Local Angiotensin II Generation in the Rat Heart

Role of Renin Uptake

From the Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine (MDC), Virchow Klinikum, Humboldt University of Berlin (Germany) (D.N.M., J.B., A.B., F.C.L.); the University of Erlangen-Nürnberg (Germany) (K.F.H.); INSERM U367, Paris, France (J.M.); and Hoffmann-LaRoche, Basel, Switzerland (W.F., J.-P.C.).

Correspondence to Friedrich C. Luft, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany. E-mail fcluft{at}mdc-berlin.de

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 · min^-1 · mg^-1) and on a larger extent by chymostatin (2.6±0.3 fmol · min^-1 · mg^-1) compared with control values (5.6±0.4 fmol · min^-1 · 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.

Key Words: transgenic rat • angiotensin • human renin • cardiac renin-angiotensin system • chymase-like activity

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