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(Hypertension. 1997;30:1598-1605.)
© 1997 American Heart Association, Inc.

Articles

Endothelium-Derived Hyperpolarizing Factor, But Not Nitric Oxide, Is Reversibly Inhibited by Brefeldin A

Johann Bauersachs; Ingrid Fleming; Dimitri Scholz; Rüdiger Popp; ; Rudi Busse

From the Institut für Kardiovaskuläre Physiologie, Zentrum der Physiologie, Klinikum der J.W. Goethe-Universität (J.B., I.F., R.P., R.B.) and Max-Planck-Institut für Physiologische und Klinische Forschung, Abt Experimentelle Kardiologie (D.S.), Germany.

Correspondence to Dr Johann Bauersachs, Institut für Kardiovaskuläre Physiologie, Zentrum der Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. E-mail r.busse{at}em.uni-frankfurt.de

Abstract The subcellular localization of the enzymes synthesizing endothelium-derived vasodilator autacoids has been proposed to play a role in determining the ability of endothelial cells to enhance autacoid production in response to stimulation. We therefore investigated the effects of brefeldin A–induced disruption of the Golgi apparatus and Golgi-plasma membrane trafficking on the production of nitric oxide (NO), prostacyclin, and the endothelium-derived hyperpolarizing factor (EDHF) by native and cultured endothelial cells. In porcine coronary artery segments, brefeldin A (35 µmol/L, 90 minutes) did not affect relaxations to sodium nitroprusside or the K⁺ channel opener cromakalim but elicited a rightward shift in the concentration-response curve to bradykinin without altering the maximum vasodilator response (R_max). Brefeldin A failed to attenuate the bradykinin-induced, NO-mediated relaxation under depolarizing conditions but inhibited the bradykinin response under conditions of combined cyclooxygenase/NO synthase blockade, suggesting that this agent selectively interferes with the production of EDHF. Indeed, incubation of porcine coronary arteries with brefeldin A, which did not affect the bradykinin-induced accumulation of either cyclic GMP or 6-keto-prostaglandin F₁, markedly and reversibly attenuated the EDHF-mediated hyperpolarization of detector smooth muscle cells in a patch-clamp bioassay system. The microtubule destabilizer nocodazole also affected both the EC₅₀ and R_max to bradykinin in porcine coronary arteries. Since EDHF is thought to be a cytochrome P450–derived metabolite of arachidonic acid and both brefeldin A and nocodazole are known to interfere with the targeting of cytochrome P450 from the Golgi apparatus to the plasma membrane, it is conceivable that brefeldin A inhibits EDHF formation by preventing the targeting of the EDHF-synthesizing enzymes to the plasma membrane.

Key Words: endothelium-derived hyperpolarizing factor • nitric oxide • cytochrome P450 • brefeldin A • microtubule • prostacyclin • endothelial cells

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