Resistin impairs endothelium-dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation.
Elevated plasma levels of fat-derived signaling molecules are associated with obesity, vascular endothelial dysfunction, and coronary heart disease; however, little is known about their direct coronary vascular effects. Accordingly, we examined mechanisms by which one adipokine, resistin, affects coronary vascular tone and endothelial function. Studies were conducted in anesthetized dogs and isolated coronary artery rings. Resistin did not change coronary blood flow, mean arterial pressure, or heart rate. Resistin had no effect on acetylcholine-induced relaxation of artery rings; however, resistin did impair bradykinin-induced relaxation. Selective impairment was also observed in vivo, as resistin attenuated vasodilation to bradykinin but not to acetylcholine. Resistin had no effect on dihydroethidium fluorescence, an indicator of superoxide (O(2)(-)) production, and the inhibitory effect of resistin on bradykinin-induced relaxation persisted in the presence of Tempol, a superoxide dismutase mimetic. To determine whether resistin impaired production of and/or responses to nitric oxide (NO) or prostaglandins (e.g., prostacyclin; PGI(2)), we performed experiments with N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin. The effect of resistin to attenuate bradykinin-induced vasodilation persisted in the presence of L-NAME or indomethacin, suggesting resistin may act at a cell signaling point upstream of NO or PGI(2) production. Resistin-induced endothelial dysfunction is not generalized, and it is not consistent with effects mediated by O(2)(-) or interference with NO or PGI(2) signaling. The site of the resistin-induced impairment is unknown but may be at the bradykinin receptor or a closely associated signal transduction machinery proximal to NO synthase or cyclooxygenase.
Dick
Gregory M
GM
Dept. of Physiology, Louisiana State University Health Sciences Center, New Orleans, USA.
Katz
Paige S
PS
Farias
Martin
M
Morris
Michael
M
James
Jeremy
J
Knudson
Jarrod D
JD
Tune
Johnathan D
JD
D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001920:Bradykinin / Q000502:physiology*; D003326:Coronary Circulation / Q000502:physiology*; D003331:Coronary Vessels / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D052243:Resistin / Q000502:physiology*; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D000975:Antioxidants; D003497:Cyclic N-Oxides; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D052243:Resistin; D013113:Spin Labels; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine; D001920:Bradykinin; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin