The dietary flavonoid quercetin activates BKCa currents in coronary arteries via production of H2O2. Role in vasodilatation.
OBJECTIVE
Large conductance Ca(2+)-activated K(+) channels (BKCa) regulate coronary artery tone in vivo, play a key role in blood pressure regulation, and have been suggested as novel potential drug targets in hypertension. Quercetin exerts systemic and coronary vasodilator effects in vitro and reduces blood pressure in several rat models of hypertension, and its consumption is associated with a lower mortality rate from coronary heart disease in epidemiological studies. We hypothesized that quercetin might activate BKCa channel in isolated myocytes from rat coronary arteries and that this mechanism might be involved in its coronary artery relaxant effects.


METHODS
Membrane currents were measured using the whole-cell configuration of the patch-clamp technique. Contractile tension was recorded in rat coronary artery rings mounted in a myograph.


RESULTS
Quercetin (>0.1 muM) increased the outward currents in the whole range of test potentials, hyperpolarized cell membranes, and increased the frequency of spontaneous transient outward currents (STOCs) carried by BKCa channels. These effects were abolished by the selective BKCa blocker iberiotoxin and by catalase. Quercetin increased dichlorofluorescein fluorescence in coronary arteries in a polyethylenglycol-catalase-sensitive manner, indicating that it increased cytosolic H(2)O(2). The membrane-permeable analogue of H(2)O(2)t-butylhydroperoxide mimicked the effects of quercetin on outward currents. The vasodilator effect of quercetin in isolated rat coronary arteries was partially inhibited by iberiotoxin.


CONCLUSIONS
Quercetin increased BKCa currents via production of intracellular H(2)O(2). This effect is involved, at least partly, in the coronary vasodilator effects of quercetin.
Cogolludo
Angel
A
Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Frazziano
Giovanna
G
Briones
Ana M
AM
Cobeño
Laura
L
Moreno
Laura
L
Lodi
Federica
F
Salaices
Mercedes
M
Tamargo
Juan
J
Perez-Vizcaino
Francisco
F
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002374:Catalase / Q000494:pharmacology; D003331:Coronary Vessels; D005638:Fruit; D006861:Hydrogen Peroxide / Q000032:analysis / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*; D014675:Vegetables
D015415:Biomarkers; D010455:Peptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014665:Vasodilator Agents; C064719:iberiotoxin; D011794:Quercetin; D006861:Hydrogen Peroxide; D015761:4-Aminopyridine; D002374:Catalase; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester