Local Angiotensin II Generation in the Rat Heart

Abstract

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. ). 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. (Circ Res. 1998;82:13-20.) Key Words: transgenic rat Ⅲ angiotensin Ⅲ human renin Ⅲ cardiac renin-angiotensin system Ⅲ chymase-like activity A ngiotensin II plays a major role in cardiovascular homeostasis, including the regulation of blood pressure, salt balance, and tissue remodeling. Ang I and Ang II are produced not only in the blood compartment but also locally in tissues. In fact, the tissues are the major site of Ang I and Ang II formation, and the release of locally formed Ang II contributes to the circulating levels of these peptides.1-3 All the components of the renin-angiotensin system have been detected in the heart, 4-6 indicating that the heart is not only a target but also a site of endocrine or paracrine Ang II formation. Local Ang II formation may result from the interaction of renin and AOGEN produced within the vessel wall or from the uptake and retention of renin and AOGEN from the plasma, on the cell surface, or the interstitial fluid. [7][8][9][10][11][12] Many studies addressing the cardiac effects of Ang II have been performed by infusing Ang I or Ang II into the coronary circulation. In vivo, the cascade leading to Ang formation is stimulated by the enzyme renin. Even though it seems not to be produced by cardiac tissue, renin may be taken up to react locally with its substrate, AOGEN.There is a current controversy regarding the major pathway for Ang II formation in the human heart. Although ACE inhibitors are highly effective in treating hypertension-associated cardiac hypertrophy and congestive heart failure, [13][14][15] studies with ACE inhibitors have raised th...

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