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.
The mechanism by which the angiotensin I (AI) converting enzyme inhibitor SQ20,881 (less than Glu-Trp-Pro-Arg-Pro-Glu-Ile-Pro-Pro) blocks the pressor response to exogenous AI was studied in vivo 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 AII that lasted for more than 6 hours as judged by the absence of immunoreactive or labeled AII 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 AII 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 (Des-Asp) AII and (Des-Asp, Arg) AII showed that the delayed pressor response to AI following SQ20,881 administration could not be accounted for by circulating peptide metabolites of AI or AII. A competitive inhibitor of AII, (D-Asp, Ile) AII completely blocked the returning pressor response, suggesting that extrapulmonary generation of AII was responsible. The data strongly suggest that the systemic vascular bed taken as a whole contains large amounts of AI converting enzyme that is capable of rapid generation of AII without releasing the peptide into circulation. The extrapulmonary enzyme is more resistant to long-lasting blockade by SQ20,881 than pulmonary converting enzyme. The physiological role of extrapulmonary conversion systemic and local circulatory homeotasis remains to be assessed.
D000803:Angiotensin I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009842:Oligopeptides / Q000378:metabolism*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011863:Radioimmunoassay; D013722:Teprotide / Q000378:metabolism* / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D009842:Oligopeptides; D000804:Angiotensin II; D000803:Angiotensin I; D013722:Teprotide