RESEARCH PROJECTS
Potential alteration of the binding kinetics of angiotensin II receptors in rat myocardial infarction model A
rat heart perfusion technique supported by confocal microscopy is used
to assess using mathematical model the binding of Angiotensin II (AngII)
on various receptor subtypes in acute myocardial infarction (AMI) rat models.
AMI is induced in Sprague-Dawley female rats by ligation of left anterior
descending coronary artery after intercostal thoracotomy. The AMI rats
will be studied after one month. The rats are grouped as: Group I,
treated with AT1-R antagonist; Group II, treated with
AT2-R antagonist; Group III, treated with both antagonists;
Group
IV, no treatment AMI rats. Sham operated rats is prepared for each
group. Radiolabeled angiotensin II is perfused to assess affinity and binding
on the coronary endothelium and myocytes. Confocal microscopy, immunofluorescence
and histological examination will be used to detect the exact location
and number of receptors and quantitatively determine the different cell
types at left ventricular infarcted region, left ventricular non-infarcted
region, and right ventricle. A.B. Bikhazi, M.E. El-Sabban. (Supported
by DTS Fund.)
Role of kupffer and parenchymal cells in hepatobiliary clearance of lipopolysaccharides in perfused rat heart Identify
role of Kupffer cells and hepatocytes in 3H-lipopolysaccharide
(3H-LPS) clearance at the microtubular system after treatment
with colchicine and gadolinium chloride (GdCl3) in perfused
rat liver. Liver perfusion involves both portal vein and thoracic inferior
vena cava cannulations as inlet and outlet respectively. Subhepatic inferior
vena cava is ligated to prevent perfusate leakage. Buffer containing 3H-LPS
is administered via inlet and collected via outlet at specified time intervals.
Rate constants for hepatocellular clearance of 3H-LPS in controls,
colchicine-treated, and colchicine plus GdCl3-treated rats is
assessed. Forward-binding, reversal-binding, residency-time, and apical-sinusoidal
influx rate constants are estimated from the data fittings using a physical
model. GdCl3-treatment reduced the residency time of 3H-LPS
binding with non-specific receptor on Kupffer cells by »
50% but with the little effect on parenchymal cells. However, colchicine
plus GdCl3 treatments reduced the forward-binding constant by
»
56% indicating Kupffer cells role in 3H-LPS trafficking and
clearance via canaliculi. A. B. Bikhazi. (Supported by LNRC.)
Neural regulation of nutrient absorption in the small intestine Our
knowledge of the mechanisms involved in the regulation of water, ions and
nutrient absorption across the intestinal epithelium has been substantially
refined over the past two decades. It is well known now that extrinsic
as well as intrinsic innervation of the gut plays a major role in regulating
water and ion transport. The possibility that specific nerves and their
neurotransmitters can modulate intestinal nutrient absorption has not been
well defined. The aim of the study is to evaluate the involvement of the
vagus nerve and more specifically the vagal capsaicin-sensitive primary
afferent fibers in regulating amino acid transport across intestinal epithelia.
Such regulation can be through a sequence of events in neural pathways
that would lead to stimulation or inhibition of nutrient absorption, or
due to the release of one or more of the neuropeptides and/or neurotransmitters
that could mediate the neural input in the absorptive function of the small
intestine. C.F. Nassar, K.A. Barada, S.F. Atweh, N.E. Saadé.
(Supported by URB and MPP.)
Inhibition of jejunal alanine absorption by intraileal alanine involves capsaicin sensitive primary afferents Luminal
nutrients have important effects on intestinal motility, absorptive and
secretory functions. Some of these effects are neurally mediated. There
are no data on the effect of intraluminal amino acids in the ileum on the
regulation of nutrient absorption by the proximal jejunum. The aim of this
study is to investigate the effect of intra-ileal alanine on jejunal alanine
absorption and to study its neural mechanisms. Preliminary results demonstrate
that intraluminal ileal alanine participates in the regulation of jejunal
alanine absorption via a neural reflex and involves intestinal capsaicin
sensitive primary afferent fibers. C.F. Nassar, K.A. Barada, N.E. Saadé,
F.H. Mourad, S.F. Atweh. (Supported by URB.)
