Abstract 604: Renin Independent Ang-(1-12) Production in both the Systemic and Coronary Circulation

Although angiotensin-(1-12) [Ang-(1-12)] is recognized as an alternate precursor for Ang II, the biochemical pathways by which the substrate is released from angiotensinogen (Aogen) are not yet described. We examined the role of renin on Ang-(1-12) formation from synthetic icosapeptide [Ang-(1-20)] in the systemic and coronary circulation of Wistar Kyoto rats (WKY). In experiment 1, rats underwent bilateral nephrectomy (BNX) or sham operation. After 48 hours, rats were assigned to sham+saline, sham+Ang-(1-20), or BNX+Ang-(1-20). Ang-(1-20) (20 nmol/kg/min) or saline was infused for 15 minutes. At the end of the study blood was collected for measuring Ang-(1-12), Ang I and Ang II by RIA. Ang-(1-20) infusion increased arterial pressure in both sham and BNX compared to sham+saline (P<0.001). Plasma Ang-(1-12), Ang I, and Ang II were significantly higher in sham+Ang-(1-20) compared to sham+saline. BNX+Ang-(1-20) showed significant increase in Ang I and a tendency for augmented Ang-(1-12) and Ang II compared to sham+saline (Figure). In experiment 2, the hearts extracted from WKY were mounted on Langendorff apparatus. After recovery, 10 nmol or 100 nmol of Ang-(1-20), or 100 nmol of Ang-(1-20) with WFML-1 (a rat renin inhibitor) were perfused in the coronary circulation. Buffer was recirculated after addition of Ang-(1-20) and WFML-1. Perfusate was collected at 0, 5, 15, 30, and 60 min for measurement of angiotensins by RIA. The 100 nmol of Ang-(1-20) increase Ang-(1-12), Ang I, and Ang II compared to 10 nmol both in the absence and in the presence of WFML-1 (Figure). We conclude that Ang-(1-12) is cleaved from Aogen by an enzyme that is not renin in both systemic and coronary circulation.