Objective. Coronary microvascular dysfunction (CMD) can complicate successful percutaneous coronary intervention (PCI). The potent endogenous vasoconstrictor peptide Endothelin-1 (ET-1) may be an important mediator. To investigate the mechanism, we sought to define the peri-procedural trans-myocardial gradient (TMG-coronary sinus minus aortic root levels) of ET-1 and its precursor peptide – Big ET-1. We then assessed correlation with pressure-wire indices of CMD: coronary flow reserve (CFR) and index of microvascular resistance (IMR). Methods. Paired blood samples from the guide catheter and coronary sinus were collected before and after pressure-wire-guided PCI from patients with stable angina. Plasma was analysed using a specific enzyme-linked immunosorbent assay for quantification of ET-1 peptides and correlated with pressure-wire data. Non normally distributed continuous variables are presented as median [IQR]. Results. ET-1 and Big ET-1 increased post-PCI in the aorta (ET-1: 0.98 [0.76–1.26] pg/ml to 1.20 [1.03–1.67] pg/ml, P<0.001 and Big ET-1: 2.74 [1.78–2.50] pg/ml to 3.36 [2.33–3.97] pg/ml, P<0.001) and coronary sinus (ET-1: 1.00 [0.81–1.28] pg/ml to 1.09 [0.91–1.30] pg/ml, P=0.03 and Big ET-1: 2.89 [1.95–3.83] pg/ml to 3.56 [2.66–4.83] pg/ml, P=0.01). TMG of ET-1 shifted negatively compared with baseline following PCI reflecting significantly increased extraction (0.03 [−0.12–0.17] pg/ml pre-PCI versus −0.16 [−0.36–0.07] pg/ml post-PCI, P=0.01). Increased ET-1 trans-myocardial extraction correlated with higher IMR (Pearson’s r = 0.293, P=0.02) and increased hyperemic transit time (Pearson’s r = 0.333, P<0.01). In subgroup analysis, mean ET-1 trans-myocardial extraction was higher amongst patients with high IMR compared with low IMR (0.73 pg/ml, SD:0.78 versus 0.17 pg/ml, SD:0.42, P=0.02). There was additionally a numerical trend towards increased ET-1 trans-myocardial extraction in subgroups of patients with low CFR and in patients with Type 4a Myocardial Infarction, albeit not reaching statistical significance. Conclusions. Circulating ET-1 increases post-PCI and upregulated ET-1 trans-myocardial extraction contributes to increased microcirculatory resistance.