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A Jovanovic

Publications and source records attributed to A Jovanovic.

At least 37 records · Page 2Linked to original sources
PubMed1999

Increased number of cardiomyocytes in cross-sections from tachycardia-induced cardiomyopathic hearts.

Based on positive identification of DNA replication and mitotic division in cardiomyocytes isolated from failing hearts, it has been proposed that adult ventricular cardiomyocytes can gain the capacity to proliferate with progression of heart failure. However, due to the lack of a reliable method to distinctly image individual cardiac cells within the myocardial syntitium, such a concept still remains largely controversial. In the present study, we used laser confocal microscopy, to image cross-sections of intact myocardium stained with fluorescein-conjugated wheat germ agglutinin and propidium iodide. This approach allowed to clearly separate the profile of individual myocytes within cardiac tissue sections. We found that in the left ventricles of dogs, subjected to tachycardia-induced cardiomyopathy, the number of cells was significantly increased in both longitudinal and transversal sections. Treatment with the angiotensin-converting enzyme inhibitor, enalapril, reversed these changes to values similar to those found in controls. Therefore, this study provides evidence, at the in situ level, for cellular hyperplasia in heart failure. This supports the more general notion that adult cardiomyocytes may not be terminally differentiated, and that an increase in cell number could contribute to the increase in left ventricular mass observed with progression of disease.

Animals↗
PubMed1998

Diadenosine 5',5"-P1,P5-pentaphosphate harbors the properties of a signaling molecule in the heart.

Dinucleotide polyphosphates (ApnA) have emerged as signaling molecules in rapidly dividing cells. The presence and role of Ap5A in the heart remain unknown. Here, we report that the myocardium contains abundant amounts of diadenosine 5',5"-P1,P5-pentaphosphate (Ap5A), a member of the ApnA family. Ischemia induced 10-fold decrease in the myocardial concentration of Ap5A. A target of Ap5A action was identified to be the cardiac ATP-sensitive K+ (K(ATP)) channel, a metabolism-sensitive ion conductance activated in ischemia. At levels found in hearts prior to ischemia, Ap5A maintained a low probability of K(ATP) channel opening, but at levels found in hearts following ischemia, Ap5A allowed a high probability of K(ATP) channel opening. Taken together, the present data suggest that Ap5A harbors the properties of a signaling molecule involved in the cardiac response to metabolic stress.

Animals↗
PubMed1998

Autotransplantation of premolars. A retrospective study.

The purpose of this clinical follow-up study was to evaluate the success rate of autotransplantation of human premolars. In the period between 1982 and 1994, 46 premolars in 31 patients were transplanted. A long-term success rate of 97.5% with a mean follow-up period of 3.5 years was achieved. It seems to be justified, therefore, in selected cases, to consider the possibility of autotransplantation as a good alternative to orthodontic or prosthetic treatment, including implant insertion, when closing a gap in the dental arch.

Adolescent↗
PubMed1998

Acquired resistance of a mammalian cell line to hypoxia-reoxygenation through cotransfection of Kir6.2 and SUR1 clones.

Reoxygenation after transient hypoxia is a common clinical condition that often causes greater tissue damage than persistent hypoxia itself. This warrants the development of a means to protect cells against hypoxia-reoxygenation injury. Adenosine triphosphate (ATP)-sensitive K+ (KATP) channels have been proposed to play an essential role in the mechanisms of endogenous cellular protection. Thus far, however, KATP channel proteins have not been exploited to generate an injury-resistant cellular phenotype by delivering KATP channel genes into injury-prone cells. A first step in this direction is the evaluation of the outcome of transferring genes encoding KATP channels into a KATP channel-deficient cell type exposed to metabolic stress. Untransfected COS-7 monkey kidney cells, which natively lack KATP channels, were found to be vulnerable to hypoxia-reoxygenation injury, which induced cytosolic Ca2+ loading, as measured by digital epifluorescent imaging. COS-7 cells cotransfected with KATP channel genes, Kir6.2 and SUR1, gained resistance to hypoxia-reoxygenation. This acquired resistance was abolished by glyburide, the KATP channel antagonist. We have previously shown that Kir6.2 and SUR1 physically associate to form a functional KATP channel, not reconstituted by either of the subunits alone. Transfection with individual channel subunits, Kir6.2 or SUR1, failed to produce resistance to hypoxia-reoxygenation induced Ca2+ loading. This is a first demonstration that transfer of KATP channel subunits can generate an injury-resistant cellular phenotype. The findings from this study may, thus, provide a framework for future therapeutic strategies based on gene delivery of KATP channel subunits in cells and tissues vulnerable to hypoxia-reoxygenation insults.

Animals↗
PubMed1997

Intracellular diadenosine polyphosphates: a novel family of inhibitory ligands of the ATP-sensitive K+ channel.

Intracellular diadenosine polyphosphates (Ap(n)A) are signal molecules that alert the cell under stress conditions. Herein, we review evidence that has recently identified a novel target for Ap(n)A, namely the ATP-sensitive K+ (K(ATP)) channel. These channels are abundant in pancreatic beta-cells and cardiac myocytes where they are essential in coupling the cellular metabolic state with membrane excitability. The potency and efficacy of Ap(n)A to inhibit K(ATP) channel activity were first described in cardiac K(ATP) channels, and appear similar to those of intracellular ATP, the primary ligand of K(ATP) channels. Also, the inhibitory ligand action of Ap(n)A is dependent upon the operative condition of K(ATP) channels and the presence of nucleotide diphosphates. In addition to a direct antagonism of channel opening, an indirect effect of Ap(n)A on K(ATP) channel activity has been associated with inhibition of adenylate kinase, a catalytic system believed essential for the regulation of channel opening. At present, the precise role for Ap(n)A-induced K(ATP) channel inhibition remains to be established. Yet, it is known that, under glucose challenge of pancreatic beta-cells, intracellular concentrations of Ap(n)A do increase to micromolar levels necessary to block K(ATP) channels, leading to insulin secretion. Thus, the Ap(n)A-mediated K(ATP) channel gating represents a previously unrecognized pathway of channel regulation.

Adenosine Triphosphate↗
PubMed1997

The effect of selenium on antioxidant system in erythrocytes and liver of the carp (Cyprinus carpio L.)

The effect of selenium-supplemented diet (sodium selenate and selenium yeast) on antioxidant in erythrocytes and liver of the carp (Cyprinus carpio L.) fingerlings was studied. With this goal, the activities of glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR) and glutathione-S-transferase (GST), as well as glutathione (GSH + GSSG) level, were determined. In the group supplemented with sodium selenate, no significant changes in the activity of the above enzymes were recorded in both the erythrocytes and in the liver, with the exception of GST activity that was significantly reduced in the plasma compared with the controls. Glutathione content was at the control level. In the group supplemented with selenium-yeast, the activities of GSH-Px, CAT, and SOD were significantly increased in erythrocytes, whereas GST activity and plasma content of GSH + GSSG were reduced compared with the controls. At the same time, the activities of hepatic SOD and GST were increased compared with the controls. These results demonstrate that organically bound selenium (selenium-yeast) acts more efficiently on antioxidant system of the carp fingerlings than inorganic selenium salts.

Animals↗
PubMed1996

Reversal of the ATP-liganded state of ATP-sensitive K+ channels by adenylate kinase activity.

The mechanism that promotes transition from the ATP- to the ADP-liganded state of ATP-sensitive K+ (KATP) channels and consequent channel opening in a cytosolic environment of high ATP concentration has yet to be understood. A mechanism examined here that could reverse the ATP-inhibited state is based on the action of adenylate kinase to catalyze phosphoryl transfer between ATP and AMP, resulting in transformation of ATP into ADP. In membrane patches excised from guinea pig cardiomyocytes, AMP alone did not affect channel behavior but increased the open probability of ATP-inhibited KATP channels. This required MgCl2 and a hydrolyzable form of ATP and was prevented by P1,P5-di-adenosine-5'-pentaphosphate, an inhibitor of adenylate kinase. The single channel amplitude and kinetics of channel openings induced by the ADP-generating substrates of adenylate kinase, AMP and MgATP, were indistinguishable from the biophysical properties of the KATP channel exhibited after addition of MgADP. In whole cell voltage-clamped cardiomyocytes, introduction of exogenous adenylate kinase along with millimolar MgATP and AMP induced a K+ current that was suppressed by a sulfonylurea blocker of KATP channels. Enriched sarcolemmal membrane preparations were found to possess ATP.AMP phosphotransferase activity with properties attributable to an extramitochondrial isoform of adenylate kinase. These results indicate that adenylate kinase is a naturally occurring component of sarcolemmal membranes that could provide dynamic governance of KATP channel opening through its phosphoryl transfer catalytic action in the microenvironment of the channel.

Adenosine Diphosphate↗
PubMed1996

Dual effect of glyburide, an antagonist of KATP channels, on metabolic inhibition-induced Ca2+ loading in cardiomyocytes.

Whether sulfonylurea therapy, which blocks ATP-sensitive K+ (KATP) channels, impedes endogenous cardioprotective mechanisms during cellular metabolic impairment remains controversial. Therefore, the effect of glyburide, a prototype sulphonylurea drug, on cytosolic Ca2+ concentration and KATP channel activity, was measured in 2-4-dinitrophenol-treated guinea-pig cardiomyocytes, using epifluorescent digital-imaging and cell-attached patch-clamp electrophysiology. Dinitrophenol (200 microM), which uncouples oxidative phosphorylation, induced opening of KATP channels and Ca2+ loading. Glyburide (6 microM) which reduced the opening of KATP channels, aggravated Ca2+ loading only when applied to dinitrophenol-pretreated myocytes but not when applied with dinitrophenol treatment. We conclude that a blocker of KATP channels has differential effects upon dinitrophenol-induced intracellular Ca2+ loading, which appear to depend upon the stage of metabolic insult.

2,4-Dinitrophenol↗
PubMed1996

Cytosolic Ca2+ domain-dependent protective action of adenosine in cardiomyocytes.

Recently, in beating cardiac cells heterogeneous spatiotemporal patterns in cytosolic Ca2+ distribution have been visualized, and associated with cell contraction. In non-beating cardiomyocytes, spatial heterogeneity of intracellular Ca2+ distribution has also been observed, yet its functional implication in resting cardiac cells is not known. Herein, distinct domains of lower versus higher concentrations of cytosolic Ca2+ (0.17 and 0.37 microM, respectively) were observed using epifluorescent digital imaging in single, non-beating, fluo-3-loaded cardiomyocytes. Extracellular K+ (16 mM) induced a uniform increase of cytosolic Ca2+, despite the initial presence of distinct domains of cytosolic Ca2+ (from 0.17 to 1.82 microM in domains with lower, and from 0.37 to 2.03 microM in domains with higher Ca2+ concentration, respectively). In contrast, adenosine (1 mM) prevented exracellular K+ to induce cytosolic Ca2+ loading selectively within domains with lower (from 0.17 to 0.18 microM), but not in domains with higher (from 0.37 to 1.4 microM) basal Ca2+ concentration. Thus, the response of a cardiomyocyte to the protective action of adenosine is heterogeneous within a resting single cell. The domain-distinct cytoprotective action of adenosine appears to be set by the basal Ca2+ concentration within a cytosolic domain.

Adenosine↗
PubMed1996

Cardiac ATP-sensitive K+ channel: a target for diadenosine 5',5''-P1,P5-pentaphosphate.

In numerous studies the intracellular mononucleotide-dependent gating of ATP-sensitive K+ (KATP) channels has been demonstrated. However, it is not known whether dinucleotide polyphosphates, a family of endogenous compounds structurally-related to ATP, could also modulate this ion conductance. Therefore, in the present study we assessed the direct effect of diadenosine 5',5''-P1,P5-pentaphosphate (Ap5A) on cardiac KATP channel activity using the inside-out configuration of the patch-clamp technique. Addition of Ap5A (50 microM) to the internal side of membrane patches, excised from guinea-pig ventricular cells, strongly inhibited KATP channel activity. The estimated NPO (where N is the number of channels in the patch and PO the open probability of each channel) was 4.16 +/- 0.50 in the absence and 0.85 +/- 0.30 in the presence of Ap5A (50 microM). This effect of Ap5A was partially reversible, and the NP0 was 2.26 +/- 0.60 after washout of Ap5A. Exposure of KATP channels to increasing concentrations of Ap5A revealed that the Ap5A-induced inhibition is concentration-dependent with the half-maximal effective concentration of 16 microM (Hill coefficient: 1.6). On the basis of these results, we conclude that Ap5A is a potent antagonist of the KATP channel activity. This represents a previously unrecognized property of Ap5A, as well as the discovery of a potentially novel endogenous ligand of myocardial KATP channels.

Adenosine Triphosphate↗
PubMed1996

Diadenosine polyphosphate-induced inhibition of cardiac KATP channels: operative state-dependent regulation by a nucleoside diphosphate.

It has been proposed that the regulatory action of mononucleotides, such as ATP and UDP, on cardiac ATP-sensitive K+ (KATP) channels is determined by the state of the channel. Recently, dinucleotides, such as diadenosine tetraphosphate (Ap4A) and diadenosine pentaphosphate (Ap5A), have been recognized as novel intracellular ligands of cardiac KATP channels. However, it is not known whether the state of KATP channels also determines the response of the channel to dinucleotides. Therefore, we examined the action of diadenosine polyphosphates on KATP channel activity during different operative channel states, using the inside-out patch clamp technique applied to patches excised from guinea-pig ventricular myocytes. Spontaneous openings of KATP channels (or operative condition 1) were inhibited by Ap4A and Ap5A. Addition of UDP, which on its own did not affect spontaneous openings of KATP channels, prevented Ap4A and Ap5A to inhibit spontaneous KATP channel activity. In contrast, following "run-down" of spontaneous channel activity, UDP induced KATP channel openings (or operative condition 2), but could no longer antagonize the inhibitory effect of Ap4A and Ap5A. We conclude that the inhibitory action of diadenosine polyphosphates on KATP channels can be blocked by UDP only when KATP channels are in operative condition 1, but not in operative condition 2. Thus, the operative condition of KATP channels determines the UDP-mediated regulation of the diadenosine polyphosphate-dependent inhibitory channel gating. This finding further suggests that the operative state of the cardiac KATP channel protein is a critical determinant of the regulatory action of an intracellular ligand.

Animals↗
PubMed1996

Diadenosine tetraphosphate-induced inhibition of ATP-sensitive K+ channels in patches excised from ventricular myocytes.

Diadenosine 5',5''-P1,P4-tetraphosphate (Ap4A) has been termed 'alarmone' due to its role in intracellular signaling during metabolic stress. It is not known whether Ap4A could modulate ATP-sensitive K+ (KATP) channels, a family of channels regulated by the metabolic status of a cell. We applied the single-channel patch-clamp technique to measure the effect of Ap4A on KATP channels. When applied to the intracellular side of patches, excised from guinea-pig ventricular myocytes, Ap4A inhibited KATP channel activity, in a reversible and concentration-dependent (half-maximal concentration approximately 17 microM) manner. We conclude that Ap4A, a naturally occurring diadenosine polyphosphate, is actually an inhibitor of the myocardial KATP channel.

Adenosine Triphosphate↗
PubMed1995

Spontaneous calcium waves without contraction in cardiac myocytes.

Spontaneous Ca2+ waves were visualized in quiescent cardiomyocytes loaded with the Ca(2+)-sensitive fluorescent probe, Fluo-3, and imaged by laser confocal microscopy. No sarcomere shortening was detected during wave propagation. This type of Ca2+ waves began at the periphery or in a central region of a myocyte and propagated the length of the cell in one or two directions. The average velocity of wave propagation was 32 microns/sec and the estimated concentration of Ca2+ oscillated from 124, at the bottom, to 311 nM, at the pick of the wave. Ca2+ waves were not confined to a single cell but could spread from cell to cell. These results describe a type of spontaneous Ca2+ waves which does not induce a contractile response in cardiomyocytes.

