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Biomedical subjects

A Aviv

Publications and source records attributed to A Aviv.

At least 55 records · Page 3Linked to original sources
PubMed1996

Cellular calcium and sodium regulation, salt-sensitivity and essential hypertension in African Americans.

The predisposition of African Americans to the salt sensitive form of essential hypertension may result from increased freely exchangeable Ca in intracellular Ca stores and a higher cellular Ca turnover (i.e., enhanced Ca entry into and accelerated Ca extrusion from the cytosol). These alterations entail higher activities of Ca extrusion transport systems, including the Na+/Ca2+ exchanger (NCE), which extrudes Ca in exchange for external Na+, and plasma membrane Ca-ATPase (PMCA) that extrudes Ca in exchange for external protons. The higher activity of PMCA, coupled with a higher metabolic activity resulting from a rise in freely exchangeable Ca, increase cellular acid load. Adaptive cellular mechanisms must evolve under these conditions, whereby increased activity of the Na/H exchanger (NHE-1) maintains normal cytosolic pH by enhancing the extrusion of cytosolic protons in exchange for extracellular Na. Cells with increased cellular Ca stores and enhanced Ca turnover may be particularly vulnerable to the factors that inhibit the Na-pump. By inhibiting the Na-pump, these factors diminish the transmembrane Na gradient and consequently inhibit the forward mode of the NCE. Since cells from African Americans show increased Ca turnover, they should retain more Ca upon exposure to Na-pump inhibitors; a heightened sensitivity to Na-pump inhibitors could therefore underlie the propensity of African Americans and other individuals with accelerated cellular Ca turnover rate to the salt sensitive form of essential hypertension. Accelerated cellular Ca turnover in African Americans also explains their better response to Ca antagonists compared with other antihypertensive drugs.

Antihypertensive Agents↗
PubMed1996

Recent advances in cellular Ca2+ homeostasis: implications to altered regulations of cellular Ca2+ and Na(+)-H+ exchange in essential hypertension.

This review covers the role of the sarco(endo)plasmic reticulum in regulating Ca2+ influx across the plasma membrane, the role of cytosolic free Ca2+ in modulating mitochondrial function, and the role of the plasma membrane in regulating sarco(endo)plasmic reticulum Ca2+, focusing on recent findings that shed a new light on cellular Ca2+ regulation. Mechanisms of interactions among the sarco(endo)plasmic reticulum, mitochondria, and the plasma membrane are discussed with a view to explain the lack of consensus regarding the relationship between the cytosolic free Ca2+ and blood pressure, and the enigmatic behavior of the Na(+)-H+ exchanger in blood cells (primarily platelets and lymphocytes) from patients with essential hypertension.

Biological Transport, Active↗
PubMed1996

Differences between store-dependent Ca2+ fluxes in lymphocytes from African Americans and whites.

OBJECTIVE: To investigate differences between store-dependent Ca2+ in African American and white men. METHOD: Thapsigargin, a potent and specific inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase, was used as a probe to elicit store-dependent Ca2+ fluxes. Treatment with this agent caused a rise in the cytosolic free Ca2+ due to the egress of Ca2+ from thapsigargin-sensitive Ca2+ stores and the acceleration of external Ca2+ influx through store-dependent Ca2+ channels. DESIGN: Lymphocytes were obtained from 22 African Americans and 23 whites. These cells were subjected to thapsigargin treatment and changes in the cellular Ca2+ profiles were monitored. RESULTS: Both in Ca(2+)-free and in Ca(2+)-containing media the increases in cytosolic free Ca2+ concentrations after thapsigargin treatment were greater in lymphocytes from African Americans than they were in those from whites. The greater levels of cytosolic Ca2+ concentration were coupled with higher rates of Ca2+ extrusion in thapsigargin-treated lymphocytes from African Americans. CONCLUSIONS: These findings suggest that store-dependent Ca2+ fluxes are greater in lymphocytes from African Americans than they are in those from whites. This phenomenon increases the Ca2+ turnover rate and might augment the sensitivity to agonists acting through Ca2+ signaling systems, thereby predisposing African Americans to essential hypertension.

Adult↗
PubMed1996

Plasmin-platelet interaction involves cleavage of functional thrombin receptor.

