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I Rubinstein

Publications and source records attributed to I Rubinstein.

At least 55 records · Page 3Linked to original sources
PubMed1998

Endothelin-1-like immunoreactivity in a new rodent model of spontaneous hypertension.

The purpose of this study was to determine plasma and tissue endothelin-1 (ET-1)-like immunoreactivity in a new rodent model of spontaneous hypertension. Plasma and tissues were procured from pentobarbital-anesthetized 16- to 18-week-old male hamsters with spontaneous hypertension and genetically/age-matched normotensive hamsters. We found that ET-1-like immunoreactivity in the plasma was similar in both groups. However, renal and cardiac ET-1-like immunoreactivity was 11- and 1.7-fold higher in spontaneously hypertensive hamsters relative to normotensive hamsters, respectively (P < .05). ET-1-like immunoreactivity was slightly, but significantly, lower in the lung and spleen of spontaneously hypertensive hamsters relative to normotensive hamsters (P < .05). ET-1-like immunoreactivity in the liver and brain was similar in both groups. We conclude that ET-1-like immunoreactivity is significantly higher in two target organs for hypertension, kidney and heart, but not in plasma or brain of adult male hamsters with spontaneous hypertension, relative to genetically/age-matched normotensive hamsters. We suggest that renal and cardiac ET-1 could play a role in the natural history of spontaneous hypertension in hamsters.

Animals↗
PubMed1998

Renal endothelin-converting enzyme in rats with congestive heart failure.

The expression and immunoreactivity of endothelin-converting enzyme (ECE) were examined in the renal tissue of rats with experimental congestive heart failure (CHF). Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that ECE mRNA was more abundant (about twofold) in the renal medulla than in the cortex. Induction of heart failure caused a significant enhancement in the expression of this key enzyme in the renal cortex of rats with compensated CHF (delta + 28%) and in animals with decompensated heart failure (delta + 58%). An identical trend was also observed in the renal medulla, although these increases were moderate compared to those in the cortex. Similar findings were observed with Western blot techniques applying two monoclonal antibodies to rat ECE (AEC32-236 and AEC27-121). Taken together, these data suggest that upregulation of ECE is an important component in the activated renal ET system in CHF.

Animals↗
PubMed1998

The nose and obstructive sleep apnea.

The role of the nasal passage in the pathophysiology of obstructive sleep apnea (OSA) is still controversial. To this end, induction of acute nasal obstruction in healthy volunteers is associated with sleep fragmentation and an increase in the number of obstructive and central apneas. Moreover, nasal topical anesthesia, which alters nasal reflexes, is associated with an increase in the number of obstructive and central apneas during sleep. Although nasal resistance is increased in patients with OSA, chronic nasal obstruction appears to play no significant role in the genesis, maintenance, or severity of OSA. Moreover, surgical correction of nasal obstruction does not alleviate OSA appreciably. The purpose of this review is to outline the current body of knowledge on the pathophysiology, diagnosis, and treatment of nasal obstruction in patients with OSA.

Female↗
PubMed1998

Smokeless tobacco-exposed oral keratinocytes increase macromolecular efflux from the in situ oral mucosa.

The purpose of this study was to determine whether supernatants of cultured human oral keratinocytes (HOK) exposed to an aqueous extract of smokeless tobacco (STE) increase macromolecular efflux from the oral mucosa in vivo and, if so, whether bradykinin mediates in part this response. Subconfluent monolayers of HOK were incubated with STE or media, and supernatants were collected 24, 48, and 72 h thereafter. Using intravital microscopy, we found that suffusion of supernatants of STE- but not media-exposed HOK elicited significant concentration- and time-dependent increases in efflux of fluorescein isothiocyanate-labeled dextran (mol mass 70 kDa) from the in situ hamster cheek pouch (P < 0.05). These effects were significantly attenuated by HOE-140 and NPC-17647 but not by des-Arg9, [Leu8]-bradykinin. Proteolytic activity was increased in supernatants of STE- but not media-exposed HOK. However, a mixture of leupeptin, Bestatin, and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid had no significant effects on HOK supernatant-induced responses. Collectively, these data suggest that oral keratinocytes modulate smokeless tobacco-induced increase in macromolecular efflux from the in situ oral mucosa in part by elaborating proteases that may account for local bradykinin production.

Animals↗
PubMed1998

Vasodilation elicited by liposomal VIP is unimpeded by anti-VIP antibody in hamster cheek pouch.

The purpose of this study was to determine whether a monoclonal anti-vasoactive intestinal peptide (VIP) antibody, which binds VIP with high affinity and specificity and catalyzes cleavage of the peptide in vitro, attenuates VIP vasorelaxation in vivo and, if so, whether insertion of VIP on the surface of sterically stabilized liposomes (SSL), which protects the peptide from trypsin- and plasma-catalyzed cleavage in vitro, curtails this response. Using intravital microscopy, we found that suffusion of monoclonal anti-VIP antibody (clone c23.5, IgG2ak), but not of nonimmune antibody (myeloma cell line UPC10, IgG2ak) or empty SSL, significantly attenuates VIP-induced vasodilation in the in situ hamster cheek pouch (P < 0.05). By contrast, anti-VIP antibody has no significant effects on vasodilation elicited by isoproterenol, nitroglycerin, and calcium ionophore A-23187, agonists that activate intracellular effector systems in blood vessels that mediate, in part, VIP vasoreactivity. Suffusion of VIP on SSL, but not of empty SSL, restores the vasorelaxant effects of VIP in the presence of anti-VIP antibody. Collectively, these data suggest that VIP catalysis by high affinity and specific VIP autoantibodies displaying protease-like activity constitutes a novel mechanism whereby VIP vasoreactivity is regulated in vivo.

Animals↗
PubMed1998

Liposomal VIP attenuates phenylephrine- and ANG II-induced vasoconstriction in vivo.

The purpose of this study was to determine whether vasoactive intestinal peptide (VIP) modulates vasoconstriction elicited by phenylephrine and ANG II in vivo and, if so, to begin to elucidate the mechanisms underlying this phenomenon. Using intravital microscopy, we found that suffusion of phenylephrine and ANG II elicits significant vasoconstriction in the in situ hamster cheek pouch that is potentiated by VIP-(10-28), a VIP receptor antagonist, but not by VIP-(1-12) (P < 0.05). Aqueous VIP has no significant effects on phenylephrine- and ANG II-induced vasoconstriction. However, VIP on sterically stabilized liposomes (SSL), a formulation where VIP assumes a predominantly alpha-helix conformation, significantly attenuates this response. Maximal effect is observed within 30 min and is no longer seen after 60 min. Empty SSL are inactive. Indomethacin has no significant effects on responses induced by VIP on SSL. The vasodilators ACh, nitroglycerin, calcium ionophore A-23187, 8-bromo-cAMP, and isoproterenol have no significant effects on phenylephrine- and ANG II-induced vasoconstriction. Collectively, these data suggest that vasoconstriction modulates VIP release in the in situ hamster cheek pouch and that alpha-helix VIP opposes alpha-adrenergic- and ANG II-induced vasoconstriction in this organ in a reversible, prostaglandin-, NO-, cGMP-, and cAMP-independent fashion.

Acetylcholine↗
PubMed1998

Regulation of intrarenal blood flow in experimental heart failure: role of endothelin and nitric oxide.

Congestive heart failure(CHF) is associated with a marked decrease in cortical blood flow and preservation of medullary blood flow. In the present study we tested the hypothesis that changes in the endothelin (ET) and nitric oxide (NO) systems in the kidney may contribute to the altered intrarenal hemodynamics in rats with aortocaval fistula, an experimental model of CHF. Cortical and medullary blood flow were measured simultaneously by laser-Doppler flowmetry in controls and rats with compensated and decompensated CHF. As previously reported [K. Gurbanov, I. Rubinstein, A. Hoffman, Z. Abassi, O. S. Better, and J. Winaver. Am. J Physiol. 271 (Renal Fluid Electrolyte Physiol. 40): F1166-F1172, 1996], administration of ET-1 in control rats produced a sustained cortical vasoconstriction and a transient medullary vasodilatory response. In rats with decompensated CHF, cortical vasoconstriction was severely blunted, whereas ET-1-induced medullary vasodilation was significantly prolonged. This prolonged response was mimicked by IRL-1620, a specific ETB agonist, and partially abolished by NO synthase (NOS) blockade. In line with these findings, expression of ET-1, ETA and ETB receptors, and endothelial NOS (eNOS), assessed by RT-PCR, and eNOS immunoreactivity, assessed by Western blotting, was significantly higher in the medulla than in the cortex. Moreover, expression of ET-1 mRNA in the cortex and eNOS mRNA in the cortex and the medulla increased in proportion to the severity of heart failure. These findings indicate that CHF is associated with altered regulation of intrarenal blood flow, which reflects alterations in expression and activity of the ET and NO systems. It is further suggested that exaggerated NO activity in the medulla contributes to preservation of medullary blood flow in the face of cortical vasoconstriction in CHF.

Animals↗
PubMed1998

Ovalbumin increases macromolecular efflux from the in situ nasal mucosa of allergic hamsters.

The purpose of this study was to determine whether bradykinin mediates ovalbumin-induced increase in macromolecular efflux from the nasal mucosa of ovalbumin-sensitized hamsters in vivo and, if so, whether the L-arginine/nitric oxide biosynthetic pathway transduces, in part, this response. We found that suffusion of ovalbumin onto the in situ nasal mucosa of ovalbumin-sensitized hamsters, but not of controls, elicited a significant time- and concentration-dependent increase in clearance of fluorescein isothiocyanate-labeled dextran (mol mass, 70 kDa; P < 0.05). HOE-140, but not des-Arg9,[Leu8]-bradykinin, and NG-L-arginine methyl ester (L-NAME), but not NG-D-arginine methyl ester, significantly attenuated ovalbumin-induced responses. L-Arginine, but not D-arginine, abolished the effects of L-NAME. L-NAME also significantly attenuated bradykinin-, but not adenosine-induced increase in macromolecular efflux from the in situ nasal mucosa. Overall, these data suggest that ovalbumin increases macromolecular efflux from the in situ nasal mucosa of ovalbumin-sensitized hamsters, in part, by producing bradykinin with subsequent activation of the L-arginine/ nitric oxide biosynthetic pathway.

Adenosine↗
PubMed1998

Mast cell chymase-like protease(s) modulates Escherichia coli lipopolysaccharide-induced vasomotor dysfunction in skeletal muscle in vivo.

This study investigated whether short-term exposure to Escherichia coli lipopolysaccharide (LPS) elicits vasomotor dysfunction in skeletal muscle in vivo and, if so, whether perivascular mast cell proteases partly modulate this response. With intravital microscopy, we found that suffusion of E. coli LPS on the in situ hamster spinotrapezius muscle for 60 min elicits immediate vasoconstriction followed by vasodilation. Vasoconstriction is abrogated by SK&F 108566, a selective, nonpeptide angiotensin II (AT II) subtype 1 receptor antagonist, chymostatin and soybean trypsin inhibitor. These compounds also attenuate E. coli LPS-induced vasodilation. By contrast, superoxide dismutase, catalase and indomethacin attenuate only E. coli LPS-induced vasodilation. Endothelin receptor antagonists, lisinopril, leupeptin, Bestatin and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid are ineffective. Histochemical analysis of the spinotrapezius muscle reveals abundant perivascular mast cells with chymostatin-inhibitable chymase-like activity. Pretreatment of hamsters with compound 48/80 for 4 days curtails E. coli LPS-induced vasoconstriction and converts vasodilation to vasoconstriction. On balance, these data indicate that E. coli LPS stimulates perivascular mast cells in the in situ hamster spinotrapezius muscle to release an AT II-producing chymase-like protease(s). AT II thus produced elicits local vasoconstriction and elaborates reactive oxygen species which, in turn, generate vasodilator prostaglandins.

Angiotensin II↗
PubMed1998

Stabilization of vasoactive intestinal peptide by lipids.

An anionic phospholipid, phosphatidylglycerol (PG), induced vasoactive intestinal peptide (VIP) to adopt a helical conformation, determined by circular dichroism studies. PG inhibited the trypsin-catalyzed, antibody-catalyzed and uncatalyzed cleavage of VIP, measured by radiometric and HPLC methods. Phosphatidylcholine, a neutral lipid, did not alter the circular dichroism spectra of VIP, and it was without detectable effect on the rates of VIP cleavage. Trypsin-catalyzed cleavage of Boc-Ile-Glu-Arg-methylcoumarinamide, a substrate unrelated in sequence to VIP, proceeded at equivalent rates in the absence and presence of PG, which suggests that the phospholipid did not exert a nonspecific inhibitory effect on the enzyme. Study of the kinetics of antibody-catalyzed VIP cleavage indicated that the inhibition by PG was due to decreased affinity for VIP, suggested by observations of increased K(m) values and unaltered Vmax values. Incorporation of VIP in the liposomes and the liposomal surface permitted maintenance of the peptide in essentially undegraded form at 37 degrees C for 8 days. The longevity of liposomal VIP administered i.v. to mice was increased by about 5-fold compared with aqueous VIP. These observations indicate that certain phospholipids and liposomes can be applied to circumvent the rapid loss of VIP in vitro and in vivo due to degradative processes.

Amino Acid Sequence↗
PubMed1998

Annexin I degradation in bronchoalveolar lavage fluids from healthy smokers: a possible mechanism of inflammation.

Annexin I is a glucocorticoid-inducible, phospholipase A2-inhibitory protein and is proposed to have an anti-inflammatory role. Although annexin I is a cytosolic protein, it is found extracellularly in secreted fluids such as semen. We have examined the expression of annexin I in bronchoalveolar lavage fluids (BALF) from smokers and nonsmokers to investigate the role of annexin I in the airway. We find that annexin I is secreted in BALF. This secretion is not due to cell death or damage, because a cytosolic protein, 3-phosphoglycerate kinase, is not seen in BALF. We observed that BALF from smokers (n = 10) had high protein concentrations as compared with BALF from nonsmokers (n = 11). Annexin I levels were higher in BALF from smokers compared with nonsmokers. However, in smokers, annexin I was exclusively found in the Mr 34,000 form that lacks the Mr 3,000 N-terminal anti-inflammatory peptide. In nonsmokers, both the Mr 37,000 native annexin I and the Mr 34,000 proteolytically cleaved form are present, with the Mr 37,000 form being most abundant. The NH2-terminal Mr 3,000 peptide of annexin I exhibits anti-inflammatory actions (G. Cirino et al, Br. J. Pharmacol., 108: 573-574, 1993). Previous studies have implicated neutrophil elastase as the protease cleaving annexin I to the Mr 34,000 protein. We observed increased elastase levels in BALF from smokers. However, we find no correlation between bronchial sample percent of neutrophils in BALF and the relative amount of the Mr 34,000 band generated. Our data clearly demonstrate that annexin I is degraded in BALF from smokers, and we propose that proteolytic cleavage of annexin I in BALF from smokers may be a mechanism by which polymorphonuclear neutrophils infiltrate sites of inflammation; thus, inactivation of annexin I in smokers' lungs may lead to chronic and uncontrolled inflammation.

Animals↗
PubMed1997

Angiotensin-converting enzyme and neutral endopeptidase modulate smokeless tobacco-induced increase in macromolecular efflux from the oral mucosa in vivo.

Smokeless tobacco elicits plasma exudation from the oral mucosa that is mediated by bradykinin, and it decreases the activity of tissue angiotensin-converting enzyme (ACE), a peptidase that cleaves and inactivates bradykinin. However, the mechanisms regulating bradykinin-induced responses during exposure to smokeless tobacco are uncertain. The purpose of this study was to begin to address this issue by determining whether inhibitors of ACE and neutral endopeptidase (NEP), a membrane-bound peptidase widely distributed in the oral mucosa that also cleaves and inactivates bradykinin, potentiate a smokeless tobacco-induced increase in macromolecular efflux from the oral mucosa in vivo. Using intravital microscopy, we found that suffusion of an aqueous extract of smokeless tobacco elicited a significant concentration-dependent increase in fluorescein isothiocyanate-labeled dextran (molecular mass 70 kd) leaky site formation in the hamster cheek pouch (p < 0.05). This response was significantly potentiated by captopril and lisinopril, two ACE inhibitors, and by phosphoramidon and thiorphan, two NEP inhibitors (p < 0.05). The effects of ACE and NEP inhibitors were additive. By contrast, a mixture of proteinase inhibitors consisting of leupeptin, Bestatin, and DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid had no significant effects on smokeless tobacco extract-induced responses. Overall, these data suggest that ACE and NEP each play a role in modulating a smokeless tobacco-induced increase in macromolecular efflux from the in situ oral mucosa, in part by regulating local bradykinin catabolism.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Interleukin-1 beta potentiates bradykinin-induced macromolecular efflux from hamster oral mucosa.

The purpose of this study was to determine whether interleukin-1 beta (IL-1 beta) elicits macromolecular efflux from the in situ oral mucosa and whether it amplifies that evoked by bradykinin. Using intravital microscopy, we found that suffusion of recombinant human IL-1 beta (50 ng/ml) had no significant effects on leaky site formation and increase in clearance of fluorescein isothiocyanate-labeled dextran (mol mass 70 kDa) from the hamster cheek pouch. However, it significantly potentiated bradykinin-induced macromolecular efflux (P < 0.05). The potentiating effects of IL-1 beta on bradykinin-induced responses were abrogated by a bradykinin B2-receptor antagonist and by a recombinant human IL-1-receptor antagonist. They were not mediated by substance P, prostaglandins, or changes in vasomotor tone. IL-1 beta had no significant effects on adenosine-induced macromolecular efflux. Collectively, these data indicate that IL-1 beta potentiates bradykinin-induced macromolecular efflux from the in situ hamster oral mucosa in a specific fashion. We suggest that this interaction could play a role in the pathogenesis of oral mucosa inflammation.

Adenosine↗
PubMed1997

Neurogenic plasma exudation mediates grain dust-induced tissue injury in vivo.

The purpose of this study was to determine whether an aqueous extract of grain sorghum dust (GDE) elicits neurogenic plasma exudation in the oral mucosa in vivo. Using intravital microscopy, we found that GDE elicited significant, concentration-dependent leaky site formation and an increase in clearance of fluorescein isothiocyanate-labeled dextran (FITC-dextran; mol mass 70 kDa) from the hamster cheek pouch (P < 0.05). The selective, nonpeptide neurokinin(1) (substance P) receptor antagonists, CP-96,345 and RP-67580, but not the 2R,3R enantiomer CP-96,344, significantly attenuated GDE-induced leaky site formation and increase in clearance of FITC-dextran (P < 0.05). Indomethacin had no significant effects on GDE-induced responses. CP-96,345 had no significant effects of adenosine-induced leaky site formation and increase in clearance of FITC-dextran from the cheek pouch. We conclude that GDE elicits neurogenic plasma exudation from the oral mucosa in vivo. We suggest that this process is one mechanism whereby grain sorghum dust elicits immediate oral mucosa inflammation in vivo.

Adenosine↗
PubMed1997

Mechanisms of vasodilation elicited by VIP in sterically stabilized liposomes in vivo.

The purpose of this study was to begin to determine the mechanisms underlying vasodilation elicited by vasoactive intestinal peptide (VIP) in sterically stabilized liposomes (SSL) in the in situ peripheral microcirculation. Using intravital microscopy, we found that suffusion of VIP in SSL (0.42 and 0.85 nmol) onto the hamster cheek pouch for 1 h elicited significant and prolonged concentration-dependent vasodilation (P < 0.05). Suffusion of VIP in SSL (0.1 nmol) for 7 min elicited a qualitatively similar response, although its magnitude was significantly smaller than that elicited by 1 h of suffusion of VIP in SSL (P < 0.05). The VIP-receptor antagonist VIP-(10-28), but not the amino-terminal fragment VIP-(1-12), significantly attenuated and delayed the onset of VIP in SSL-induced vasodilation (P < 0.05). The nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), but not NG-nitro-D-arginine methyl ester (D-NAME), abrogated VIP in SSL-induced responses. We conclude that VIP in SSL elicits significant and prolonged vasodilation in the in situ peripheral microcirculation, which is specific, partly receptor dependent, and partly transduced by the L-arginine/NO biosynthetic pathway.

Animals↗
PubMed1997

Methotrexate potentiates bradykinin-induced increase in macromolecular efflux from the hamster oral mucosa.

The purpose of this study was to determine whether methotrexate modulates bradykinin-induced increase in macromolecular efflux from the in situ oral mucosa and whether this response is mediated by the L-arginine/nitric oxide biosynthetic pathway. Using intravital microscopy, we found that suffusion of methotrexate alone onto the hamster cheek pouch had no significant effects on leaky site formation and increase in clearance of fluorescein isothiocyanate-labeled dextran (molecular mass, 70 kDa). However, methotrexate significantly potentiated bradykinin-induced responses (P < 0.05). These effects were associated with significant increases in nitrites concentration and guanosine 3',5'-cyclic monophosphate-like immunoreactivity in the suffusate and were abrogated by N(G)-nitro-L-arginine methyl ester (L-NAME) but not N(G)-nitro-D-arginine methyl ester (D-NAME). L-Arginine, but not D-arginine, abolished L-NAME-induced responses. ZnCI2 and indomethacin had no significant effects on methotrexate-induced responses. Methotrexate had no significant effects on adenosine- and ionomycin-induced increases in macromolecular efflux. Collectively, these data indicate that methotrexate amplifies bradykinin-induced increase in macromolecular efflux from the in situ oral mucosa in a specific, receptor- and L-arginine/nitric oxide biosynthetic pathway-dependent fashion.

Adenosine↗