RESEARCH PROJECTS
Mg-dependent, Zn ATPase Zn is important to maintain tertiary structure and hence functionality
of many proteins including enzymes. Steady state levels of Zn seems to
be maintained by ZnATPase. An assay to measure Zn activated ATPase activity
in the intestinal mucosa was developed in collaboration with I.S. Edelman
and A. Wang. The enzyme was also found to be present in the kidney, other
tissues are being screened. Purification of the enzyme is underway, a 100-fold
enrichment was achieved. This will allow us to develop the tools (N-terminal
sequences, antibodies, etc…) to attempt to clone the enzyme. A number of
putative inhibitors are also being screened. Two publications in preparation
are entitled “Mg-Dependent, Zn-ATPase: I. Enzymatic Characteristics” and
“Mg-Dependent, Zn-ATPase: II. Ion Specificities and Tissue Distribution”.
N. Cortas. (Supported by Judith P. Sulzberger Foundation and gifts
from Mr. & Mrs. Frederic A. Bourke.)
Comparison between the antifungal and nephrotoxic effects of amphotericin B and liposomal amphotericin B Liposomal amphotericin B (L-AmB) is a new preparation of the
drug that is claimed to be less nephrotoxic while maintaining equivalent
antifungal activity compared to amphotericin B-deoxychoplate (D-AmB). However,
there is no definitive evidence in the literature to support this claim.
The present pcompares the effects of each formulation on: 1) renal function
and hemodynamics after acute intravenous injections of increasing doses,
2) fungal cell viability in-vitro by evaluating minimal inhibitory concentrations
of each formulation against several fungal pathogens and 3) in-vitro nephrotoxicity
as measured by the effect of various concentrations of the two formulations
on intracellular calcium levels in glomerular mesangial cell and on their
contractility using spectrofluorometric and imaging techniques. So far,
we have shown that L-AmB at doses 25 times the nephrotoxic dose of D-AmB
has no influence on renal hemodynamics or function. In vitro, however,
it is equipotent in inducing a fungistatic effect and 3 to 6 times less
potent in its fungicidal activity. Mesangial cell culture has been established
and studies are underway to achieve aim #3. R. Sabra. (Supported
in part by the LNCSR, MPP and URB.)
Influence of phenobarbital on renal and systemic hemodynamics and on renal function in portal hypertensive rats Our recent studies indicate that renal sodium retention in
animal models of cirrhosis occurs only when liver function (assessed by
the aminopyrine breath test) decreases below a critical threshold. This
could reflect the critical role of liver metabolic processes in controlling
renal function possibly through influencing the synthesis of neuro-humoral
factors. The relationship between liver function and renal function is
being studied and further characterized in animal models of liver dysfunction
and portal hypertension. Since phenobarbital is known to stimulate liver
enzymes, its effect on the renal and systemic consequences of liver dysfunction
have been examined. It was shown that phenobarbital pretreatment markedly
attenuates the development of sodium retention after PVL and reduces the
severity of peripheral vasodilation. In parallel, although liver function
is reduced after PVL, the extent of reduction is less with phenobarbital.
These results support the hypothesis that a critical reduction in liver
function is essential for inducing sodium retention in this model of portal
hypertension, and possibly in cirrhosis. R. Sabra. (Supported by
the MPP and DTS.)
Mechanisms of potentiation by cocaine of adrenergic responses: possible role for beta adrenoceptor sensitization The mechanism by which cocaine potentiates the effects of
catecholamines is believed to be inhibition of reuptake by the nerve terminals.
However, a number of in-vitro studies suggest actions at the post-synaptic
terminal. The first part of this proposal looking at the interaction of
adrenergic agonists, the alpha adrenoceptor antagonist phenoxybenzamine
and cocaine has been completed. The results support the suggestion that
cocaine acts by enhancing cardiac responses to adrenergic agonists at the
beta adrenoceptor level and not only by inhibiting uptake of neurotransmitters,
indicating a possible sensitization of cardiac beta-adrenergic receptors
by cocaine. More recent results suggest that cocaine, through a central
effect likely to result in inhibition of sympathetic tone, sensitizes the
heart to the actions of sympathomimetic agents at a post-junctional site.
Further studies are planned to examine the influence of acute and chronic
treatment with cocaine and related compounds, e.g. tricyclic anti-depressants,
on beta-adrenoceptor binding characteristics in the heart. R. Sabra.
(Supported in part by the LNCSR and DTS.)
