Novel bioactivity of NHERF1 in corneal neovascularization.

PURPOSE: This paper aimed to determine the involvement of Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) in experimental murine corneal neovascularization (NV), and to study the effect of NHERF1 on the biological properties of HUVEC and related mechanisms. METHODS: Using loss- and gain-function, we investigated the biological effects of NHERF1 on HUVEC. Western blotting was used to detect the expression of NHERF1 in cells. A carboxyfluorescein succinimidyl ester (CFSE) labeling assay and scarification test were used to measure the proliferation and migration activity, respectively, of HUVEC. The cell cycle distribution of the cells was assessed by flow cytometry analysis. The effect of NHERF1 on the phosphorylation levels of Akt and the changes of matrix metalloproteinase (MMP)-2 and MMP-9 levels were detected by western blotting analysis. Change in the NHERF1 expression in the alkali burn-induced corneal NV model was detected by microarray, real-time PCR, and immunofluorescence. RESULTS: Overexpression of exogenous NHERF1 in HUVEC slightly inhibited the proliferation and significantly reduced the migration of the cells. NHERF1 also significantly downregulated Akt1 phosphorylation induced by platelet-derived growth factor BB (PDGF-BB) and the secretion of MMP-2 and MMP-9 compared with control cells. NHERF1 was upregulated in corneas challenged with alkali burns. CONCLUSIONS: Our results indicated that NHERF1 might serve as a potential target for manipulating neovascularization-related diseases. This discovery contributes to a better understanding of the bioactivity of NHERF1 in angiogenesis.

Acute SGLT-2i treatment improves cardiac efficiency during myocardial ischemia independent of Na+/H+ exchanger-1.

AIMS: Sodium glucose co-transporter 2 inhibitors (SGLT2i) demonstrate cardioprotective benefits independent of a glucose lowering effect including preservation of cardiac function during a myocardial ischemia. Sodium­hydrogen exchanger-1 (NHE-1), has been hypothesized to contribute to the cardiac effects of SGLT2i. We characterized the beneficial effects of acute pre-ischemia exposure to SGLT2i and explored the possibility that these effects are explained by NHE-1 inhibition. METHODS AND RESULTS: Swine were anesthetized and instrumented for invasive hemodynamic measurements. After baseline data collection, swine received a 15-30 min intravenous infusion of vehicle (DMSO), the SGLT2i canagliflozin (~1 mg/kg), or the NHE-1 inhibitor cariporide (~0.03 mg/kg) ending immediately prior to occlusion of the left circumflex artery. Measurements were obtained at baseline, during a 60-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, left anterior descending artery flow, and associated myocardial oxygen consumption were unaffected by acute pre-treatment with canagliflozin or cariporide during ischemia and reperfusion. Acute pre-ischemic treatment with canagliflozin significantly increased diastolic filling and stroke work, producing a rightward shift in the Frank-Starling relationship, and also improved cardiac work efficiency relative to untreated control hearts during ischemia. Effects of NHE-1 inhibition with cariporide were modest and dissimilar. Examination of AP-1 cells transfected with wild-type NHE-1 and iPSC-derived cardiomyocytes confirmed dose-dependent-inhibition of NHE-1 activity by cariporide, while canagliflozin had no significant effect on NHE-1 activity. CONCLUSION: Acute pre-treatment with SGLT2i produces cardioprotective effects during ischemia, including improved work efficiency. These effects are not explained by NHE-1 inhibition. TRANSLATIONAL PERSPECTIVE: SGLT2 inhibitors have been shown to improve cardiac outcomes in patient including reducing myocardial infarction incidence and mortality. The mechanism(s) explaining this effect are not clear. This manuscript demonstrates a protective effect from acute SGLT2i exposure, as short as 15 min, prior to experimental infarction in swine. These effects were independent of NHE1 inhibition. These observations suggest that SGLT2 inhibitors can confer cardioprotective effects on a very short time scale. It is possible that such effects provide an ongoing contribution to ischemic protection even in the setting of chronic treatment.

Sodium/hydrogen-exchanger inhibition during cardioplegic arrest and cardiopulmonary bypass: an experimental study.

