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Endothelin‐1 shifts the mediator of bradykinin‐induced relaxation from NO to H 2 O 2 in resistance arteries from patients with cardiovascular disease
Author(s) -
Leurgans Thomas M,
Bloksgaard Maria,
Brewer Jonathan R,
Bagatolli Luis A,
Fredgart Maise H,
Rosenstand Kristoffer,
Hansen Maria L,
Rasmussen Lars M,
Irmukhamedov Akhmadjon,
De Mey Jo GR
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13467
Subject(s) - bradykinin , myograph , vasodilation , chemistry , endocrinology , medicine , endothelin receptor , endothelin 1 , electrical impedance myography , phenylephrine , endothelium , xanthine oxidase , biochemistry , enzyme , blood pressure , receptor
Background and Purpose We tested the hypothesis that in resistance arteries from cardiovascular disease (CVD) patients, effects of an endothelium‐dependent vasodilator depend on the contractile stimulus. Experimental Approach Arteries dissected from parietal pericardium of cardiothoracic surgery patients were studied by myography and imaging techniques. Segments were sub‐maximally contracted by K + , the TxA 2 analogue U46619 or endothelin‐1 (ET‐1). Key Results Relaxing effects of Na‐nitroprusside were comparable, but those of bradykinin (BK) were bigger in the presence of ET‐1 compared with K + or U46619. BK‐induced relaxation was (i) abolished by L‐NAME in K + ‐contracted arteries, (ii) partly inhibited by L‐NAME in the presence of U46619 and (iii) not altered by indomethacin, L‐NAME plus inhibitors of small and intermediate conductance calcium‐activated K + channels, but attenuated by catalase, in ET‐1‐contracted arteries. This catalase‐sensitive relaxation was unaffected by inhibitors of NADPH oxidases or allopurinol. Exogenous H 2 O 2 caused a larger relaxation of ET‐1‐induced contractions than those evoked by K + or U46619 in the presence of inhibitors of other endothelium‐derived relaxing factors. Catalase‐sensitive staining of cellular ROS with CellROX Deep Red was significantly increased in the presence of both 1 μM BK and 2 nM ET‐1 but not either peptide alone. Conclusions and Implications In resistance arteries from patients with CVD, exogenous ET‐1 shifts the mediator of relaxing responses to the endothelium‐dependent vasodilator BK from NO to H 2 O 2 and neither NADPH oxidases, xanthine oxidase nor NOS appear to be involved in this effect. This might have consequences for endothelial dysfunction in conditions where intra‐arterial levels of ET‐1 are enhanced.