We tested the hypothesis that the inhibition of thrombin-induced platelet activation by plasmin is mediated via the enzymatic action of plasmin on the functional thrombin receptor. We monitored the binding of the anti-thrombin receptor antibody [anti-TR-(34-46)] to platelets; this binding is sensitive to the cleavage of the thrombin receptor at amino acid residues Arg-41 to Ser-42. Plasmin inhibited anti-TR-(34-46) binding in dose- and time-dependent manners. The inactive synthetic peptide with the amino acid sequence 40-55 of the thrombin receptor (D-FPRSFLLRNPNDKYEPF) was similarly cleaved by thrombin and plasmin to an active peptide (SFLLRNPNDKYEPF) that produced robust cytosolic Ca2+ responses. At high concentrations, plasmin itself can activate platelets. We explored this effect with the use of anti-TR-(1-160). This antibody abolished the cytosolic Ca2+ responses to thrombin and to the thrombin receptor-activating peptide SFLLRN but did not attenuate the plasmin-induced cytosolic Ca2+ response. Thus plasmin inhibits thrombin-evoked platelet activation by cleaving the thrombin receptor, but the plasmin-induced cytosolic Ca2+ response is not due to the generation of the tethered peptide of the thrombin receptor.

Amino Acid Sequence↗
PubMed1996

Inositol treatment of obsessive-compulsive disorder.

OBJECTIVE: Earlier studies reported that inositol, a simple polyol second messenger precursor, was effective in controlled trials for patients with depression and panic. In this study its effectiveness in obsessive-compulsive disorder was investigated. METHOD: Thirteen patients with obsessive-compulsive disorder completed a double-blind, controlled crossover trial of 18 g/day of inositol or placebo for 6 weeks each. RESULTS: The subjects had significantly lower scores on the Yale-Brown Obsessive Compulsive Scale when taking inositol than when taking placebo. CONCLUSIONS: The authors conclude that inositol is effective in depression, panic, and obsessive-compulsive disorder, a spectrum of disorders responsive to selective serotonin reuptake inhibitors.

Adult↗
PubMed1995

Role of cyclic nucleotides in store-mediated external Ca2+ entry in human platelets.

This study explores the role of cyclic nucleotides (i.e. cyclic AMP and cyclic GMP) in store-regulated external Ca2+ entry in human platelets. To stimulate store-regulated external Ca2+ entry, thapsigargin was used to deplete Ca2+ from the dense tubules, and sodium nitroprusside and iloprost respectively were used to stimulate endogenous cyclic GMP and cyclic AMP formation. Pretreatment with sodium nitroprusside and iloprost (a) attenuated the thapsigargin-evoked external Ca2+ entry and (b) reduced the rate of Ca2+ release from the dense tubules. The effects on external Ca2+ entry and Ca2+ release from the dense tubules were exerted independently and were apparently mediated through activation of the respective cyclic nucleotide-dependent protein kinases. Both sodium nitroprusside and iloprost reduced tyrosine kinase phosphorylation of a number of proteins, particularly a 72 kDa protein band. Both agents also attenuated the thapsigargin-evoked tyrosine kinase phosphorylation of the 72 kDa band. Intracellular Ca2+ depletion resulted in a reduction in tyrosine kinase-mediated phosphorylation of a number of protein bands, including the 72 kDa band and the further attenuation of thapsigargin-mediated tyrosine phosphorylation of this band. The effects of the cyclic nucleotides on cellular Ca2+ homoeostasis in thapsigargin-treated platelets were not exerted via acceleration of Ca2+ extrusion or Ca2+ sequestration into the mitochondria. We conclude that cyclic nucleotides participate in store-regulated control of external Ca2+ entry by slowing down the rate of external Ca2+ entry and Ca2+ release from intracellular Ca2+ stores. These effects are apparently mediated via cyclic nucleotide-dependent protein kinases and the attenuation of protein phosphorylation by tyrosine kinases.

Biological Transport↗
PubMed1995

Duality of plasmin effect on cytosolic free calcium in human platelets.