OBJECTIVE: We sought to determine whether pretreatment with a sodium/hydrogen-exchange inhibitor (EMD 96 785) improves myocardial performance and reduces myocardial edema after cardioplegic arrest and cardiopulmonary bypass. METHODS: Anesthetized dogs (n = 13) were instrumented with vascular catheters, myocardial ultrasonic crystals, and left ventricular micromanometers to measure preload recruitable stroke work, maximum rate of pressure rise (positive and negative), and left ventricular end-diastolic volume and pressure. Cardiac output was measured by means of thermodilution. Myocardial tissue water content was determined from sequential biopsy. After baseline measurements, hypothermic (28 degrees C) cardiopulmonary bypass was initiated. Cardioplegic arrest (4 degrees C Bretschneider crystalloid cardioplegic solution) was maintained for 2 hours, followed by reperfusion-rewarming and separation from cardiopulmonary bypass. Preload recruitable stroke work and myocardial tissue water content were measured at 30, 60, and 120 minutes after bypass. EMD 96 785 (3 mg/kg) was given 15 minutes before bypass, and 2 micromol was given in the cardioplegic solution. Control animals received the same volume of saline vehicle. Arterial-coronary sinus lactate difference was similar in both animals receiving EMD 96 785 and control animals, suggesting equivalent myocardial ischemia in each group. RESULTS: Myocardial tissue water content increased from baseline in both animals receiving EMD 96 785 and control animals with cardiopulmonary bypass and cardioplegic arrest but was statistically lower in animals receiving EMD 96 785 compared with control animals (range, 1.0%-1.5% lower in animals receiving EMD 96 785). Preload recruitable stroke work decreased from baseline (97 +/- 2 mm Hg) at 30 (59 +/- 6 mm Hg) and 60 (72 +/- 9 mm Hg) minutes after cardiopulmonary bypass and cardioplegic arrest in control animals; preload recruitable stroke work did not decrease from baseline (98 +/- 2 mm Hg) in animals receiving EMD 96 785 and was statistically greater at 30 (88 +/- 5 mm Hg) and 60 (99 +/- 4 mm Hg) minutes after bypass and arrest compared with control animals. CONCLUSIONS: Sodium/hydrogen-exchanger inhibition decreases myocardial edema immediately after cardiopulmonary bypass and cardioplegic arrest and improves preload recruitable stroke work. Sodium/hydrogen-exchange inhibition during cardiac procedures with cardiopulmonary bypass and cardioplegic arrest may be a useful adjunct to improve myocardial performance in the immediate postbypass or arrest period.

Direct inhibition of the sodium/hydrogen exchanger after prolonged regional ischemia improves contractility on reperfusion independent of myocardial viability.

BACKGROUND: A mechanism for myocardial dysfunction after ischemia and reperfusion is Na(+)/H(+) exchanger activation. Although past in vivo models of limited ischemia and reperfusion intervals demonstrate that Na(+)/H(+) exchanger inhibition confers myocardial protection when administered at the onset of ischemia, the effect of Na(+)/H(+) exchanger inhibition on myocardial function after prolonged ischemia and reperfusion remains unknown. This investigation tested the hypothesis that Na(+)/H(+) exchanger inhibition instituted at reperfusion and after prolonged coronary occlusion in pigs would influence myocardial contractility independent of myocardial viability. METHODS: A coronary snare and sonomicrometry crystals were placed in pigs (n = 21, 32 kg). Coronary occlusion was instituted for 120 minutes followed by reperfusion for 180 minutes. At 105 minutes of ischemia, pigs were randomized to ischemia and reperfusion only (saline solution, n = 11) or Na(+)/H(+) exchanger inhibition (HOE-642, 3 mg/kg intravenously, n = 10). Myocardial injury was determined by tissue staining and measurement of plasma myocyte-specific enzymes. Myocardial contractility was determined by calculation of the regional end-systolic pressure-dimension relation (millimeters of mercury per centimeter) and by assessment of interregional shortening. RESULTS: Infarct size was not different between groups (39% +/- 6%, P =.26). Moreover, at 180 minutes of reperfusion, plasma troponin-I and creatine kinase MB values had increased to identical levels in the ischemia and reperfusion-only and Na(+)/H(+) exchanger inhibition groups (300 +/- 35 and 50 +/- 6 ng/mL, respectively). At 90 minutes of ischemia, regional end-systolic pressure-dimension relation decreased from baseline (5.7 +/- 0.5 versus 2.7 +/- 0.3, P <.05) in the area at risk. By 30 minutes of reperfusion, regional end-systolic pressure-dimension relation decreased further in the ischemia and reperfusion-only group (1.6 +/- 0.2, P <.05), but improved with Na(+)/H(+) exchanger inhibition (4.4 +/- 0.7, P <.05). CONCLUSIONS: Na(+)/H(+) exchanger inhibition instituted at reperfusion improved contractility independent of myocardial viability as assessed by absolute infarct size and myocyte-specific enzyme release. Thus, modulation of Na(+)/H(+) exchanger activity in the setting of prolonged ischemia and reperfusion may hold therapeutic potential.

