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

In human pericardial resistance arteries, effects of the endothelium-dependent vasodilator bradykinin are mediated by NO during contraction induced by K ⁺ or the TxA ₂ analogue U46619 and by H ₂O ₂ during contraction by endothelin-1 (ET-1), respectively. We tested the hypotheses that ET-1 reduces relaxing effects of NO and increases those of H ₂O ₂ in resistance artery smooth muscle of patients with cardiovascular disease. Arterial segments, dissected from the parietal pericardium of 39 cardiothoracic surgery patients, were studied by myography during amplitude-matched contractions induced by K ⁺, the TXA ₂ analogue U46619 or ET-1. Effects of the NO donor Na-nitroprusside (SNP) and of exogenous H ₂O ₂ were recorded in the absence and presence of inhibitors of cyclooxygenases, NO synthases and small and intermediate conductance calcium-activated K ⁺ channels. During contractions induced by either of the three stimuli, the potency of SNP did not differ and was not modified by the inhibitors. In vessels contracted with ET-1, the potency of H ₂O ₂ was on average and in terms of interindividual variability considerably larger than in K ⁺-contracted vessels. Both differences were not statistically significant in the presence of inhibitors of mechanisms of endothelium-dependent vasodilatation. In resistance arteries from patients with cardiovascular disease, ET-1 does not selectively modify smooth muscle relaxing responses to NO or H ₂O ₂. Furthermore, the candidate endothelium-derived relaxing factor H ₂O ₂ also acts as an endothelium-dependent vasodilator.