Plasmin caused a modest and gradual increase in platelet cytosolic Ca2+, mediated through both Ca2+ mobilization and external Ca2+ entry. This response was associated with accelerated Ca2+ extrusion and protein tyrosine phosphorylation. Plasmin-enhanced external Ca2+ entry and Ca2+ extrusion (but not Ca2+ mobilization) were attenuated by the tyrosine kinase inhibitor, genistein. Plasmin inhibited the thrombin-evoked increase in cytosolic Ca2+ and also inhibited the Ca2+ response to the tethered peptide TRAP-6 of the thrombin receptor. Furthermore, plasmin inhibited the binding of 125I-labeled alpha-thrombin to platelets. The inhibitory effect of plasmin on the thrombin response shared some characteristics with the effect of protein kinase C stimulators but was not reversed by protein kinase C inhibitors. Plasmin did not change platelet cyclic nucleotides. These results suggest a dual effect of plasmin. Plasmin produces a small rise in platelet cytosolic Ca2+ and a tyrosine kinase-dependent enhancement of Ca2+ turnover (external Ca2+ influx and Ca2+ efflux). However, it also attenuates the thrombin-evoked cytosolic Ca2+ response by blocking Ca2+ mobilization and slowing the rate of external Ca2+ influx. The latter feature would result in a plasmin-induced inhibition of thrombogenesis.

Blood Platelets↗
PubMed1995

Increased calcium stores in platelets from African Americans.

Differences in cation transport have been observed between African Americans and whites. These differences may underlie the increased predisposition of African Americans to essential hypertension. To further explore these racial differences, we used platelets as a cellular model for calcium regulation. We measured 45Ca fluxes in platelets from 21 African American and 25 white men. Additionally, using fura 2, we measured cytosolic free calcium levels in resting platelets and platelets treated with ouabain and thrombin. Platelet 45Ca uptake was described by two exchangeable pools: a small, rapidly exchangeable pool and a larger, slowly exchangeable pool. Both pools were larger in platelets from African Americans than from whites (263 versus 185 pmol per 1 x 10(8) platelets for the rapidly exchangeable pool, P < .05; 744 versus 532 pmol per 1 x 10(8) platelets for the slowly exchangeable pool, P < .01). 45Ca washout was described by a rapidly exchangeable pool and a static pool. The former was also higher in platelets from African Americans than from whites (246 versus 202 pmol per 1 x 10(8) platelets, P < .01). The cytosolic free calcium concentrations in resting platelets were lower in African Americans than in whites. After treatment with ouabain and thrombin, the sustained posttransient levels of cytosolic free calcium increased to a greater extent in platelets from African Americans (46.7 nmol/L) than from whites (34.5 nmol/L, P = .033). Platelets from African Americans demonstrate higher intracellular calcium stores than platelets from whites. This racial difference could explain the sensitivity of African Americans to vasoactive agents acting through calcium mobilization from intracellular stores and cytosolic calcium.

Adult↗
PubMed1995

Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder.

OBJECTIVE: Because they found in an earlier study that inositol, an important intracellular second-messenger precursor, was effective against depression in open and double-blind trials, the authors studied its effectiveness against panic disorder. METHOD: Twenty-one patients with panic disorder with or without agoraphobia completed a double-blind, placebo-controlled, 4-week, random-assignment crossover treatment trial of 12 g/day of inositol. RESULTS: The frequency and severity of panic attacks and the severity of agoraphobia declined significantly more after inositol than after placebo administration. Side effects were minimal. CONCLUSIONS: The authors conclude that inositol's efficacy, the absence of significant side effects, and the fact that inositol is a natural component of the human diet make it a potentially attractive therapeutic for panic disorder.

Adult↗
PubMed1995

The endothelin receptor profile in L6 myotubes.

In this study we characterized the endothelin (ET) receptors of cultured L6 myotubes in order to gain a further insight into the mechanism of the ET effect on skeletal muscle cells. Displacements of 125I-ET-1 by unlabeled ET-1, ET-2 and ET-3 revealed receptors with a high affinity (Kd < 1 nmol/l) to ET-1 and ET-2 and a low affinity (Kd > 100 nmol/l) to ET-3, which suggested the presence of primarily ETA receptors on L6 myotubes. These findings were complemented by displacement binding kinetics, in which the ETA receptor antagonist JKC-301 was used. More-over, the ET-1-evoked increase in the cytosolic free Ca was blocked by JKC-301 but not by the ETB receptor antagonist IRL-1038. Collectively, these findings indicate that the ET-mediated response in cultured skeletal muscle cells is through the ETA receptor.