The role and mechanism of action of IL-1 on intestinal epithelial cell function in inflammatory bowel disease. In
inflammation, cells that secrete various inflammatory cytokines infiltrate
the intestinal mucosa. Increased cytokine levels, such as IL-1, have been
reported in inflamed tissue, and could regulate ion transport. The goal
of the project is to investigate the role and mechanism of action of IL-1
in the regulation of epithelial cell function. The role of phospholipase
A2 (PLA2) and cyclooxygenase (COX) enzymes, and sphingomyelin
signaling pathway in the action of IL-1 are assessed. We are studying:
the effect of IL-1 on ceramide and sphingosine accumulation; the effect
of ceramide and IL-1 on PLA2 and COX enzymes activity and/or
levels, and on PGE2 production. Understanding how inflammatory
mediators alter epithelial cell function will enable us to better understand
the mechanism of the changes that occurs in inflammatory bowel disease.
F.R.
Homaidan, G.S. Dbaibo, M.E. El-Sabban. (Supported by URB, LNCSR, DTS,
and MPP.)
Adhesion and gap junctional communication between macrophages and intestinal epithelial cells In
inflammation, the intestinal mucosa is infiltrated by inflammatory cells
including macrophages, which are capable of regulating intestinal epithelial
cell (IEC) function by different mechanisms. These mechanisms include interaction
through soluble mediators released by the cells, and/or by direct cytosolic
communication through gap junctions formed between the two types of cells.
The goal of this proposal is to investigate the role and mechanism of action
of soluble mediators in the regulation of epithelial cell function and
the significance of IEC-macrophage (Mf
) interaction. The immediate and long time effects of IL-1 on IEC function
and on IEC-Mf
cocultures are investigated. The role of the various phospholipids messengers
in increasing the interaction between the two cell types is also assessed.
F.R.
Homaidan, M.E. El-Sabban. (Supported by URB, LNCSR, and DTS.)
Reversibility of structural alterations in the pulmonary vascular wall and of right ventricular remodeling in experimental pulmonary hypertension in the rat The
sequence of alterations in the structure of the rat right ventricle (RV)
and in the pulmonary circulation is being investigated using Monocrotaline
(MCT) a pyrrolizidine alkaloid known to cause pulmonary vascular lesions
similar to those seen in patients with pulmonary hypertension. MCT increased
the percent medical thickness of the pulmonary vascular wall and the ratio
of lung wet weight/lung dry weight the latter demonstrating perivascular
edema. While RV total collagen is seen to increase concomitantly with and
in response to the pulmonary vascular lesions, total protein content decreases
significantly within the second week after MCT administration and thereafter.
This failure of protein content to increase may possibly have resulted
from accelerated protein degradation and/or diminished protein synthesis.
This issue is currently being addressed together with that of reversibility
of the pulmonary vascular alterations and right ventricular remodusing
endothelium-dependent and -independent mechanisms. M. G. Nasser, W.
A. Medawar, H. G. Kaspar, M. E. El-Sabban. (Supported by URB, MPP,
LNCSR.)
The role of the thalamus in pain transmission and gating mechanisms The
thalamus continues to be regarded as a most important structure for the
perception of pain. However, several clinical studies have shown that thalamic
lesions can produce pain and thalamic stimulation can relieve chronic pains.
The mismatch between the traditional view and the clinical data led to
a paradox: how can a function carried by a neural structure be reduced
when that structure is stimulated and exaggerated when that structure is
ablated. Our experimental data provide an alternative view for the role
of the thalamus in the processing of nociceptive information and pain.
N.E.
Saadé, S.J. Jabbur, S.F. Atweh. (Supported by URB.)