The cardiodynamic and electrophysiological effects of drugs on the isolated heart and their modification of the effects of the cardiac glycosides represented by ouabain The effect of many drugs has already been explored and comparisons
were made between them. The last was an exploration of the effect of amiodarone
on the arrhythmogenic activity of ouabain. Amiodarone is known to produce
its main antiarrhythmic effects by lengthening the duration of the action
potential, a time-dependent process. However, amiodarone is available as
an intravenous preparation and is often given by this route for the acute
treatment of arrhythmias. The findings of our studies have not shown a
significant effect of amiodarone on ouabain-induced arrhythmias given acutely
in the isolated heart. Comparisons with another class III antiarrhythmic
sotalol that has in addition a beta-adrenoceptor blocking activity is under
exploration. J. Simaan. (Supported by LNCSR.)
The interaction between acetylcholine and drugs with positive inotropic effect in the isolated heart Acetylcholine produces minimal negative inotropic and chronotropic
effects on the isolated heart. During the effect of isoproterenol, these
effects are drastically exaggerated and not only neutralize the isoproterenol-mediated
stimulation, but also produce additional depression below the level under
control conditions. The potentiative effect of the sympathetic system,
represented by isoproterenol is under exploration. Other classes with positive
inotropic effect are also under exploration for their potentiative effect
and the mechanisms involved.
J. Simaan. (Supported by LNCSR.)
The effect of acetylcholine on the coronary vascular bed and the role of nitric oxide in its vasorelaxant action is under exploration in the cat modified heart-lung preparation compared with the results of previous studies on the leg and mesenteric vascular beds J. Simaan. (Supported by LNCSR.)
*Bernardo, J., Sabra, R. and *Branch, R.A.: Amphotericin B. In Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals, ed. Porter, G.A., De Broe, M.E., Bennett, W.M., and Verpooten, G.A., 135-151. The Netherlands: Kluwer Academic Publishers, 1998. Major, S., Badr, S., Bahlawan, L., Hassan, G., Khogaoghlanian, T., Khalil, R., Melhem, A., Richani, R., Yeretzian, J., Khogali, M., and Sabra, R.:, Drug related hospitalization at a tertiary teaching center in Lebanon: incidence, associations, and relation to self-medicating behavior. Clinical Pharmacology and Therapeutics 64, 450-461, 1998. Sawaya,
J.I., *Jazra, C., Eid, E., and Sabra, R.: Gender differences in the diagnosis
and treatment of acute myocardial infarction in Lebanon. Lebanese Medical
Journal, 47, 2-6, 1999.
ABSTRACTS,
PRESENTATIONS ANS PROCEEDINGS
Sabra, R., Shuman, S.: Influence of phenobarbital (PhB) on changes in sodium handling, hemodynamics and liver function induced by partial portal vein ligation. Hepatology, 28 (4 Pt 2), 559A, 1998. Sabra, R., Zeinoun, N.: Comparison of the nephrotoxic and antifungal effects of amphotericin B-deoxycholate (D-AmB) and liposomal amphotericin B (L-AmB). Naunyn Schmiedberg's Archives of Pharmacology, 358 (Suppl 2), R524, 1998. Simaan, J., The acute cardiodynamic and electrophysiologic effects of amiodarone and their modification of the effects of ouabain explored in the cat heat-lung preparation. Naunyn-Schmiedeberg’s Archives of Pharmacology, 358, 36.16, 1998. ———, A comparative study of the role of nitric oxide in acetylcholine-induced vasodilatation in the intact autoperfused hind limb and mesenteric vascular beds of the cat. The Physiologist, 41, 278, 1998. ———, The effects of acetylcholine infusions on cardiodynamic parameters and their modification by different inotropic drugs explored in the cat heart-lung preparation. The FASEB Journal, 13, A108, 1999. Simaan, J., and K. Farhat: The cardiodynamic and electrophysiologic effects of different parasympathomimetic drugs and their interaction with ouabain explored in the isolated heart. The FASEB Journal, 12, A410, 1998. Simaan,
J., and Younis, R., The cardiodynamic and electrophysiologic effects of
calcium channel blockers and their interaction with ouabain explored in
the isolated heart. The Pharmacologist, 39 ( 1), 74, 1997.
Farhat, K., The effect of the parasympathomimetic drugs, acetylcholine, carbachol, pilocarpine and physostigmine on the cardiodynamic an electrophyiological parameters of the isolated heart and their modification on the effects of ouabain (1997). J. Simaan. Hajj, H., The effect of acetylcholine infusions on cardiodynamic and electrophysiologic parameters and tmodification by different positive inotropic drugs explored in the cat heart-lung preparation (1999). J. Simaan. Khouri, H., Potentiation by cocaine of cardiac adrenergic responses: possible role for post-synaptic mechanisms (1999). R. Sabra. Shuman, S., Influence of partial portal vein ligation on hemodynamics, liver function and renal sodium handling, and their modification by phenobarbital (1998). R. Sabra. Zeinoun,
N., Amphotericin B and liposomal amphotericin B: a comparison of therapeutic
and toxic effects (1998). R. Sabra.
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