Calcium↗
PubMed1994

Inhibition of Ca2+ entry by Ca2+ overloading of intracellular Ca2+ stores in human platelets.

1. This study examined the effect of overloading human platelet intracellular Ca2+ stores on the rate of agonist-evoked external Ca2+ entry. To overload the Ca2+ stores (presumably dense tubules), external Na(+)-dependent Ca2+ efflux via Na(+)-Ca2+ exchange was inhibited by pretreating the cells with ouabain or Na(+)-free medium. Ca2+ regulation was then examined after exposure to thrombin, ADP and thapsigargin. Cytosolic free Ca2+ levels were monitored using the fluorescent probe fura-2 and external Ca2+ influx was assessed by the rates of extracellular Mn2+ or 45Ca2+ uptake. 2. Both ouabain and Na(+)-free pretreatments caused a slight increase in the resting cytosolic free Ca2+. 3. In 1 mM Ca(2+)-containing medium, Ca(2+)-overloaded platelets showed similar thrombin-evoked cytosolic free Ca2+ responses to those of control platelets. However, in Ca(2+)-free medium, they showed substantially greater thrombin-evoked cytosolic free Ca2+ responses than control platelets. Moreover, increased thrombin-evoked Ca2+ mobilization from Ca2+ storage sites was accompanied by a diminished rate of thrombin-evoked external Ca2+ entry. 4. Similar reductions in the rate of external Ca2+ entry were observed after treatment with ADP and thapsigargin. 5. Protein kinase C inhibitors (calphostin C and staurosporine) failed to reverse the effect of ouabain pretreatment on thrombin-induced changes in the cytosolic free Ca2+ response. 6. Inositol 1,4,5-trisphosphate profiles in ouabain-treated and non-treated platelets were not significantly different. 7. These data indicate that increased Ca2+ in the dense tubules is associated with diminished agonist-evoked external Ca2+ influx.

Adenosine Diphosphate↗
PubMed1994

Cytosolic Ca2+, Na+/H+ antiport, protein kinase C trio in essential hypertension.

The relationships among the cytosolic free Ca2+ (Cai), protein kinase C (PKC), and the Na+/H+ antiport may hold the key to unraveling the causes and origin of essential hypertension. Increased cellular Ca2+, accelerated Cai turnover rate, or both occur in concert with activation of PKC and the Na+/H+ antiport in a variety of cells. In the vascular smooth muscle cell a rise in Cai produces increased tone and in the kidney it enhances sodium retention through stimulation of the Na+/H+ antiport in the renal tubules. In skeletal muscle increased Cai and augmented PKC activity produces insulin resistance, which is a major characteristic of essential hypertension. Moreover, elevation of Cai, in conjunction with increased activities of PKC and the Na+/H+ antiport, may exert trophic effects on the vasculature and the heart, thereby explaining the narrowing of the vascular lumen in peripheral arteries and the cardiac hypertrophy of long-standing hypertension. Because essential hypertension is a common disorder, its evolutionary advantage in primeval times could rest in skeletal muscle, where higher Ca2+ stores and increased Na+/H+ antiport activity enhanced muscular performance and provided a crucial survival element.

Animals↗
PubMed1994

Role of external Na+ and cytosolic pH in agonist-evoked cytosolic Ca2+ response in human platelets.

The role of external Na+ in agonist-evoked platelet Ca2+ response is poorly understood. This was explored in this study. Removal of external Na+ decreased both cytosolic Ca2+ mobilization and external Ca2+ entry, induced by thrombin but not by ADP or vasopressin. That external Na+ regulates thrombin activities was demonstrated by 1) Na+ dependency of the amidolytic activity of thrombin, 2) inhibition of thrombin binding to the high-affinity binding sites in Na(+)-free medium, and 3) attenuation of thrombin-induced inositol 1,4,5-trisphosphate production in Na(+)-free medium. Moreover, Ca2+ response to the thrombin receptor 6-amino acid peptide was independent of external Na+. The role of external Na+ in modifying agonist-evoked Ca2+ response through activation of Na+/H+ antiport and cytosolic alkalinization was then explored. Cytosolic alkalinization by monensin or NH4Cl enhanced thrombin, ADP, and thimerosal-induced external Ca2+ entry. Thimerosal-induced acceleration of external Ca2+ entry was diminished by the inhibition of Na+/H+ antiport. Thus external Na+ enhances thrombin activities, and cytosolic pH mediates store-regulated external Ca2+ entry. However, Na+/H+ antiport activation is not essential for agonist-evoked Ca2+ mobilization and external Ca2+ entry.