Aniline Compounds↗
PubMed1995

Role of genetic factors in the etiology of squamous cell carcinoma of the head and neck.

OBJECTIVE: To determine the role of genetic predisposition in the etiology of head and neck squamous cell carcinoma. DESIGN: Retrospective study. SETTING: The outpatient clinics of the departments of otorhinolaryngology and maxillofacial surgery. PATIENTS: First-degree relatives of patients with new head and neck cancer, with first-degree relatives of the patients' spouses as controls. MAIN OUTCOME MEASURE: Occurrence of cancer of the respiratory and upper digestive tract in relatives of patients with head and neck cancer and controls. RESULTS: First-degree relatives (n = 617) of 105 patients with head and neck cancer had 31 cases of cancer of the respiratory and upper digestive tract vs 10 cases in the control group (n = 618) (relative risk, 3.5; P = .0002). This higher rate of cancer was even larger in siblings (16 vs 2, relative risk, 14.6; P = .0001). CONCLUSIONS: Genetic predisposition is an important risk factor for squamous cell carcinoma of the head and neck.

Carcinoma, Squamous Cell↗
PubMed1994

Risk of multiple primary tumors following oral squamous-cell carcinoma.

The follow-up of 727 patients with squamous-cell carcinoma (SCC) of the lip and oral cavity has been used for the risk analysis of multiple primary tumors (MPTs) following SCC of the lip and oral cavity. Age-, gender- and site-specific cancer-incidence rates from the general population have been applied to the appropriate persons-years of follow-up of patients with SCC of the lip and oral cavity. The study indicates that patients with a primary SCC of the lip and oral cavity have, compared with the general population, a significantly elevated risk of developing an additional cancer of the oral cavity and/or pharynx, the risk being 74.7-fold for males and 190.4-fold for females. Furthermore, a 24.6 and 45.3 times higher risk of an additional esophageal tumor was found in males and females respectively. The risk of cancer of the lung and pharynx was less elevated compared with the risk of cancer of the upper digestive tract. No elevated risks were established in organs outside the respiratory and upper digestive tract.

Aged↗
PubMed1994

Second respiratory and upper digestive tract cancer following oral squamous cell carcinoma.

727 patients with squamous cell carcinoma (SCC) of the lip and oral cavity have been followed for the occurrence of second primary tumours (SPTs) in the respiratory and upper digestive tract (RUDT). 74 patients (10%) developed at least one SPT in the RUDT. The incidence of SPTs was expressed per 1000 person-years of follow-up. In our study about 28 SPTs per 1000 person-years of follow-up were seen in the RUDT. Patients were at risk for a second primary tumour, at a steady rate of approximately 2.8% per year during at least 10 years. Furthermore, patients with an index tumour in the lower part of the mouth (floor of mouth, retromolar area and lower alveolar process), which is more related to tobacco and/or alcohol, seem to be more at risk for SPTs than patients with an index tumour in the other (sub)sites of the mouth.

Aged↗
PubMed1994

[Second primary tumors following treatment of squamous cell carcinoma of the oral cavity].

In the hospital of the Free University in Amsterdam (the Netherlands) 727 patients with primary squamous cell carcinoma of the oral cavity and lip have been studied for the incidence of second primary tumors occurring in the respiratory and upper digestive tract. Out of the 727 patients, 74 (10.2%) developed a second primary tumor in these tracts. The incidence of second primary tumors was expressed per 1.000 person-years of follow-up; 28 second primary tumors per 1.000 person-years of follow-up were seen in the respiratory and upper digestive tract. The patients ran the risk of developing a second primary tumor at a steady rate of approximately 2.8% per year during at least ten years. Furthermore, an increasing incidence of second primary tumors could be observed in case of increasing use of tobacco.

Aged↗