Endothelium-derived hyperpolarizing factor in coronary microcirculation: responses to arachidonic acid.
In coronary resistance vessels, endothelium-derived hyperpolarizing factor (EDHF) plays an important role in endothelium-dependent vasodilation. EDHF has been proposed to be formed through cytochrome P-450 monooxygenase metabolism of arachidonic acid (AA). Our hypothesis was that AA-induced coronary microvascular dilation is mediated in part through a cytochrome P-450 pathway. The canine coronary microcirculation was studied in vivo (beating heart preparation) and in vitro (isolated microvessels). Nitric oxide synthase (NOS) (N(omega)-nitro-L-arginine, 100 microM) and cyclooxygenase (indomethacin, 10 microM) or cytochrome P-450 (clotrimazole, 2 microM) inhibition did not alter AA-induced dilation. However, when a Ca(2+)-activated K(+) channel channel or cytochrome P-450 antagonist was used in combination with NOS and cyclooxygenase inhibitors, AA-induced dilation was attenuated. We also show a negative feedback by NO on NOS-cyclooxygenase-resistant AA-induced dilation. We conclude that AA-induced dilation is attenuated by cytochrome P-450 inhibitors, but only when combined with inhibitors of cyclooxygenase and NOS. Therefore, redundant pathways appear to mediate the AA response in the canine coronary microcirculation.
Oltman
C L
CL
Department of Veterans Affairs, Iowa City, IA 52246, USA. christine-oltman@uiowa.edu
Kane
N L
NL
Fudge
J L
JL
Weintraub
N L
NL
Dellsperger
K C
KC
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001685:Biological Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D001685:Biological Factors; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D016718:Arachidonic Acid