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I Rubinstein

Publications and source records attributed to I Rubinstein.

At least 37 records · Page 2Linked to original sources
PubMed2000

Electro-osmotically induced convection at a permselective membrane

The paper is concerned with convection at an ion exchange electrodialysis membrane induced by nonequilibrium electro-osmosis in the course of concentration polarization under the passage of electric current through the membrane. Derivation of nonequilibrium electro-osmotic slip condition is recapitulated along with the linear stability analysis of quiescent electrodiffusion through a flat ion exchange membrane. Results of numerical calculation for nonlinear steady state convection, developing from the respective instability, are reported along with those for a slightly wavy membrane. Besides these results, we report those of time dependent calculations for periodic and chaotic oscillations, resulting from instability of the respective steady state flows, and also the results of recent experiments with modified membranes. These latter rule in favor of electro-osmotic versus bulk electroconvective origin of overlimiting conductance through ion exchange membranes.

Journal Article↗
PubMed2000

Subtilisin increases macromolecular efflux from the oral mucosa.

The purpose of this study was to determine whether subtilisin, a potent serine proteinase derived from Bacillus species contaminating smokeless tobacco, increases macromolecular efflux from the oral mucosa and, if so, whether local elaboration of bradykinin mediates this response. Using intravital microscopy, I found that suffusion of subtilisin elicits significant, concentration-dependent leaky site formation and an increase in the clearance of fluorescein isothiocyanate-labeled dextran (molecular mass, 70 kDa) from the in situ hamster cheek pouch (P<0.05). Heat-inactivated subtilisin had no significant effects on macromolecular efflux. Subtilisin-induced responses were significantly attenuated by Hoe 140 and NPC 17647, two structurally distinct selective bradykinin B(2) receptor antagonists, but not by des-Arg(9)-[Leu(8)]bradykinin, a selective bradykinin B(1) receptor antagonist, or CP-96,345, a selective neurokinin-1 receptor antagonist. Aprotinin, but not leupeptin, significantly attenuated subtilisin-induced increase in macromolecular efflux. Indomethacin had no significant effects on subtilisin-induced responses. Collectively, these data indicate that subtilisin increases the macromolecular efflux from the in situ hamster cheek pouch in a catalytic-site-dependent fashion through local elaboration of bradykinin. This response does not involve the stimulation of local afferent nerves or the production of prostaglandins.

Animals↗
PubMed2000

Smokeless tobacco potentiates VIP-induced DNA synthesis and inactivates NEP 24.11 in oral keratinocytes.

The purpose of this study was to determine whether exposure of cultured chemically transformed hamster oral keratinocytes (HCPC-1) to an aqueous extract of smokeless tobacco (STE) potentiates DNA synthesis elicited by vasoactive intestinal peptide (VIP), an autocrine neuropeptide, and, if so, whether this response is associated with inactivation of neutral endopeptidase 24.11 (NEP 24. 11), an ectoenzyme that cleaves and inactivates VIP very effectively, in these cells. I found that STE and VIP each elicited a modest, albeit significant, increase in DNA synthesis in cultured HCPC-1 cells (P < 0.05). However, incubation of HCPC-1 cells with STE together with VIP evoked a significant, concentration- dependent increase in DNA synthesis that was mediated by VIP receptors. The effects of STE and VIP were synergistic. Maximal response was observed after a 48-h incubation. STE significantly attenuated NEP 24.11 activity in HCPC-1 cells at a time when VIP-induced DNA synthesis was maximal. Collectively, these data indicate that STE potentiates VIP-induced DNA synthesis in cultured oral keratinocytes, and that this response is temporally related to STE-induced inactivation of NEP 24.11 in these cells. I suggest that NEP 24.11 modulates the mitogenic effects of smokeless tobacco in the oral epithelium, in part, by inactivating VIP.

Animals↗
PubMed2000

Tyrosine kinase inhibitors modulate agonist-induced vasodilation in the hamster cheek pouch.

The purpose of this study was to determine whether inhibitors of tyrosine kinase attenuate vasodilation elicited by endogenously elaborated and exogenously applied nitric oxide in the in situ peripheral microcirculation. Using intravital microscopy, we found that pretreatment with genistein (1.0 microM) and tyrphostin 25 (10.0 microM), two structurally unrelated tyrosine kinase inhibitors, significantly attenuated acetylcholine-, bradykinin- and nitroglycerin-induced dilation of second-order arterioles (51 +/- 1 microm) in the in situ hamster cheek pouch (P < 0.05). Both inhibitors nearly abrogated acetylcholine-induced responses but only partially blocked bradykinin- and nitroglycerin-induced vasodilation. Genistein and tyrphostin 25 alone had no significant effects on resting arteriolar diameter and on adenosine-induced vasodilation in the cheek pouch. On balance, these data indicate that tyrosine kinase inhibitors attenuate endogenously elaborated and exogenously applied nitric oxide-induced vasodilation in the in situ hamster cheek pouch. However, the extent of tyrosine kinase inhibitor-sensitive pathway involvement in this response appears to be agonist dependent.

Acetylcholine↗
PubMed2000

PGH(2)-TxA(2)-receptor blockade restores vasoreactivity in a new rodent model of genetic hypertension.

The purpose of this study was to determine whether activation of prostaglandin H(2)-thromboxane A(2) (PGH(2)-TxA(2)) receptors impedes vasodilation in the in situ peripheral microcirculation of spontaneously hypertensive hamsters, a new rodent model of high-renin genetic hypertension. Using intravital microscopy, we found that vasodilation elicited by suffusion of acetylcholine and vasoactive intestinal peptide (VIP), two neurotransmitters localized in perivascular nerves in the peripheral circulation, on the in situ cheek pouch was significantly attenuated in spontaneously hypertensive hamsters relative to age- and genetically matched normotensive hamsters (P < 0.05). However, nitroglycerin-induced vasodilation was similar in both groups. Pretreatment with SQ-29548, a selective and potent PGH(2)-TxA(2)-receptor antagonist, restored acetylcholine- and VIP-induced vasodilation in spontaneously hypertensive hamsters. SQ-29548 had no significant effects on resting arteriolar diameter and on nitroglycerin-induced vasodilation in both groups. SQ-29548 slightly but significantly potentiated VIP- but not acetylcholine-induced vasodilation in normotensive hamsters. Collectively, these data indicate that activation of PGH(2)-TxA(2) receptors impedes agonist-induced vasodilation in the in situ cheek pouch of spontaneously hypertensive hamsters. We suggest that this model is suitable for studying the role of prostanoids in mediating vasomotor dysfunction observed in genetic hypertension.

Acetylcholine↗
PubMed2000

Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma.

Prolonged use of prednisone is associated with serious side effects, such as osteoporosis, particularly among elderly individuals. Macrolide antibiotics exhibit anti-inflammatory effects that are distinct from their antimicrobial properties. Thus, the purpose of this case report is to describe the effects of prolonged treatment with clarithromycin, 500 mg bid, in reducing prednisone requirements in three elderly patients with prednisone-dependent asthma. Three patients (one woman and two men) aged 63 to 69 years, who had been treated with 5 to 10 mg prednisone daily for at least the last 12 months, were given clarithromycin, 500 mg bid. They were followed regularly for changes in daily prednisone dose, spirometry, quality of life, and adverse events. The prednisone dose was tapered in a stepwise fashion at each clinic visit. Within 3 to 6 months of initiation of treatment with clarithromycin, and throughout the 12-month follow-up, two of three patients discontinued prednisone therapy, while the third patient displayed increased spirometry readings and noted an increasingly better quality of life. Pulmonary function tests were stable or improved over this time period, with no reported adverse events, including increased rate of infections. One patient relapsed upon discontinuation of clarithromycin therapy but has since responded to re-initiation of treatment. Long-term oral clarithromycin may have a role in reducing prednisone requirements in elderly patients with prednisone-dependent asthma.

Administration, Oral↗
PubMed1999

Cardiac dysfunction in murine autoimmune myocarditis.

We have investigated the pathophysiological basis of cardiac dysfunction in autoimmune myocarditis and in the resulting dilated cardiomyopathy. To this end we utilized the myosin-induced autoimmune myocarditis model in BALB/c mice. Myocarditis has been found to be associated with massive ventricular lymphocyte infiltration and a 50% reduction in tail artery blood flow, reflecting the depressed cardiac function in myocarditis. Action potential characteristics of control and diseased isolated ventricular myocytes were (mean+/-SEM): resting potential: -68.1+/-1. 1,-68.3+/-0.7 mV; action potential amplitude: 96.5+/-10.4, 92.3+/-4. 4 mV; action potential duration at 80% repolarization (APD80) 38+/-5, 116+/-24* ms; * P<0.05. We utilized the whole cell voltage clamp technique to explore ion currents involved in APD prolongation and arrhythmogenic activity, and found that in diseased myocytes the transient outward current (Ito) was markedly attenuated. At a membrane potential of +40 mV, in control and in diseased myocytes, I(to) current density was 14.7+/-1.5 and 6.5+/-1.4 pA/pF, respectively, P<0.005. In contrast, the L-type Ca2+current (ICa,L) remained unchanged. To further explore the basis for cardiac impairment, we simultaneously measured [Ca2+]i transient and contraction in isolated normal and diseased myocytes. The major findings indicated that both the relaxation kinetics of [Ca2+]i transients and myocyte contraction were significantly faster in the diseased myocytes. In conclusion, substantial, potentially reversible, electrophysiological and mechanical perturbations in ventricular myocytes from mice with myosin-induced autoimmune myocarditis appear to contribute to disease-related cardiac dysfunction.

Action Potentials↗
PubMed1999

Conformation and vasoreactivity of VIP in phospholipids: effects of calmodulin.

The purpose of this study was to determine the conformation and vasorelaxant effects of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized phospholipid micelles (SSM) and whether calmodulin modulates both of these processes. Circular dichroism spectroscopy revealed that VIP is unordered in aqueous solution at room temperature but assumes appreciable a helix conformation in SSM. This conformational transition was amplified at 37 degrees C and by a low concentration of calmodulin (0.1 nM). Suffusion of VIP in SSM elicited significant time- and concentration-dependent potentiation of vasodilation relative to that elicited by aqueous VIP in the in situ hamster cheek pouch (P < 0.05). This response was significantly potentiated by calmodulin (0.1 nM). Collectively, these data indicate that exogenous calmodulin interacts with VIP in SSM to elicit conformational transition of VIP molecule from a predominantly random coil in aqueous environment to alpha helix in SSM. This process is associated with potentiation and prolongation of VIP-induced vasodilation in the in situ peripheral microcirculation.

Animals↗
PubMed1999

A novel formulation of VIP in sterically stabilized micelles amplifies vasodilation in vivo.

PURPOSE: To determine whether human vasoactive intestinal peptide (VIP)-poly(ethylene glycol) (PEG)-grafted distearoyl-phosphatidylethanolamine (DSPE) micelles elicit potent and stable vasodilation in vivo. METHODS: PEG-DSPE micelles were prepared by co-precipitation. VIP was loaded into micelles by incubation at room temperature. Vasoactivity of VIP in SSM was determined by monitoring changes in diameter of resistance arterioles in the in situ hamster cheek pouch using intravital microscopy. RESULTS: VIP easily undergoes self-assembly into small PEG-DSPE micelles (mean [+/-SEM] size, 18+/-1 nm) in a time-dependent fashion. This generates a potent vasoactive matrix at nanomole concentrations of VIP as manifested by approximately 3-fold potentiation and prolongation of vasodilation relative to that evoked by aqueous VIP alone (p < 0.05). This response is specific and mediated by the L-arginine/nitric oxide (NO) biosynthetic pathway. Micellar VIP dispersion remains vasoactive for at least 14 days after preparation and storage at 4 degrees C. CONCLUSIONS: A novel, self-associated, small and stable PEG-DSPE micellar formulation of VIP amplifies vasodilation in the in situ peripheral microcirculation in a specific fashion by elaborating NO. An optimized formulation could be considered for certain cardiovascular disorders associated with L-arginine/NO biosynthetic pathway dysfunction.