Blood Platelets↗
PubMed1994

Endothelin mobilizes calcium and enhances glucose uptake in cultured human skeletal myoblasts and L6 myotubes.

In this study we used endothelin as a paradigm to explore the concept that some vasoactive agents, acting through mobilization of Ca2+ and stimulation of protein kinase C, can interact with human skeletal muscle and modify its glucose transport. Cultured human skeletal myoblasts from the vastus lateralis demonstrated two subclasses of high-affinity endothelin receptors and a robust increase in cytosolic free Ca2+ upon exposure to endothelin. The endothelin-evoked rise in cytosolic free Ca2+ primarily resulted from Ca2+ mobilization from intracellular organelles. Both endothelin and insulin enhanced [3H]deoxy-D-glucose uptake in human myoblasts, but their effects were not additive. These findings also were observed in differentiated myotubes of L6 skeletal muscle cells. Moreover, [3H]deoxy-D-glucose uptake in human myoblasts was enhanced by treatment with phorbol 12-myristate 13-acetate. The endothelin- and insulin-mediated increases in [3H]deoxy-D-glucose were totally ablated by treatment with calphostin C. Such observations suggest that endothelin can enhance glucose uptake in human skeletal muscle. This is mediated through mechanisms that are at least partially protein kinase C dependent. Thus, increased levels of endothelin in vascular beds may contribute to altered glucose metabolism in essential hypertension.

Animals↗
PubMed1994

Blood pressure inversely correlates with thrombin-evoked calcium rise in platelets.

Earlier investigations showed a positive correlation between basal cytosolic free calcium in human platelets and blood pressure; however, recent studies have failed to show this relation. We undertook the present work to examine which platelet cytosolic calcium parameters (namely, cytosolic calcium in resting or stimulated states in calcium-containing and calcium-free media) present the least variability and best correlation with blood pressure. We studied 17 healthy white men on three different occasions separated by 1- and 4-week intervals. Their manual and ambulatory automated 24-hour blood pressure measurements were correlated with cytosolic calcium in resting and stimulated (thrombin-treated) fura 2-loaded platelets. The following cytosolic calcium parameters were measured in 1 mmol/L calcium and calcium-free media: basal cytosolic calcium, peak thrombin-evoked cytosolic calcium, and post-transient cytosolic calcium 5 minutes after thrombin treatment. The highest and lowest coefficients of variation were respectively shown by the basal cytosolic calcium (22.8%) and peak thrombin-evoked cytosolic calcium (10.1%) in calcium medium. Basal cytosolic calcium did not correlate with any of the blood pressure parameters. Of the cytosolic calcium parameters, peak thrombin-evoked cytosolic calcium in calcium medium demonstrated consistent (negative) correlations with blood pressure, with better correlations shown with diastolic than systolic blood pressure of both automated and manual blood pressure readings. Peak thrombin-evoked cytosolic calcium in calcium medium showed similar correlations with nighttime and daytime automated blood pressure measurements. There were no correlations between peak thrombin-evoked cytosolic calcium in calcium-free medium and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Differences in platelet calcium regulation between African Americans and Caucasians: implications for the predisposition of African Americans to essential hypertension.

OBJECTIVE: To study differences in cytosolic free calcium regulation between African Americans and Caucasians, using platelets as a model for studying cellular physiology. DESIGN: Platelet calcium regulation in apparently healthy African American and Caucasian males was examined. METHODS: Using fura-2, calcium influx and cytosolic calcium extrusion were monitored after treatment with thapsigargin, an inhibitor of the Ca-ATPase in the dense tubular membrane system. RESULTS: Compared with Caucasians, platelets from African Americans demonstrated a higher calcium influx into the cytosol (from the external medium and dense tubular membrane system), as well as enhanced calcium extrusion from the cytosol. CONCLUSIONS: Such findings indicate that platelets from African Americans have increased intracellular calcium stores or increased cellular calcium turnover, or both. If these racial differences involve other cells, such as vascular smooth muscle cells, they could underlie the predisposition of African Americans to essential hypertension.

Adult↗