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Interaction between bradykinin and urodilatin - a possible mechanism of clinical relevance
BMC Pharmacologyvolume 11, Article number: P21 (2011)
Bradykinin (BK) plays a significant role in pathophysiology of different diseases from angioedema to brain stroke and heart attack by inducing vasodilatation and increasing capillary permeability. We investigate the potential effects of natriuretic peptides on BK signaling by measuring membrane potential (Vm) of HEK293 cells using the whole cell patch clamp technique. HEK293-cells are an excellent model since they display the natriuretic peptide receptor type A as well as both BK receptors (BR1 and BR2).
Starting Vm was -53.5 ± 1.1 mV, n = 184. To detect viability of the cells hyperkalemic conditions were used (changing K+ from 3.6 mM to 18.6 mM) which depolarized HEK293 cells by 9.7 ± 0.4 mV, n = 182. BK (100 nM) depolarized HEK293 cells by ΔVm = 3.0 ± 0.2 mV, n=57 (figure 1). Our preliminary results show that the BK induced depolarization by activating bradykinin receptor type 2 (BR2) and further down the signaling pathway activation of Ca2+-dependent Cl- channels (Figure 1).
Natriuretic peptides display different effects on the BK-induced depolarization due to activation of Ca2+-dependent Cl--channels. While ANP, urodilatin, BNP (all acting though guanylate cyclase A) and 8-Br cGMP inhibited the BK-induced depolarization, CNP (acting through guanylate cyclase B) failed to do so (Figure 1). Effects of urodilatin on BK-induced deoplarization could be reversed by inhibiting protein kinase G (using the specific inhibitor KT5823) suggesting an inhibitory role of natriuretic peptides via GC-A, cGMP and PKG in BK signaling.
From our results we could speculate that natriuretic peptides might display beneficial effects in different pathological conditions caused by BK.
These materials are based on work financed by the National Foundation for Science, Higher Education and Technological Development of the Republic of Croatia and the CardioPep Pharma GmbH, Germany.