title: Local angiotensin II generation in the rat heart: role of renin uptake.
abstract: To elucidate the local effects of renin in the coronary circulation, we examined local angiotensin (Ang) I and II formation, as well as coronary vasoconstriction in response to renin administration, and compared the effects with exogenous infused Ang I. We perfused isolated hearts from rats overexpressing the human angiotensinogen gene in a Langendorff preparation and measured the hemodynamic effects and the released products. We also investigated cardiac Ang I conversion, including the contribution of non-angiotensin-converting enzyme-dependent Ang II-generating pathways. Finally, we studied Ang I conversion in vitro in heart homogenates. Renin and Ang I infusion both generated Ang II. Ang II release and vasoconstriction continued after renin infusion was stopped, even though renin disappeared immediately from the perfusate. In contrast, after Ang I infusion, Ang II release and coronary flow returned to basal levels. Ang I conversion (Ang II/Ang I ratio) was higher after renin infusion (0.109+/-0.027 versus 0.026+/-0.003, 15 minutes, P<.02) compared with infused Ang I. Remikiren added to the renin infusion abolished Ang I and II; captopril suppressed only Ang II, whereas an AT1 receptor blocker did not affect Ang I and II formation. All the drugs prevented renin-induced coronary flow changes. Total cardiac Ang II-forming activity was only partially inhibited by cilazaprilat (4.1+/-0.1 fmol x min(-1) x mg[-1]) and on a larger extent by chymostatin (2.6+/-0.3 fmol x min(-1) x mg[-1]) compared with control values (5.6+/-0.4 fmol x min(-1) x mg[-1]). We conclude that renin can be taken up by cardiac or coronary vascular tissue and induces long-lasting local Ang II generation and vasoconstriction. Locally formed Ang I was converted more effectively than infused Ang I. Furthermore, the comparison of in vivo and in vitro Ang I conversion suggests that in vitro assays may underestimate the functional contribution of angiotensin-converting enzyme to intracardiac Ang II formation.
authors.affiliation: Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine, Virchow Klinikum, Humboldt University of Berlin, Germany.
authors.forename: D N
authors.initials: DN
authors.lastname: Müller
authors.forename: W
authors.initials: W
authors.lastname: Fischli
authors.forename: J P
authors.initials: JP
authors.lastname: Clozel
authors.forename: K F
authors.initials: KF
authors.lastname: Hilgers
authors.forename: J
authors.initials: J
authors.lastname: Bohlender
authors.forename: J
authors.initials: J
authors.lastname: Ménard
authors.forename: A
authors.initials: A
authors.lastname: Busjahn
authors.forename: D
authors.initials: D
authors.lastname: Ganten
authors.forename: F C
authors.initials: FC
authors.lastname: Luft
mesh_terms: D000803:Angiotensin I / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D000804:Angiotensin II / Q000187:drug effects / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D053818:Chymases; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000008:administration & dosage / Q000493:pharmacokinetics; D012697:Serine Endopeptidases / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D000092502:Renin Inhibitors
chemical_list: D000803:Angiotensin I; D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002216:Captopril; D053818:Chymases; D007093:Imidazoles; D019808:Losartan; D011480:Protease Inhibitors; D012083:Renin; D012697:Serine Endopeptidases; D013777:Tetrazoles; D000092502:Renin Inhibitors; C066026:losartan carboxylic acid; C065581:remikiren