Astrocyte stellation in saline media lacking bicarbonate: possible relation to intracellular pH and tyrosine phosphorylation.

Primary cultures of astrocytes exhibit a polygonal morphology, but on treatment with agents that increase cAMP they change to stellate cells. We found that astrocyte stellation also occurred on replacing the culture medium with saline buffered with HEPES. However, stellation did not occur when the medium was replaced with saline buffered with bicarbonate/CO(2) provided Ca(2+) was present. Since exposure of astrocytes to media lacking bicarbonate results in a decrease in intracellular pH (pH(i)) we sought evidence for an association between pH(i) and morphology. Astrocytic pH(i) was monitored for 60 min after transferring the cells to HEPES or bicarbonate-buffered saline. HEPES-induced stellation was associated with transient acidification which coincided with the morphological changes. Acidification was not observed in cells transferred to bicarbonate-saline. However when cytoplasmic acidification of cells in bicarbonate-saline was induced pharmacologically, rapid stellation occurred. Stellation induced by cAMP is reversed by activation of the RhoA pathway with lysophosphatidic acid (LPA). Here we found that LPA inhibited HEPES-induced stellation, but only with Ca(2+) present. Inhibition of stellation by LPA+Ca(2+) was associated with transient acidification followed by modest alkanization. A close association of tyrosine phosphorylation with stellation and pH(i) was observed. Thus incubation of astrocytes in HEPES-saline with orthovanadate to inhibit dephosphorylation abolished stellation and acidification; conversely incubation of cells in bicarbonate-saline with genistein to inhibit tyrosine kinases caused stellation and major acidification. Acidification may be one of several factors resulting in stellation, but it is not a necessary factor since stellation without acidification was observed in bicarbonate-saline lacking Ca(2+).

Positive inotropic effect of angiotensin II. Increases in intracellular Ca2+ or changes in myofilament Ca2+ responsiveness?

Although it is well known that Angiotensin II (Ang II) has a direct positive inotropic effect in several species, the mechanisms of this action are still poorly understood. The aim of this review is to analyze the possible subcellular mechanisms underlying Ang II-induced positive inotropic action. The binding of Ang II to its receptor triggers a complex signal transduction cascade that stimulates the intracellular formation of two second messengers, inositol 1,4,5-triphosphate (IP3), and 1,2, diacylglycerol (DAG). IP3 triggers the release of Ca2+ from intracellular stores in several cell types and has been shown to increase myofilament Ca2+ sensitivity. DAG activates protein kinase C (PKC), an enzyme that catalyzes the phosphorylation of different cellular proteins, including several proteins of the myofibrils. Distinct ionic transporters, like the Na+/H+ antiporter and the Na(+)-independent Cl-/HCO3- exchanger, implicated in the regulation of intracellular pH, and the Na+/Ca2+ exchanger which contribute to the intracellular Ca2+ homeostasis, have been shown to be activated by a PKC-dependent mechanism. Thus, either one of the Ang II-induced second messengers, that is, IP3 and DAG, has the potential to affect myocardial contractility by modifying either intracellular Ca2+, myofilament Ca2+ responsiveness, or both. As described herein, the available data do not allow a definitive single model to explain the mechanism of the Ang II-induced positive inotropic effect. Moreover, it is possible that the final action of Ang II on myocardial inotropism is the end product of a complex interaction of several of the mechanisms triggered by the hormone.

