A human platelet angiotensin I-processing system. Identification of components and inhibition of angiotensin-converting enzyme by product.
Mechanisms controlling the local generation of angiotensin II by vascular tissue are incompletely understood. Human platelets were examined for their ability to metabolize angiotensin I. Platelet-dependent angiotensin I metabolism was detected by a high performance liquid chromatography assay which allowed quantitation of angiotensin I substrate utilized and products formed. The major product of platelet-dependent angiotensin I metabolism was identified as des-Leu10-angiotensin I. The platelet des-Leu10-angiotensin I-generating activity had a pH optimum of 6.0-6.5 and was inhibited 100% by mersalyl acid (10(-4) M), 86% by leupeptin (10(-4) M), and 95% by iodoacetamide (10(-2) M). The activity had an approximate Mr = 70,000 as determined by Sephacryl S-200 gel filtration. Intact human platelets stimulated with calcium ionophore (1-10 microM) released 13.7-30.8% of the des-Leu10-angiotensin I-generating activity. Des-Leu10-angiotensin I, the major product of platelet angiotensin I metabolism, inhibited human serum and purified rabbit lung angiotensin-converting enzymes with an I50 of 3.7 X 10(-6) and 2.0 X 10(-6) M, respectively. These results suggest that the platelet may control local angiotensin II formation at vascular sites both by metabolism of the precursor peptide angiotensin I and by generation of an endogenous angiotensin-converting enzyme inhibitor, des-Leu10-angiotensin I. This platelet-dependent pathway may contribute to the control of local levels of vasoactive peptides, such as bradykinin and angiotensin II, so as to alter local tissue blood flow.
Snyder
R A
RA
Watt
K W
KW
Wintroub
B U
BU
D000803:Angiotensin I / Q000031:analogs & derivatives / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007460:Iodoacetamide / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D008634:Mersalyl / Q000494:pharmacology; D008970:Molecular Weight; D011817:Rabbits
D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D007976:Leupeptins; C045857:angiotensin I, des-Leu(10)-; D008634:Mersalyl; D000803:Angiotensin I; C032854:leupeptin; D007460:Iodoacetamide