%0 Generic
%A Zubakova, Radka
%D 2007
%F heidok:7382
%K Kallikrein-Kinin-System , Renin-Angiotensin-System , Adenosin , Adenosinrezeptor , StickstoffoxidsynthaseKallikrein-Kinin System , Renin-Angiotensine-Aldosterone System , Adenosine , Adenosine receptors , NO Synthase
%R 10.11588/heidok.00007382
%T Analysis of the mechanisms influencing the expression of blood pressure regulating systems
%U https://archiv.ub.uni-heidelberg.de/volltextserver/7382/
%X Abstract Zubakova Radka, pharmacist               oral examination on 15th May 2007  ANALYSIS OF THE MECHANISMS INFLUENCING THE EXPRESSION OF BLOOD PRESSURE REGULATING SYSTEMS Referees: Prof. Dr. Ulrich Hilgenfeldt, Prof. Dr. Gert Fricker Several hormonal and autocrine systems are involved in the physiology and pathophysiology of blood pressure regulation and salt-water homeostasis including the renin-angiotensin-aldosterone system, the kallikrein-kinin system, nitric oxide and the adenosine system. Within the scope of this project, the influence of high salt diet and aldosterone on the regulation of NO, NO synthase, adenosine-, and bradykinin-receptors should be examined in kininogen-deficient BNK rats and in control BN rats. For 10 days BNK and BN rats were given a standard or high salt diet in presence or absence of the aldosterone antagonist, spironolactone.  Gene expression analysis was performed in tissue of kidney, atria, and ventricles using real-time RT-PCR. The activity of NO synthase was elicited by measuring NO metabolites in urine and plasma. In addition in a HEC cell line we measured the effects of different kinins on the bradykinin B1- and B2-receptor of rat, mouse and human via analysing fluorometrically the intracellular calcium influx.  We found lower NOx production in plasma and urine of BNK rats in almost all experimental groups. Moreover, we could determine that in the kidney of BNK but not of BN rats high salt diet down-regulated the expression of nNOS and iNOS. The decreased NO level might be one of the factors responsible for the salt-sensitive hypertension in kininogen-deficient BNK rats.  Furthermore, expression analysis of the kidney showed, that aldosterone plays an important role in the regulation of A1AR, A3AR and of nNOS. An increased salt intake seems to have no significant effect on renal adenosine receptors, NOS and B2R. Nevertheless, we found that high salt intake significantly up-regulated B1R in BN, but not in BNK rats. The enhanced B1R expression after high salt diet in the kidney of BN rats might have a protective effect. Down-regulation of A3AR and nNOS in ventricles of BNK rats after increased salt intake in BNK rats is probably one of the reasons for the increased cardiac sensitivity towards ischemia. We conclude that the lower NO levels and altered gene expression in kininogen- deficient BNK rats might contribute to the development of hypertension and salt-sensitivity. Furthermore, we could demonstrate for the first time that in the kidney aldosterone plays an important role in the regulation of A1AR, A3AR and nNOS.  In addition, we showed that the efficacy and potency of BK, KAL and KLP on the B2R is similar in rat, mouse and human. Moreover, we demonstrated that des-Arg9-BK, des-Arg10-KAL and des-Arg10-KLP display similar effects on the B1R of rat, mouse and human.