Animals↗
PubMed1999

Exogenous calmodulin potentiates vasodilation elicited by phospholipid-associated VIP in vivo.

The purpose of this study was to determine whether exogenous calmodulin potentiates vasoactive intestinal peptide (VIP)-induced vasodilation in vivo and, if so, whether this response is amplified by association of VIP with sterically stabilized liposomes. Using intravital microscopy, we found that calmodulin suffused together with aqueous and liposomal VIP did not potentiate vasodilation elicited by VIP in the in situ hamster cheek pouch. However, preincubation of calmodulin with liposomal, but not aqueous, VIP for 1 and 2 h and overnight at 4 degrees C before suffusion significantly potentiated vasodilation (P < 0.05). Calmodulin-induced responses were significantly attenuated by calmidazolium, trifluoperazine, and NG-nitro-L-arginine methyl ester (L-NAME) but not D-NAME. The effects of L-NAME were reversed by L- but not D-arginine. Indomethacin had no significant effects on calmodulin-induced responses. Calmodulin had no significant effects on adenosine-, isoproterenol-, acetylcholine-, and calcium ionophore A-23187-induced vasodilation. Collectively, these data indicate that exogenous calmodulin amplifies vasodilation elicited by phospholipid-associated, but not aqueous, VIP in the in situ peripheral microcirculation in a specific, calmodulin active sites-, and nitric oxide-dependent fashion. We suggest that extracellular calmodulin, phospholipids, and VIP form a novel functionally coordinated class of endogenous vasodilators.

Acetylcholine↗
PubMed1999

Dexamethasone attenuates grain sorghum dust extract-induced increase in macromolecular efflux in vivo.

The purpose of this study was to determine whether dexamethasone attenuates grain sorghum dust extract-induced increase in macromolecular efflux from the in situ hamster cheek pouch and, if so, whether this response is specific. By using intravital microscopy, we found that an aqueous extract of grain sorghum dust elicited significant, concentration-dependent leaky site formation and increase in clearance of FITC-labeled dextran (FITC-dextran; mol mass, 70 kDa) from the in situ hamster cheek pouch (P < 0.05). This response was significantly attenuated by dexamethasone (10 mg/kg iv). Dexamethasone also attenuated substance P-induced leaky site formation and increase in clearance of FITC-dextran from the cheek pouch but had no significant effects on adenosine-induced responses. Dexamethasone had no significant effects on arteriolar diameter in the cheek pouch. On balance, these data indicate that dexamethasone attenuates grain sorghum dust extract- and substance P-induced increases in macromolecular efflux from the in situ hamster cheek pouch in a specific fashion.

Adenosine↗
PubMed1999

Dexamethasone attenuates acute macromolecular efflux increase evoked by smokeless tobacco extract.

The purpose of this study was to determine whether dexamethasone attenuates the acute increase in macromolecular efflux from the oral mucosa elicited by an aqueous extract of smokeless tobacco (STE) in vivo, and, if so, whether this response is specific. Using intravital microscopy, we found that 20-min suffusion of STE elicited significant, concentration-related leaky site formation and an increase in clearance of fluorescein isothiocyanate-labeled dextran (FITC-dextran; mol mass 70 kDa) from the in situ hamster cheek pouch (P < 0.05). This response was significantly attenuated by dexamethasone (10 mg/kg iv). Dexamethasone also attenuated the bradykinin-induced leaky site formation and the increase in clearance of FITC-dextran from the cheek pouch. However, it had no significant effects on adenosine-induced responses. Dexamethasone had no significant effects on baseline arteriolar diameter and on bradykinin-induced vasodilation in the cheek pouch. Collectively, these data indicate that dexamethasone attenuates, in a specific fashion, the acute increase in macromolecular efflux from the in situ oral mucosa evoked by short-term suffusion of STE. We suggest that corticosteroids mitigate acute oral mucosa inflammation elicited by smokeless tobacco.

Adenosine↗
PubMed1998

Involvement of nitric oxide system in experimental muscle crush injury.