Interaction between monensin and CCl4 after chronic treatment: dolichol and retinol content of rat liver sinusoidal cells.

The aim of this investigation was to study retinol, which is known to decrease in hepatic stellate cells during fibrogenesis, and dolichol, which influences membrane fluidity and decreases in liver injury, in freshly isolated liver parenchymal and nonparenchymal cells after intoxication of rats with CCl4 combined with the ionophore monensin for 3, 5 and 7 weeks. To study the interrelationship between dolichol and vitamin A transport, a load of vitamin A was given to batches of rats 3 days before sacrifice. Monensin did not modify the action of CCl4 in hepatocytes. On administration of CCl4 and CCl4-monensin, dolichol decreased independently of vitamin A load, while retinol increased, especially when a load of vitamin A was given to rats 3 days before sacrifice. Hepatocytes appeared to no longer be able to export or metabolize vitamin A. In a subfraction of hepatic stellate cells (Ito-1 cells) dolichol always decreased, while retinol was no longer stored after each treatment; dolichol and retinol showed the same behavior but the decrease was more pronounced in monensin after vitamin A load and after 3 weeks. These data support the hypothesis that by modulating membrane characteristics, dolichol might be involved in intracellular or intercellular retinol transport and that altered transport between hepatocytes and Ito-1 cells might accompany liver injury. The data regarding another subfraction, Ito-2 cells, partly resemble those for the Ito-1 fraction and are in agreement with the heterogeneity of hepatic stellate cells. In Kupffer and sinusoidal endothelial cells, dolichol and retinol content was not homogeneous and was only slightly altered after the treatments. Monensin and CCl4 are not interactive. Although both drugs alter membrane lipids, their association allows some sinusoidal cell responses to be differentiated.

NHE8 mediates amiloride-sensitive Na+/H+ exchange across mosquito Malpighian tubules and catalyzes Na+ and K+ transport in reconstituted proteoliposomes.

Following a blood meal, the mosquito Aedes aegypti will have acquired an enormous sodium load that must be rapidly excreted to restore ion homeostasis. It is a process that demands robust sodium and fluid transport capabilities. Even though the identities of the components involved in this ion transport across the mosquito Malpighian tubule epithelia have not been completely determined, electrophysiological studies suggest the contribution of a Na(+)/H(+) exchanger extruding cations into the lumen driven secondarily by the proton gradient created by the V-type H(+)-ATPase in the tubules' apical membrane. We have identified the putative exchanger and designated it AeNHE8. Immunolocalization studies demonstrated that AeNHE8 is expressed in the apical membranes of Malpighian tubules, gastric caecae, and rectum. When heterologously expressed in salt-sensitive yeast cells lacking Na(+) extrusion and Na(+)/H(+) exchange proteins, AeNHE8 rescues the salt-sensitive phenotype and restores the cells' ability to grow in high NaCl media. Furthermore, heterologous expression of AeNHE8 in NHE-deficient fibroblast cells results in an amiloride-sensitive (22)Na(+) uptake. To determine the exchanger's kinetic properties, we reconstituted membranes from yeast cells expressing the protein into lipid proteoliposomes and assayed for cation-dependent H(+) exchange by fluorimetric methods. Our results indicate that AeNHE8 mediates saturable exchange of Na(+) and K(+) for H(+). We propose that AeNHE8 may be coupled to the inward H(+) gradient across the Malpighian tubules and plays a role in the extrusion of excess sodium and potassium while maintaining steady intracellular pH in the principal cells.

Signaling pathways in the biphasic effect of ANG II on Na+/H+ exchanger in T84 cells.

