LOCAL ANGIOTENSIN-II GENERATION IN THE RAT-HEART - ROLE OF RENIN UPTAKE

To elucidate the local effects oi renin in the coronary circulation, w e examined local angiotensin (Ang) I and II formation, as well as coro nary vasoconstriction in response to renin administration, and compare d the effects with exogenous infused Ang I. We perfused isolated heart s from rats overexpressing the human angiotensinogen gene in a Langend orff preparation and measured the hemodynamic effects and the released products. We also investigated cardiac Ang I conversion, including th e contribution of non-angiotensin-converting enzyme-dependent Ang II-g enerating pathways. Finally, we studied Ang I conversion in vitro in h eart homogenates. Renin and Ang I infusion both generated Ang II. Ang II release and vasoconstriction continued after renin infusion was sto pped, even though renin disappeared immediately from the perfusate. In contrast, after Ang I infusion, Ang II release and coronary now retur ned 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 infus ion abolished Ang I and II; captopril suppressed only Ang II, whereas an AT, receptor blocker did not affect Ang I and II formation. All the drugs prevented renin-induced coronary now 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 fm ol.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 gene ration and vasoconstriction. Locally formed Ang I was converted more e ffectively than infused Ang I. Furthermore, the comparison of in vivo and in vitro Ang I conversion suggests that in vitro assays may undere stimate the functional contribution of angiotensin-converting enzyme t o intracardiac Ang II formation.