SVIBOR - Project code: 3-01-273

MINISTRY OF SCIENCE AND TECHNOLOGY

Strossmayerov trg 4, HR - 10000 ZAGREB
tel.: +385 1 459 44 44, fax: +385 1 459 44 69
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Project code: 3-01-273


MECHANISMS OF TRANSPORT REGULATION IN THE KIDNEY


Main researcher: SAMARŽIJA, ITA (44416)


Assistants
Type of research: basic
Duration from: 01/01/91. to 12/31/93.
Papers on project (total): 62
Papers on project quoted in Current Contents: 5
Institution name: Farmaceutsko-biokemijski fakultet, Zagreb (6)
Department/Institute: Department of Parmacology Faculty of Pharmacy and Biochemistry University of Zagreb
Address: Domagojeva 2
City: 10000 - Zagreb, Croatia
Communication
Phone: 385 (0)41 446622
Fax: 385 (0)41 446622
E-mail: -
Summary: Inside the kidney, there are performed numerous and very complex selective reabsorption processes or elimination of electrolytes, substrates, drugs, their metabolites and other harmful by-products. On that way homeostatic regulation of body fluids is achived and creation of end-urine. The substances transit processes are performed paracellular or transcellular with help of transporters which are located in luminal and / or basolateral membranes in particular nephron segments. Those investigations made efforts to explain regulatory mechanisms and functional dynamism of particular membrain protein - transporters (ionic pump, co-transporters, antiporters, ionic channels). About twenty of renal and extrarenal hormones and mediators are involved in regulation of ion transport mechanisms such as: angiotensin II, aldosterone, vasopressin, Na-uretic hormone, dopamine, prostaglandins etc.. It is established that angiotensin II, beside already known vasoactive effect, stimulation of aldosterone secretion and blood pressure increase, also act directly on kidney tubules through specific receptors. At least two of its isoreceptors, with low and high affinity exist in basolateral membrane of proximal tubules. Milimolar concentrations of angiotensin II, added from the peritubular side of tubule, have shown mild depolarization of cell potential, which is formed as signal transduction reflection of low-affinity isoreceptor on diminishing c-AMP and increasing Na/H-antiporter activity located in luminal membrane. On that way stimulation of Na-ions reabsorption was achived. In patients with clinical manifested essential hypertension it is also increased Na/H-exchanger activity which is identical with in vivo experimental information. Investigation on cellular level also showed that pharmacological diuretic, amiloride, interacts inside the kidney with several transport processes. As long as micromolar concentrations inhibit Na-channels in distal tubules and colecting ducts, milimolar concentrations inhibit Na/H antiporter and potassium conductance in basolateral membrane of proximal tubules. This means that, depend on amiloride concentration, its cathions non-selectivity is proved. Interferences between antirheumatics and tubular transport processes are still not completely cleared. It has shown that diclofenac beside the inhibiton of prostaglandins and stimulation of vasopressin interfere with renal blood flow as well as with tubular ion transport by which increase of dissolved substances and consequently diminished diuresis are achived. With additional furosemide application it is possible to prevent diminished diuresis caused by diclofenac. Optimal doses are stated with kinetics of each medicine folowing it separately and together. Some diuretics of plant origin has also been defined more accurate with biological experiments on intacted rats. Clinical investigations in adult patients or children with different acute or chronical kind of kidney's diseases or intoxication include pharmacologic treatment or the choose of most fauvorable treatments such as hemodialysis, peritoneal dialysis plasmapheresis, biofiltration and possibility of success donor or cadavere kidney transplantation with postoperative immunosuppression.

Keywords: electrophysiological methods,intracellular microelectrodes, hormonal regulation, drugs and inhibitors, hypertension, dialysis and transplantation

Research goals: The main topics of this research in experimental nephrologyinclude explanations of mechanisms of transport processes in themamal kidney tubules as well as hormonal regulation and influenceof numerous different factors on salt and water excess excretionfrom the body. Further topics were explanations of therapeuticaleffects and molecular mechanisms activity of some diuretics(amiloride, furosemide, plant diuretics) and antirheumatics (diclofenac). Beside topics above, evidence of possible interactions of mentioned drugs inside the kidney are also included. Elevated salt (sodium chloride) content and damage of kidney in the body leads to hypertension. The kidney which may prevent this by increasing salt excretion, regulate renal salt excretion by a cascade of blood circulating hormones: renin, angiotensin II and aldosterone. Opposite to that, when the salt deficite is present, aldosterone concentration increases. That stimulates NaCl absorption in some segments of renal tubules and thereby diminishes salt excretion in urine. Recent studies reported that angiotensin II also stimulates NaCl absorption directly inside the kidney. Therefore, it was investigated, in which tubular segments aldosterone and angiotensin II act and how they act there. Also many drugs not only act inside the kidney, but are excreted through the kidney and therefore can interfere with processes which take place there. The effects of antirheumatic drugs such as diclofenac inside the kidney are still not completely clarified. Therefore, the effects of diclofenac (diminished diuresis response) were studied on the rats and continuosly electrolyte analysis were performed. Different concentrations of furosemide were investigated in the presence or absence of diclofenac and their interferences. These preclinical informations are important and useful for a basis for further clinical investigations and possibility of better and more succesful dialysis treatment or after transplantation with less side-effects.

COOPERATION - PROJECTS


  1. Name of project: Med 1, KIDTRAN Regulation of salt excretion by the kidney
    Name of institution: Zentrum der Physiologie, J.W. Goethe Universitat
    City: 6000 - Frankfurt, Germany

COOPERATION - INSTITUTIONS


  1. Name of institution: Centar za dijalizu,Klinike za urologiju,KBC,Rebro
    Type of institution: International organization
    City: 10000 - Zagreb, Croatia
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