Muscle crush injury is often complicated by hemodynamic shock, electrolyte disorders, and myoglobinuric renal failure. In this study, we examined the involvement of the nitric oxide (NO) system in the development of muscle damage in an experimental model of crush injury induced by exertion of standardized mechanical pressure on tibialis muscle of rat. The intact limb served as a control. Four days after injury, the crushed muscle was characterized by extreme capillary vasodilatation as demonstrated by histological morphometric analysis. These changes were accompanied by muscle hyperperfusion as evaluated by measurements of femoral blood flow (ultrasonic flowmetry) and capillary blood flow (laser-doppler flowmetry). Treatment with Nomega-nitro-L-arginine methyl ester, a NO synthase (NOS) inhibitor, largely decreased the hyperperfusion. Furthermore, the expression of the different NOS isoforms, assessed by reverse transcription-PCR and immunoreactive levels, determined by Western blot, revealed a remarkable induction of the inducible NOS in the crushed limb. Similarly, endothelial NOS mRNA increased gradually after the induction of muscle damage. In contrast, the major muscular NOS, i.e., neuronal isoform remained unchanged. In line with the alterations in the mRNA levels, Western blot analysis revealed parallel changes in the immunoreactive levels of the various NOS. These findings indicate that muscle crush is associated with activation of the NO system mainly due to enhancement of iNOS. This may contribute to NO-dependent extreme vasodilatation in the injured muscle and aggravate the hypovolemic shock after crush injury.

Animals↗
PubMed1998

Sterically stabilized phospholipids attenuate human neutrophils chemotaxis in vitro.

The purpose of this study was to determine whether sterically stabilized liposomes (SSL) and poly(ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE) attenuate polymorphonuclear neutrophils (PMNs) chemotaxis in vitro and, if so, whether incorporation of vasoactive intestinal peptide (VIP), a pleiotropic neuropeptide, on the surface of SSL amplifies SSL-induced responses. Using a modified blind-well chamber chemotaxis assay, we found that N-formyl-methionyl-leucyl-phenylalanine (FMLP; 0.1 microM) and zymosan opsonized with purified human complement (2 x 10(9) yeast wall particles/ml) elicit significant human PMNs chemotaxis (95+/-9 and 103+/-3 cells/high power field; p<0.05). These effects are significantly attenuated by SSL and PEG-DSPE (p<0.05). By contrast, aqueous VIP and VIP on SSL have no significant effects on FMLP- and zymosan-induced responses. We conclude that certain sterically stabilized liposomes and phospholipids attenuate human PMNs chemotaxis in vitro and that VIP does not modulate this response.

Chemotaxis, Leukocyte↗
PubMed1998

Increased tissue neutral endopeptidase 24.11 activity in spontaneously hypertensive hamsters.

The purpose of this study was to determine whether tissue neutral endopeptidase (NEP) 24.11 activity, a membrane-bound metalloenzyme widely distributed in the peripheral circulation that cleaves and inactivates vasodilator peptides, is increased in spontaneously hypertensive hamsters relative to genetically/age-matched normotensive hamsters. Mean arterial pressure and heart rate were 163 +/- 11 mm Hg and 312 +/- 7 beats/min in spontaneously hypertensive hamsters and 99 +/- 3 mm Hg and 302 +/- 10 beats/min in normotensive hamsters, respectively (mean +/- SEM). NEP 24.11 activity is significantly increased in the kidney, cheek pouch, and spinotrapezius muscle, and significantly decreased in the heart and aorta of spontaneously hypertensive hamsters relative to controls (P < .05). Lung and brain NEP 24.11 activity is similar in both groups. Renal NEP 24.11 activity increases and to a similar extent in spontaneously hypertensive and normotensive hamsters as chloride anion concentration in the assay buffer is increased. Substituting citrate for chloride anion significantly attenuates renal NEP 24.11 activity. Taken together, these data indicate that NEP 24.11 activity in spontaneously hypertensive hamsters is increased in two organs that contribute appreciably to peripheral vascular resistance, skeletal muscle, and kidney. We suggest that the spontaneously hypertensive hamster is a suitable model to study the role of skeletal muscle and renal NEP 24.11 in regulating vasomotor tone in essential hypertension.

Animals↗