Titel

Untersuchungen �ber das Renin-Angiotensin-Aldosteron System und seine Beeinflussung durch einen Kaliumkanal�ffner bei der Ratte

Titel(englisch)

Name:

Stumm, Karin

Ort und Jahr der Promotion

Gie�en, Univ., Diss., 1994

Abstract

Investigations into the effect of substances on the renin-angiotensin system in small laboratory animals, such as the rat, call for the modification of existing and the development of new methods for the analysis of meaningful parameters. In the first part of the present study, the development or modification of methods, and in the second part the results of the animal experiment with bimakalim are presented. It was the main aim of all these investigations to reduce the amount of sample material while at the same time performmg extensive tests in each animal. By this approach repeated blood sampling can be avoided and meaningful information be gained with a smaller number of experimental animals. The present report provides an investigative profile for detecting effects on the renin-angiotensinaldosterone system in small laboratory animals. The invesbgabon includet rat serum and plasma, urine collected over 24 hours and homogenate of rat adrenals. In the diskussion of the methods, the advantages and disadvantages of other published methods are dealt with. Radioimmunologic methods of analysis for the determinabon of corticosterone, aldosterone and of thc plasma renin activity were adapted to the demands relating to the use of material obtained from rats. In dolng so, commerclally available reagent sets, so- called kits, were used. Corticosterone and tetrahydroaldosterone were simultaneously analyzed by a HPLC method. Cholesterol and triglycerides in the adrenal homogenate were analyzed after extracbon according to modified enzymatlc methods that are commonly used for analytics in serum. The protein content in the adrenal tissue was determined using a dye dilubon method with Poneeau S. The radioimmunologic and photometric methods were subjected to am abbreviated validabon. It had been the objective of the animal expenment describedin the present report to study the effect of the potassium channel activator bimakalim, a potassium channel acbvator developed by E. Merck, Darmstadt. on the renin-aldosterone system and the adrenalfunctionof male Wistar rats after daily oral administraion of 3 mg / kg over a period of 6 months. At vanous sections dming the study, the serum concentrabons of aldosterone and corticosterone, and the plasma remin activity were determined 2 and 24 hours after treatment. The aldosterone, corticosterone, cholesterol, tnglycende and protein concentrations in the adrenal homogenate were determined In the unne that was collected several bmes during the study the following parameters werc examinded: amount, general unne status and specific gravity, aldosterone, tetrahydroaldosterone, corticosterone, sodmm, chlonde, calcium amd potassium excrebon. A marked increase in the plasma renin acbvity was regularly observed 2 hours after reatment After 24 hours, this effect was no longer demonstrable. The serum concentrabon of aldosterone and corbcosterone were increased 2 hours after treatment. 24 hours after treatment, this increase was eighter less pronounced or had disappeared. Two hours after administration bhe corbcosterone content in the adrenal bssue was obseved to have decreased. This was no longer true at the 24 hour readings. In the course of the study, the cholesterol content showed a tendency to be increased, but not in a stabsbcally significant way. The protein and tnglycende values remauned unaffected by treatment. The adrenal weights of the treated animals mcreased in the course of the study. The administration of bimakalim led to an increased urine and a decreased specific weight of the urine. The exceretion of aldosterone and corticosterone in the urine was increased over the entire period. Also the excretion of tetrahydroaldosterone, a aldosterone metabolite, increased in the course of the study. The potassium exeration in the urine remained unaffected, by treatment. Starting in the fourth week of the study, an increased exeration of sodium and chloride be demonstraset. An inhibitory effect on the calcium exeration was observed. The urine status renained inconspicuous during the study. The results obtauned indicate, as a whole, taht the renin-angiotensin-aldosterone system is generally stimmulated by the adiministration of 3 mg/kg bimakalim.