1. To investigate whether S-nitrosothiols, in addition to NO, mediate bradykinin-induced vasorelaxation, porcine coronary microarteries (PCMAs) were mounted in myographs. 2. Following preconstriction, concentration-response curves (CRCs) were constructed to bradykinin, the NO donors S-nitroso-N-penicillamine (SNAP) and diethylamine NONOate (DEA-NONOate) and the S-nitrosothiols L-S-nitrosocysteine (L-SNC) and D-SNC. All agonists relaxed PCMAs. L-SNC was approximately 5-fold more potent than D-SNC. 3. The guanylyl cyclase inhibitor ODQ and the NO scavenger hydroxocobalamin induced a larger shift of the bradykinin CRC than the NO synthase inhibitor L-NAME, although all three inhibitors equally suppressed bradykinin-induced cGMP responses. 4. Complete blockade of bradykinin-induced relaxation was obtained with L-NAME in the presence of the large- and intermediate-conductance Ca(2+)-activated K(+)-channel (BK(Ca), IK(Ca)) blocker charybdotoxin and the small-conductance Ca(2+)-activated K(+)-channel (SK(Ca)) channel blocker apamin, but not in the presence of L-NAME, apamin and the BK(Ca) channel blocker iberiotoxin. 5. Inhibitors of cytochrome P450 epoxygenase, cyclooxygenase, voltage-dependent K(+) channels and ATP-sensitive K(+) channels did not affect bradykinin-induced relaxation. 6. SNAP-, DEA-NONOate- and D-SNC-induced relaxations were mediated entirely by the NO-guanylyl cyclase pathway. L-SNC-induced relaxations were partially blocked by charybdotoxin+apamin, but not by iberiotoxin+apamin, and this blockade was abolished following endothelium removal. ODQ, but not hydroxocobalamin, prevented L-SNC-induced increases in cGMP, and both drugs shifted the L-SNC CRC 5-10-fold to the right. 7. L-SNC hyperpolarized intact and endothelium-denuded coronary arteries. 8. Our results support the concept that bradykinin-induced relaxation is mediated via de novo synthesized NO and a non-NO, endothelium-derived hyperpolarizing factor (EDHF). S-nitrosothiols, via stereoselective activation of endothelial IK(Ca) and SK(Ca) channels, and through direct effects on smooth muscle cells, may function as an EDHF in porcine coronary microarteries.

Animals, Biological Factors/*physiology, Bradykinin/*pharmacology, Comparative Study, Coronary Vessels/*drug effects/physiology, Dose-Response Relationship, Drug, Endothelium, Vascular/*drug effects/physiology, In Vitro, Microcirculation/drug effects/physiology, Research Support, Non-U.S. Gov't, S-Nitrosothiols/*pharmacology, Swine, Vasodilation/*drug effects/physiology
dx.doi.org/10.1038/sj.bjp.0705747, hdl.handle.net/1765/13351
British Journal of Pharmacology
Erasmus MC: University Medical Center Rotterdam

Batenburg, W.W, Popp, R, Fleming, I, de Vries, R.R.P, Garrelds, I.M, Saxena, P.R, & Danser, A.H.J. (2004). Bradykinin-induced relaxation of coronary microarteries: S-nitrosothiols as EDHF?. British Journal of Pharmacology, 142(1), 125–135. doi:10.1038/sj.bjp.0705747