Endothelin‐1 shifts the mediator of bradykinin‐induced relaxation from NO to H₂O₂ in resistance arteries from patients with cardiovascular disease

Abstract

BACKGROUND AND PURPOSEWe tested the hypothesis that in resistance arteries from cardiovascular disease (CVD) patients, effects of an endotheliumdependent vasodilator depend on the contractile stimulus. EXPERIMENTAL APPROACHArteries 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 RESULTSRelaxing 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 IMPLICATIONSIn resistance arteries from patients with CVD, exogenous ET-1 shifts the mediator of relaxing responses to the endotheliumdependent 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.

Relaxing Responses to Hydrogen Peroxide and Nitric Oxide in Human Pericardial Resistance Arteries Stimulated with Endothelin‐1

“…and table ). Figure A confirms earlier findings in pericardial resistance arteries from a different group of patients .…”

“…Albeit small, the significantly smaller efficacy of H 2 O 2 during contraction stimulated by U46619 compared to ET‐1 persisted in the presence of inhibitors of COX, NOS, K Ca 2.3 and K Ca 3.1 (table ). Figure B confirms earlier findings in pericardial resistance arteries from a different group of patients .…”

“…Cytochrome P450 epoxygenases and myo‐endothelial gap junctions can also contribute to EDR but these were not inhibited in this investigation. In a previous study , indomethacin, L‐NAME with or without catalase already reduced the relaxing effects of bradykinin by more than 90%.…”

“…Still, Gutterman et al . and our group reported substantial relaxing responses to stimuli of endothelium‐dependent relaxations (shear stress and bradykinin) during contraction induced by exogenous endothelin‐1 (ET‐1) in coronary, pericardial and adipose tissue resistance arteries from patients with ischaemic heart disease . We recently demonstrated that in pericardial resistance arteries from patients with CVD, relaxing responses to the endothelium‐dependent vasodilator bradykinin are mediated by NO during contraction induced by high K + or thromboxane TP receptor agonist but by H 2 O 2 during contraction induced by ET‐1 .…”

Angeli's Salt, a nitroxyl anion donor, reverses endothelin-1 mediated vascular dysfunction in murine aorta

“…In this study, we used an ET-1-induced model of endothelial dysfunction, as studies have demonstrated that ET-1 induces hypertension, with endothelial dysfunction and increased ROS generation (Savoia & Schiffrin, 2006; 2007; Schiffrin, 2007; Wynne et al , 2009; Pollock & Pollock, 2011; Rodrigo et al , 2011; Idris-Khodja et al , 2016; Leurgans et al , 2016). Our data demonstrate that aorta incubated overnight with ET-1 induces increased Phe-mediated contraction and a decrease in ACh-mediated relaxation.…”