Formation of angiotensin II by tonin-inhibitor complex.

Abstract

SUMMARY Enzymatic activity of tonin-o^-macroglobulin complex was studied in vitro and in vivo, using an immunoimmobilization technique. Tonin-ai-macroglobulin complex, which was immunologically immobilized by anti-a r macroglobulin antibody covalently coupled to agarose gels, could quantitatively hydrolyze angiotensin I and synthetic tridecapeptide renin substrate to form angiotensin II. However, the solid-phase antibody-bound tonin-a,-macroglobulin complex could not hydrolyze the plasma protein renin substrate. Phenylmethylsulfonyl fluoride, a serine protease inhibitor, inhibited both free tonin and the solid-phase antibody-bound tonin-a|-macroglobulin complex. The hydrolytic activity of the solid-phase antibody-bound tonin-«,-macroglobulin complex against angiotensin I was not inhibited by soybean trypsin inhibitor (molecular weight, 23,000), a potent inhibitor of free tonin. Taken together, these results suggest that tonin bound to c^-macroglobulin keeps the active site intact and that inhibition of the enzyme activity is due to a steric hindrance. When 500 /xl of tonin was administered intravenously to rats, the immunoimmobilization method was used to show that the tonin-a r -macroglobulin complex in the plasma formed angiotensin II. Thus, the tonin-a r macroglobulin complex in the plasma may be linked to some forms of hypertension through angiotensin II formation. (Hypertension 11: 63-70, 1988) KEY WORDS • tonin immunoimmobilization angiotensin I • angiotensin II • a r -macroglobulin

Regulation of Proximal Tubule Transport by Endogenously Produced Angiotensin II

“…Cathepsin G and chymase can convert angiotensin I to angiotensin II [34, 35, 36, 37, 38, 39, 40, 41]. Converting enzyme inhibitors do not inhibit these enzymes.…”

“…Converting enzyme inhibitors do not inhibit these enzymes. In addition, other proteases such as kallikrein and tonin can generate angiotensin II directly from angiotensinogen [39, 40, 41]. Yosipiv and El-Dahr [38]showed that angiotensin II was generated in the newborn rat kidney in the presence of a converting enzyme inhibitor, indicating the presence of alternate modes of angiotensin II production.…”

Chymase-dependent angiotensin II formation in human blood vessels

“…32,33 Tonin is normally inactivated in plasma by the endogenous inhibitor alpha 1 -macroglobulin, however, it has recently been shown that even when bound to alpha 1 -macroglobulin, tonin can still generate angiotensin II, which is resistant to ACE inhibition. 34 …”

The Cardiac Renin-Angiotensin System

“…[27][28][29][30] Recently, an aspartyl protease with cathepsin D-like properties was shown to convert Ao to Ang I in adult rat myofibroblasts isolated from ventricular scar tissue. 31 This suggests that unlike resident cardiac fibroblasts, 1,5,7 these transformed fibroblastlike cells synthesize Ang I via a non-renin-dependent pathway.…”