title: Role of endothelium-derived hyperpolarizing factor in ACE inhibitor-induced renal vasodilation in vivo.
abstract: Although the angiotensin-converting enzyme (ACE) inhibitor-induced bradykinin enhances nitric oxide (NO) release, bradykinin may also stimulate the production of an additional vasodilator, endothelium-derived hyperpolarizing factor (EDHF). This study examined the role of EDHF in mediating the NO-independent action of ACE inhibitors in canine renal microcirculation in vivo. We used intravital CCD camera videomicroscopy that allowed direct visualization of renal microcirculation in superficial and juxtamedullary nephrons in an in vivo, in situ, and relatively intact setting. In the presence of E4177 (an angiotensin receptor blocker), cilazaprilat (30 microg/kg) had no effect on diameter of superficial afferent arterioles (Aff), but it increased renal contents of bradykinin and nitrate plus nitrite, and it elicited dilation of juxtamedullary Aff (from 24.0+/-0.2 to 28.2+/-0.8 microm), juxtamedullary efferent arterioles (Eff) (from 24.2+/-0.2 to 28.0+/-0.8 microm), and superficial Eff (from 18.2+/-0.2 to 19.7+/-0.2 microm). These changes in diameters were prevented by N(alpha)-adamantaneacetyl-d-Arg-[Hyp(3),Thi(5,8),D-Phe(7)]bradykinin, a bradykinin receptor antagonist. The pretreatment with nitro-l-arginine methylester (l-NAME) plus E4177 eliminated the dilator response of juxtamedullary/superficial Eff and the increase in renal nitrate plus nitrite levels induced by cilazaprilat. In contrast, in the presence of E4177+l-NAME, cilazaprilat still caused 8%+/-3% dilation of juxtamedullary Aff, which was completely eliminated by proadifen, a cytochrome-P450 and K(Ca) channel blocker. Collectively, the ACE inhibitor exerts multiple vasodilator mechanisms, including the inhibition of angiotensin II formation; blockade of angiotensin II activity appears to be a dominant mechanism in superficial Aff, whereas the bradykinin-induced NO acts on superficial Eff and juxtamedullary Aff/Eff. Furthermore, a putative EDHF is an additional mechanism for the ACE inhibitor-induced vasodilation of juxtamedullary Aff in vivo.
authors.affiliation: Department of Internal Medicine School of Medicine, Keio University, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. khayashi@sc.itc.keio.ac.jp
authors.forename: Hiroto
authors.initials: H
authors.lastname: Matsuda
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.forename: Eiji
authors.initials: E
authors.lastname: Kubota
authors.forename: Masanori
authors.initials: M
authors.lastname: Honda
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Tokuyama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takamatsu
authors.forename: Satoru
authors.initials: S
authors.lastname: Tatematsu
authors.forename: Takao
authors.initials: T
authors.lastname: Saruta
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D001920:Bradykinin / Q000378:metabolism; D017315:Cilazapril / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004285:Dogs; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D017315:Cilazapril; D009569:Nitric Oxide; D001920:Bradykinin; C045980:cilazaprilat