Dorsal column input into various brainstem areas Electrophysiological
evidence is gathered in the search for a dorsal column input(s) into various
brainstem nuclear groups involved in pain inhibition. This work appears
to give further support to our hypothesis about the existence of a dorsal
column-brainstem-spinal loop playing a role in pain modulation. S.J.
Jabbur, S.F. Atweh, N.E. Saadé. (Supported by LNCSR.)
Barada, K.A., Abdallah, L., Nassar, C.F., Age influence on intestinal taurine transport in mice. Comparative Biochemistry and Physiology, 118A (1), 159-163, 1997. Barada, K.A., Dika, S.S., Atweh, S.F., Saadé, N.E., Nassar, C.F., Acute and neonatal capsaicin treatment inhibit amino acid transport through a sodium dependent mechanism. American Journal of Physiology, 272, (Gastrointestinal Liver Physiology 35), G815-G821, 1997. Barada, K.A., Saadé, N.E., Atweh, S.F., Nassar, C.F., Neural mediation of VIP inhibitory effect on alanine absorption across the small intestine. American Journal of Physiology, 275 (Gastrointest. Liver Physiology 38), G822-828, 1998. Bikhazi, A.B., Formulations and drug delivery II. Investigational Drugs Weekly Highlights, Week 47, 46-49, 1997. Bikhazi, A.B., Bitar, K.M., Kreydiyyeh, S.I., Saleh, R.S., El-Kasti, M.M, Ibrahim, Z.M., Abul-Khoudoud. O.R., Binding and distribution of some prototype calcium channel blockers in perfused rat liver. Molecular and Cellular Biochemistry, 169 (1-2), 1-11, 1997. Bikhazi, A.B., Haddad, R.E., Nahlé, Z.A., Bitar, K.M., Angiotensin II delivery and binding at the microvascular endothelium and cardiac myocyte surfaces in perfused rat hearts. Journal of Pharmaceutical Sciences, 87, 1363-1367, 1998. Bikhazi, A.B, Nahlé, Z., Kreydiyyeh, S.I., Haddad, R., Bitar, K., Haddad, G., Abdelnoor, A., Endotoxin binding on capillary endothelium and myocyte plasma membranes in perfused rat hearts. Journal of Endotoxin Research, 4 (1), 45-51, 1997. Bikhazi, A.B., Nahlé, Z.A., El-Sabban, M.E., Bitar, K.M., Peptides and their Antagonists in endothelium of the coronary vasculature and myocytes. Emerging Therapeutic Targets, 2 (1), 65-67, 1998. Bikhazi, A.B., Saadeh, F.A., Haddad, R.E., Nahlé, Z.A., Abou Fares, M.F., Bitar, K.M., Birbari, A.E, Insulin receptor binding characteristics in perfused SHR and WKY rat hearts. Comparative Biochemistry and Physiology, Part C 120, 127-136, 1998. El-Sabban, M.E., Martin, C.A., Homaidan, F.R., Signaling between immune cells and intestinal epithelial cells in vitro. In Gap Junctions, ed. R. Werner, 178-182. The Netherlands: IOS Press, 1998. Kanj, N.A., Samaha, M., Nassar, C.F., Effects of capsaicin and capsaicin desensitization on alanine accumulation in rat hemidiaphragms. General Pharmacology, 31 (1), 121-123, 1998. Kreydiyyeh, S.I., El-Kasti, M.M., Bikhazi, A.B., A possible mechanism for the insulin stimulation of alanine uptake by isolated rat hepatocytes. Comparative Biochemistry and Physiology, 116C (3), 245-253, 1997. Haddad, G.E., Saadeh, F.A., Sharaf, L.H., Nahlé, Z.A., Abou Fares, M.F., Haddad, R.E., Bitar, K.M., Bikhazi, A.B., Alteration in IGF-I binding on cardiac myofibers and capillary endothelium during chronic volume-overload-induced hypertrophy. Journal of Biochemistry, Molecular Biology