The effect of ANG II on pH(i), [Ca(2+)](i) and cell volume was investigated in T84 cells, a cell line originated from colon epithelium, using the probes BCECF-AM, Fluo 4-AM and acridine orange, respectively. The recovery rate of pH(i) via the Na(+)/H(+) exchanger was examined in the first 2 min following the acidification of pH(i) with a NH(4)Cl pulse. In the control situation, the pH(i) recovery rate was 0.118 +/- 0.001 (n = 52) pH units/min and ANG II (10(-12) M or 10(-9) M) increased this value (by 106% or 32%, respectively) but ANG II (10(-7) M) decreased it to 47%. The control [Ca(2+)](i) was 99 +/- 4 (n = 45) nM and ANG II increased this value in a dose-dependent manner. The ANG II effects on cell volume were minor and late and should not interfere in the measurements of pH(i) recovery and [Ca(2+)](i). To document the signaling pathways in the hormonal effects we used: Staurosporine (a PKC inhibitor), W13 (a calcium-dependent calmodulin antagonist), H89 (a PKA inhibitor) or Econazole (an inhibitor of cytochrome P450 epoxygenase). Our results indicate that the biphasic effect of ANG II on Na(+)/H(+) exchanger is a cAMP-independent mechanism and is the result of: 1) stimulation of the exchanger by PKC signaling pathway activation (at 10(-12) - 10(-7) M ANG II) and by increases of [Ca(2+)](i) in the lower range (at 10(-12) M ANG II) and 2) inhibition of the exchanger at high [Ca(2+)](i) levels (at 10(-9) - 10(-7) M ANG II) through cytochrome P450 epoxygenase-dependent metabolites of the arachidonic acid signaling pathway.

Quantitative structure-activity relationship study of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)guanidines as potent Na/H exchange inhibitors.

We have previously reported that N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-car bonyl)guanidine (4b) methanesulfonate salt (KB-R9032) is a potent and highly water-soluble Na/H exchange inhibitor. In a series of studies on Na/H exchange inhibitors, we designed and synthesized N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)guanidines (5) as more potent inhibitors with high water-solubility. The design strategy for 5 was based on a quantitative structure-activity relationship (QSAR) study, involving the proportional relationship between the biological activity and hydrophobicity of the ring structure of compounds 4. As expected, compounds 5 showed more potent activity than 4. It was found by using the QSAR analysis that 5 were about five-fold more potent than 4. The increase in potency of compounds 5 well agreed with our previous QSAR analysis result. The most potent derivative was the methanesulfonate salt 5d of the 4-isopropyl derivative (IC50=0.0091 microM). And in addition to the in vitro study, 5d showed significant protective activity against a rat acute myocardial infraction model.

[Rapid acid extrusion response triggered by alpha-1a adrenoceptor in CHO cells].

Using a microphysiometer with synchronized valve switching, we investigated real-time acid extrusion from CHO cells, in which human alpha-1a adrenoceptor (AR) is stably expressed, in response to noradrenaline (NA). The time course of the extracellular acidification rate after stimulation had two phases: in the first phase, it transiently reached a rate several times greater than the base rate with a peak at around 10 s, and in the second, it reached to 2 times the base rate and reached a plateau in 2 min. Both phases showed concentration-dependent increase of acidification rates in response to NA, but had distinct pEC50 values: 5.6 for the transient phase and 7.2 for the steady phase. HOE642, an inhibitor of Na(+)-H+ exchanger (NHE) 1, inhibited the acid extrusion response in a concentration-dependent manner. HOE642 had high pIC50 values (7.3) for inhibition of the transient phase response. In contrast, it revealed the presence of two components in the steady phase response: one had high pIC50 values (8.2) and the other had low pIC50 values (6.0). As Ca2+ was depleted, the transient phase disappeared, while the steady phase was not affected. These results suggest that alpha-1a AR drives two acid extrusion systems in CHO cells upon stimulation: one elicits the transient response that is largely mediated by a HOE642-sensitive and Ca(2+)-dependent NHE, presumably NHE1, and the other induces the steady acid extrusion that is mediated by NHE1 and another NHE that has low sensitivity to HOE642.

The Na+/K+ATPase mediates the alpha 1-adrenoceptor stimulated increase in 86Rb(+)-uptake in isolated ventricular cardiomyocytes from adult rat heart.

