Müller D N, Fischli W, Clozel J P, Hilgers K F, Bohlender J, Ménard J, Busjahn A, Ganten D, Luft F C
Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine, Virchow Klinikum, Humboldt University of Berlin, Germany.
Circ Res. 1998;82(1):13-20. doi: 10.1161/01.res.82.1.13.
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.
为阐明肾素在冠脉循环中的局部作用，我们检测了局部血管紧张素（Ang）I和II的生成，以及给予肾素后冠脉血管收缩情况，并将这些效应与外源性输注Ang I的效应进行比较。我们在Langendorff装置中灌注过表达人血管紧张素原基因大鼠的离体心脏，测量血流动力学效应和释放产物。我们还研究了心脏Ang I转化，包括非血管紧张素转换酶依赖性Ang II生成途径的作用。最后，我们在心脏匀浆中进行了体外Ang I转化研究。输注肾素和Ang I均能生成Ang II。停止输注肾素后，Ang II释放和血管收缩仍持续存在，尽管肾素立即从灌注液中消失。相比之下，输注Ang I后，Ang II释放和冠脉血流恢复至基础水平。与输注Ang I相比，输注肾素后Ang I转化率（Ang II/Ang I比值）更高（15分钟时为0.109±0.027对0.026±0.003，P<0.02）。加入雷米吉仑可消除输注肾素所致的Ang I和II；卡托普利仅抑制Ang II，而AT1受体阻滞剂不影响Ang I和II的生成。所有药物均能防止肾素引起的冠脉血流变化。与对照值（5.6±0.4 fmol·min-1·mg-1）相比，西拉普利拉仅部分抑制总心脏Ang II生成活性（4.1±0.1 fmol·min-1·mg-1），而抑肽酶在更大程度上抑制该活性（2.6±0.3 fmol·min-1·mg-1）。我们得出结论，肾素可被心脏或冠脉血管组织摄取，并诱导持久的局部Ang II生成和血管收缩。局部生成的Ang I比输注的Ang I更有效地转化。此外，体内和体外Ang I转化的比较表明，体外试验可能低估了血管紧张素转换酶对心内Ang II生成的功能贡献。
