Angiotensin generation in the brain and drinking: indications for the involvement of endopeptidase activity distinct from cathepsin D.
The dipsogenic activity of two artificial renin substrates, tetradecapeptide and tridecapeptide, was studied. The dose-response curves obtained with these peptides, following intracerebroventricular administration, were similar to that of angiotensin I. The angiotensin II antagonist, Sar1, Ala8-angiotensin II, inhibited the dipsogenic effect of tetradecapeptide, indicating the conversion of the latter peptide into angiotensin II. The lower dipsogenic activity of tridecapeptide points to a conversion of this renin substrate into angiotensin III. Specific inhibition of tetradecapeptide induced drinking by the endopeptidase inhibitor N-acetyl-pepstatin suggests the involvement of an endopeptidase in the conversion of the renin substrates in the brain. Two endopeptidases present in the brain (cathepsin D and renin), were compared with respect to their capacity to generate angiotensin I from artificial renin substrate in vitro. Cathepsin D was active under only acidic pH conditions, whereas renin showed a wider pH range with maximal activity in the non-acidic region. Moreover, cathepsin D did not generate angiotensin I from natural, cerebrospinal fluid-angiotensinogen in vitro, and lacked dipsogenic activity following central administration. Small amounts of renin, however, were able to release angiotensin I from cerebrospinal fluid in vitro. In addition, this enzyme induced high dipsogenic activity upon intracerebroventricular injection. These results support the existence of a functionally active central renin-angiotensin system and provide an argument against the involvement of cathepsin D in the formation of angiotensin I in the brain.
D000803:