The aim of the present study was to identify the mechanism(s) responsible for the alpha 1-adrenoceptor stimulated increase in potassium uptake in ventricular cardiomyocytes isolated from adult rat heart. The Na+/K+ATPase blocker ouabain the Na+/K+/2Cl(-)-cotransporter blocker bumetanide, the Na+/H(+)-exchanger blocker HOE 694 and the potassium channel blocker 4-aminopyridine were used as experimental tools. 86Rb+ was used as potassium analogue. The basal 86Rb(+)-uptake rate was 0.25 +/- 0.01 ml/g protein x min. Maximal alpha 1-adrenoceptor stimulation increased the 86Rb(+)-uptake 38 +/- 2%. Ouabain dose dependently eliminated the alpha 1-adrenoceptor stimulated response with a -logIC50-value of 3.64 +/- 0.23. Bumetanide did not affect the stimulated response, and there was no effect of bumetanide on the ouabain sensitive component. HOE 694 and 4-aminopyridine had no effect on the stimulated 86Rb(+)-uptake. Ouabain and HOE 694 also dose dependently inhibited a portion of the basal 86Rb(+)-uptake (about 60% and 20%, respectively), but there was no effect of bumetanide or 4-aminopyridine on the basal 86Rb(+)-uptake. The results show that the Na+/K+ATPase alone mediates the alpah 1-adrenoceptor stimulated increase in potassium uptake in this preparation of ventricular cardiomyocytes isolated from adult rat heart.

Signaling pathways in the biphasic effect of angiotensin II on apical Na/H antiport activity in proximal tubule.

Low concentrations of angiotensin II (Ang II) increase, whereas high concentrations inhibit the apical Na/H antiporter activity in the proximal tubule, but the respective roles of the different signaling pathways in mediating these effects remains unsettled. We studied the effects of both low and high doses of Ang II in the presence of selective signaling pathway inhibitors, on the apical Na/H antiport activity of rat proximal tubule. Experiments were carried out in intact cells of freshly prepared tubule fragments obtained from the outer third of cortex, that is, devoid of basolateral Na/H antiport activity in the absence of bicarbonate transport and H(+)-ATPase activity. In tubules acid-loaded by an NH4Cl prepulse, Na/H antiport activity was assessed by the initial rate of intracellular pH recovery (dpHi/dt), measured with BCECF. When tubules were preincubated with low dose Ang II (10(-11) M for 3 min), dpHi/dt increased by 25 +/- 8%, whereas incubation with high dose Ang II (10(-7) M for 3 min) decreased dpHi/dt by 30 +/- 4%, compared to control (P < 0.01 in both cases). Both effects were abolished in the presence of 2.10(-3) M amiloride. Low dose Ang II-induced increase in dpHi/dt was not affected by preincubation with a specific PKA inhibitor, Rp-CPT-cAMP 10(-4) M, and was completely abolished by preincubation with PKC inhibitors, staurosporine 10(-7) M, sphingosine 5.10(-6) M, or calphostin 10(-6) M. In addition, pretreatment of rats with pertussis toxin led to a partial inhibition of the effect of low dose Ang II. The high dose-Ang II-induced decrease in dpHi/dt was not affected by pretreatment with a calcium-calmodulin kinase inhibitor W-7 10(-4) M. Conversely, pretreatment with the cytochrome P-450 inhibitor econazole 10(-5) M reversed the inhibitory effect of high dose Ang II to a stimulatory effect (24 +/- 8%, P < 0.01), quantitatively similar to the effect of low dose Ang II. In addition, arachidonate was found to exert an econazole-sensitive dose-dependent inhibitory effect on dpHi/dt, and 5,6-EET 10(-6) M, a cytochrome P-450 derived-arachidonic acid metabolite, induced a 38 +/- 9% inhibition, similar to that observed with high dose Ang II alone. There was no additive effect of 5,6-EET and high dose Ang II. Finally, pretreatment with two PLA2 inhibitors (BromoPhenacylBromide, 6.10(-6) M, and oleyloxyethyl phosphorylcholine, 5.10(-6) M) reversed the inhibitory effect of high dose Ang II to a stimulatory effect (32 +/- 11% and 25 +/- 11%, respectively, P < 0.05 for both inhibitors). We conclude that, in intact rat proximal cells, low dose Ang II stimulates the apical Na/H antiport through a pertussis toxin-sensitive G protein-dependent PKC pathway, whereas high dose Ang II inhibits the Na/H antiport activity through the PLA2- and cytochrome P-450-dependent metabolites of arachidonate.

