Mechanism of angiotensin I converting enzyme inhibition by SQ20,881 (less than Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) in vivo. Further evidence for extrapulmonary conversion.

Abstract

SUMMARYThe mechanism by which the angiotensin I (AI) converting enzyme inhibitor SQ20,881 (<Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) blocks the pressor response to exogenous AI was studied in mo in the intact anesthetized dog. When administered as a single dose 250 times that of Injected AI (250 nmoles/kg) into either the pulmonary or systemic circulation, SQ20,881 produced inhibition of pulmonary conversion of exogenous AI to AH that lasted for more than 6 hours as judged by the absence of immunoreactive or labeled AH in the pulmonary venous effluent. In contrast, the pressor response to exogenous AI began to reappear within 1 hour of SQ20.881 administration. Six hours following SQ20.881, the pressor response to AI had nearly returned to normal, still in the absence of demonstrable intrapulmonary conversion and without release of detectable amounts of All into the pulmonary venous effluent. These experiments demonstrated that AI has a pressor effect in the presence of SQ20.881 that is independent of pulmonary conversion. Studies with (DesAsp The nonapeptide SQ20.881 (<Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro) is a potent and long-lasting competitive inhibitor of angiotensin I converting enzyme in vivo and in vitro. 5 "* Previous studies from our laboratory have shown that SQ20.881 inhibits both the acute pressor response and the generation of All seen immediately after the injection of AI into the pulmonary circulation of the dog.' Because of the importance of converting enzyme inhibitors such as SQ2O.881 as tools for elucidating the role of the reninangiotensin system in normal circulatory homeostasis and in the pathophysiology of hypertension, further studies of the mechanism of antihypertensive action of SQ20.881 were undertaken. The time course of converting enzyme inhibition by a single dose of SQ20.881 was evaluated in the pulmonary circulation of the intact dog. The pressor response to injected AI returned before demonstrable intrapulmonary conver-