and Biophysics, 3, 65-74, 1999. Haddad, R.E, Jurjus, A.R., Ibrahim, M.Z.M, Nahlé, Z.A., El-Kasti, M.M., Bitar, K.M., Kreydiyyeh, S.I., Saadeh, F.A., Bikhazi, A.B., Binding of 125I-insulin on capillary endothelial and myofiber cell membranes in normal and streptozotocin-induced diabetic perfused rat hearts. Comparative Biochemistry and Physiology, 117A, 523-530, 1997. Homaidan, F.R., Martello, L.A., Melson, S., Burakoff, R., Regulation of electrolyte transport by nitric oxide in the cecum of normal and colitic mouse. European Journal of Pharmacology, 350, 93-99, 1998. Homaidan, F.R., Tripodi, J., Zhao, L.M., Burakoff, R., Regulation of electrolyte transport by histamine in mouse cecum. European Journal of Pharmacology, 331, 199-204, 1997. Homaidan, F.R., Zhao, L.M., Burakoff, R., IL-1 induces the synthesis of phospholipase A2-activating protein in the distal colon. American Journal of Physiology, 272, G1338-G1346, 1997. Martin, C.A., El-Sabban, M.E., Zhao, L.M., Burakoff, R., Homaidan, F.R., Adhesion and cytosolic dye transfer between macrophages and intestinal epithelial cells. Cell Adhesion and Communication, 5, 83-95, 1998. Martin, C.A., Homaidan, F.R., Zhao, L.M., Burakoff, R., El-Sabban, M.E., Gap junctional communication between macrophages and intestinal epithelial cells. Cell Adhesion and Communication, 5, 437-449, 1998. Medawar,
W.A, Kaspar, H.G., Ibrahim, H., Al-Tayeh, A.U., Krayem, H.K., Nasser, M.G.,
Sequential Alterations in the Pulmonary Vascular Wall and in the Right
Ventricle in Monocrotaline-Induced Pulmonary Hypertension in the Rat. FASEB
Journal, 12 (5), A976, 1998.
ABSTRACTS,
PRESENTATIONS AND PROCEEDINGS
Barada, K.A., Saadé, N.E., Atweh, S.F., Nassar, C.F., Intravenous and intracerebral injection of calcitonin gene related peptide inhibits amino acid absorption across the rat jejunum. Digestion, 65 (3), 1998. Bikhazi, A.B., International forum on angiotensin II receptor antagonism (part II). Investigational Drugs Weekly Highlights, Week 8, 22-25, 1999. Bikhazi, A.B., Hassan, K.A., Gebrael, J.H., Bitar, K.M., Angiotensin II-AT1-subtype receptor binding with antagonist and potential activation of AT2-dubtype receptor. International Forum on Angiotensin II Receptor Antagonism, 15, Monte-Carlo/Monaco, January 27-30, 1999 Bikhazi, A.B., Nahlé, Z., Abou Fares, M.F., Haddad, R.E., Bitar, K.M., Polypeptide delivery at myocyte-surfaces in a perfused rat heart Preparation. Conference on Formulations and Drug Delivery II, 84, San Diego/California/U.S.A., October 5-8, 1997. Bikhazi, A.B, Nahlé, Z., Haddad, R., Bitar, K., Comparative binding of angiotensin II and DUP753 on capillary endothelium and myofibers perfused rat hearts. 1998 Experimental Biology Annual Meeting, FASEB Journal, 12 (A408), San Francisco/California/USA, April 18-22, 1998. Bikhazi, A.B., Ziadeh, A.G., Abbud, R.A., Nabhan, S. I., Haddad, G.E., Two uncompetitive titrated sites of the Na+/H+ exchanger in perfused rat kidney. 1998 AAPS Meeting, Pharmaceutical Sciences, 1, S-391, San Francisco/California/USA, November 14-19, 1999. Haddad, G., Saadeh, F., Sharaf, L., Nahlé, Z., Abou Fares, M., Bitar, K., Bikhazi, A., Kinetics of IGF-I binding on cardiac myofibers and capillary endothelium during chronic eccentric hypertrophy. 1998 Experimental Biology Annual Meeting, FASEB Journal, 12, A709, San Francisco/California/USA, April 18-22, 1998. Homaidan, F.R., El-Assaad, W., Chakroun, I., Dbaibo, G., El-Sabban, M.E., IL-1 increases ceramide production and induces COX-2 in intestinal epithelial cells. American Gastroenterological Association, New Orleans, LA, U.S.A., 1998. ———, Activation of the sphingomyelin pathway in intestinal epithelial cells by IL-1. Society of General Physiologists, Woods Hole, MA, U.S.A., 1998. Homaidan, F.R., Martin, C.A., El-Sabban, M.E., Signaling between immune cells and intestinal epithelial cells in vtiro. International Gap Junction Conference, Key Largo, FL, U.S.A., 1997. Homaidan, F.R., Zhao, L.M., Burakoff, R., IL-1 induces the synthesis of phospholipase A2-aprotein and COX-2 in a murine epithelial cell line Mode-K cells. American Gastroenterological Association, Washington D.C./U.S.A., 1997. ———, The mechanism of interleukin-1 regulation of PGE2 production by rabbit colonic epithelial cells. American Gastroenterological Association, New Orleans, LA, U.S.A., 1998. Kafrouni, M.I., Barada, K.A., Saadé, N.E., Mourad, F.M., Atweh, S.F., Nassar, C.F., Intestinal glucose absorption at high intraluminal concentrations is inhibited by capsaicin. The FASEB Journal, 13 (5), A1011, 1999. Kanj, N.A., Nasser, M.G., Medawar, W.A., Al Tayeh, A.U., Khoury, M.Y., Nassar, C.F., Reversal of impaired calcium homeostasis in the rat diaphragm subjected to monocrotaline-induced pulmonary hypertension. Toxicology Letters, 105, 177-182, 1999. Lopez, A.L., Homaidan, F.R., Zhao, L.M., Burakoff, R., Basal and stimulated electrical transport characteristics of the murine proximal colon. American Gastroenterological Association, New Orleans, LA, U.S.A., 1998. Mourad, F.H., Khuri, M., Shouaib, F., Nassar, C.F., Protective effect of molsidomine on indomethacin and aspirin-induced gastric injury in rats. Digestion, 59 (Suppl. 3), 209, 1998. Mourad, F.H., Nassar, C.F., Vasoactive intestinal polypeptide VIP antagonism prevents cholera toxin induced fluid secretions in rat jejunum. Gut, 7 (3), A-39, 1997. Nassar, C.F., Barada, K.A., Atweh, S.F., Saadé, N.E., Extrinsic and intrinsic neuronal mechanisms involved in the inhibitory effects of VIP on alanine intestinal absorption. The FASEB Journal, 12, (4 ), A-369, 1998. Taha, A.M., Hejazi, N.E., Saadé, N.E., Nassar, C.F., The effect of hemorrhagic shock on the absorption of amino acids in the rat jejunum. The FASEB Journal, 11 (3), A-34(198), 1997. Zhao,
L.M., Homaidan, F.R., Burakoff, R., Interleukin-10 inhibits interluekin-1
mediated stimulation of the cyclooxygenase pathway. American Gastroenterological
Association, New Orleans, LA, U.S.A., 1998.
Al-Tayeh, A., Monocrotaline-induced structural alterations and remodeling in the rat pulmonary system and right ventricle (1998). M. G. Nasser, H. G. Kaspar. Hassan, K., Potential alteration of the binding kinetics of angiotensin II receptors in rat myocardial infarction model (1999). A.B. Bikhazi, M.E. El-Sabban. Khoury,
F., Chemical alterations of the enteric neuronal activities influence Jejunal
Alanine Absorption (1999). C. F. Nassar, N. E. Saadé.
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