Analisis ecocardiografico del efecto de diferentes inhibidores del intercambiador Na+/H+ sobre la estructura y funcion sistolica del ventriculo izquierdo en ratas espontaneamente hipertensas / Echocardiographic analysis of the effect of different Na+/H+ exchanger inhibitors on left

El presente estudio fue proyectado para analizar mediante ecocardiograma los efectos del HOE 642 (cariporide) (HOE) y del BIIB 723 (BIIB) sobre la estructura y función sistólica del ventrículo izquierdo en ratas espontáneamente hipertensas (SHR)- 8 con 30 mg/kg/día de HOE, 8 con 30 mg/kg/día de BIIB durante 30 días y 4 sin tratamiento (grupo control) durante esos 30 días. Los distintos parámetros analizados no mostraron cambios durante ese período en las ratas controles. Si bien el HOE determinó un leve descenso de la presión arterial (C: 184 ± 1.75 mm Hg; 30d:176.20 ± 2.60 mm Hg, p <0.01), no detectada con BIIB,ambas drogas provocaron un aumento del estrés sistólico pico (HOE C:166 ± 29 kdinas/cm2; 30d: 204 ± 34kdinas/cm2, p <0.04. BIIB C: 164 ± 25.90 kdinas/cm2; 30d: 234 ± 29.30 kdinas/cm2, p<0.02).Tanto HOE comoBIIB redujeron significativamente la masa ventricular izquierda (MVI) (HOE C: 612.50±50 mg; 30d:452 ± 37 mg,p <0.01; BIIB C: 544 ± 16mg; 30 d: 374 ± 25 mg, p<0.01). El porcentaje de acortamiento endocárdico no semodificó luego del tratamiento con HOE (C: 62.30 ± 2.75; 30d 65.50 ± 2.40%, ns) y BIIB (C: 63.20 ± 2.39%;30d 67.20 ± 1.62%, ns). Los resultados analizados permiten concluir que ambos inhibidores determinaron similarreducción de la MVI. Esa reducción se acompañó de mejoría en los índices de evaluación de la función sistólica ventricular izquierda, pese al incremento del estrés sistólico pico. Estas evidencias sugieren que independientemente del inhibidor utilizado se encuentra un aumento del inotropismo, previamente comprometidodurante el desarrollo de la hipertrofia

The aim of this study was to analyze by echocardiogram, the action of two Na+/H+ exchange, inhibitors, HOE 642 (HOE) and BIIB 723 (BIIB) on left ventricular (LV) mass and LV systolic function. We studied 16 spontaneously hypertensive rats (SHR), 8 treated with HOE 30 mg/kg/day, 8 with 30 mg/kg/day of BIIB during 30 days and 4 SHR as controls during those 30 days. Results are expressed as mean values ± SEM. The systolic blood pressure and theechocardiograpic parameters examined did not evidence changes during that period in the controls rats. Eventhough HOE determined a slight decrease in blood pressure (HOE C: 184 ± 1.75 mm Hg; HOE 30d: 176.20 ±2.60 mm Hg - p <0.01) which was not detected with BIIB, both drugs provoked an increase of peak systolic stress (HOE C: 166 ± 29 kdynes/cm2; HOE 30d: 204 ± 34 kdynes/cm2, p <0.04; BIIB C: 164 ± 25.90 kdynes/cm2; BIIB 30d: 234 ± 29.30 kdynes/cm2, p <0.02). HOE and BIIB reduced LV mass after 30 days of administration (HOE C: 612.50 ± 50 mg; 30d: 452 ± 37 mg, p <0.01. BIIB C: 544 ± 16mg; 30d: 374 ± 25 mg, p <0.01). LV endocardial shortening was similar independently of the NHE inhibitors used (HOE C: 62.30 ± 2.75%; 30d: 65.50 ± 2.40%, ns. BIIB C: 63.20 ± 2,39%; 30d 67,20 ± 1.62%, ns). These data demonstrate that long-treatment with HOE or BIIB produced similar LV mass regression without changes in endocardial fractional shortening in spite of the increase of peak systolic stress. This finding could represent an increased inotropism previously depressed by the development of hypertrophy