—Whereas nitric oxide (NO) has been implicated in the pathophysiology of heart failure (HF), the significance and functional role of different NO synthase (NOS) isoforms in this pathology are controversial. Our aim was to study in the myocardium of rats with volume-overload-induced HF the expression, activity, and localization of endothelial (eNOS) and inducible (iNOS) isoforms and the involvement of iNOS
We studied the rat model system of high-vs. low-capacity runner (HCR vs. LCR) rats to question th... more We studied the rat model system of high-vs. low-capacity runner (HCR vs. LCR) rats to question the atherogenic properties (oxidative stress, triglycerides and cholesterol metabolism) in the rat macrophages, serum, liver and heart. Half of the LCR or HCR rats consumed pomegranate juice (PJ; 15 μmol of gallic acid equivalents/rat/day) for 3 weeks and were compared to placebo-treated rats. At the end of the study blood samples, peritoneal macrophages (RPM), livers, and hearts were harvested from the rats. RPM harvested from HCR vs. LCR demonstrated reduced cellular oxidation (21%), increased paraoxonase 2 activity (28%) and decreased triglycerides mass (44%). Macrophage uptake rates of fluorescein-isothiocyanate-labeled low-density lipoprotein (LDL) or oxidized LDL were significantly lower, by 37% or by 18%, respectively, in HCR vs. LCR RPM. PJ consumption significantly decreased all the above atherogenic parameters with more substantial beneficial effects observed in the LCR vs. the HCR rats (~80% vs.~40% improvement, respectively). Similar hypo-triglyceridemic pattern was noted in serum from HCR vs. LCR. In contrast to the above results, liver oxidation and triglycerides mass were both minimally increased in HCR vs. LCR rats by 31% and 28%, respectively. In the heart, lipid content was very low, and interestingly, an absence of any significant oxidative stress, along with modest triglyceride accumulation, was observed.
Aldosterone plays an important role in the pathophysiology of congestive heart failure (CHF), and... more Aldosterone plays an important role in the pathophysiology of congestive heart failure (CHF), and spironolac- tone improves cardiovascular function and survival rates in patients with CHF. We hypothesized that the mineralocor- ticoid receptor blockade (MRB) exerted its beneficial effects by reducing oxidative stress and changing the balance between the counter-acting enzymes angiotensin-converting enzyme (ACE) and ACE2. Monocyte-derived macrophages were obtained
PPSA to 5⅐10 Ϫ7 M Ach was also reduced [Ϫ9Ϯ3 % vs. Ϫ23Ϯ2 % in C-C group, pϽ0.05]. This impairment... more PPSA to 5⅐10 Ϫ7 M Ach was also reduced [Ϫ9Ϯ3 % vs. Ϫ23Ϯ2 % in C-C group, pϽ0.05]. This impairment of relaxant responses was prevented by AG treatment in cases of decrease of PPPA to 5⅐10 Ϫ8 M Ach [Ϫ69Ϯ13 % in MCT-AG group vs. MCT-C group, pϽ0.05], to 1⅐10 Ϫ8 M FPTO [Ϫ64Ϯ10% in MCT-AG group didn't differ from Ϫ78Ϯ28% in C-AG group] and PPSA to 5⅐10 Ϫ7 M Ach [Ϫ54Ϯ10 % in MCT-AG group vs. MCT-C group, pϽ0.05].
The Israel Medical Association journal : IMAJ, 2007
Inherited forms of proteinuria constitute a rare and heterogeneous group of diseases, the most pr... more Inherited forms of proteinuria constitute a rare and heterogeneous group of diseases, the most prominent of which is glomerular dysfunction, which leads to proteinuria. Investigation of the genetic background underlying these diseases has provided significant data on the normal operation of the glomerular filter. Among the different components of the glomerulus, the podocyte slit diaphragm is considered the main source for genetically derived protein alteration, which leads in turn to proteinuria. Investigation of the different proteins revealed that the lack of nephrin and podocin is the leading cause of several inherited forms of proteinuria. It was also proposed that the lack of podocin is linked to cardiac anomalies. This review suggests that the absence of slit diaphragm proteins and the open zipper phenomenon are associated with cardiac anomalies.
News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society, 2001
The kidney is both a source of endothelin (ET) generation and an important target organ of this p... more The kidney is both a source of endothelin (ET) generation and an important target organ of this peptide. The highest concentrations of ET-1 in the body exist in the renal medulla, where it mediates natriuretic and diuretic effects through the ET(B) receptor subtype. It is proposed that aberrations in the renal ET system may lead to sodium and water retention and subsequently to the development of hypertension.
Visualization of the intramuscular microcirculation during and after compartmental syndrome was s... more Visualization of the intramuscular microcirculation during and after compartmental syndrome was studied by microangiograms and histologic cross sections. A marked reduction in the circulation of the endomysial capillary network was found during compartment tamponade, whereas the perimysium arteriolar system was patent. Revascularization took place by formation of distorted blood vessels accompanied by intramuscular hematomas in muscles 7 and 14 days after the compartment insult. The cross sections show massive fibroblastic activity around blood vessels that caused concealed intramuscular pressure-ischemic contracture resulting in the foci of myofibrillar necrosis seen within normal muscle tissue. The muscle located in the tamponaded compartment profusely bleeds when it is touched, even though its viability is in doubt. The explanation for this clinical observation might be the abnormal intramuscular revascularization that was found in this work.
Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic... more Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS) in a mouse model.
Worsening renal function (WRF) and congestion are inextricably related pathophysiologically, sugg... more Worsening renal function (WRF) and congestion are inextricably related pathophysiologically, suggesting that WRF occurring in conjunction with persistent congestion would be associated with worse clinical outcome. We studied the interdependence between WRF and persistent congestion in 762 patients with acute decompensated heart failure (HF). WRF was defined as ‡0.3 mg/dl increase in serum creatinine above baseline at any time during hospitalization and persistent congestion as ‡1 sign of congestion at discharge. The primary end point was all-cause mortality with mean follow-up of 15 -9 months. Readmission for HF was a secondary end point. Persistent congestion was more common in patients with WRF than in patients with stable renal function (51.0% vs 26.6%, p <0.0001). Both persistent congestion and persistent WRF were significantly associated with mortality (both p <0.0001). There was a strong interaction (p [ 0.003) between persistent WRF and congestion, such that the increased risk for mortality occurred predominantly with both WRF and persistent congestion. The adjusted hazard ratio for mortality in patients with persistent congestion as compared with those without was 4.16 (95% confidence interval [CI] 2.20 to 7.86) in patients with WRF and 1.50 (95% CI 1.16 to 1.93) in patients without WRF. In conclusion, persisted congestion is frequently associated with WRF. We have identified a substantial interaction between persistent congestion and WRF such that congestion portends increased mortality particularly when associated with WRF. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;115:932e937)
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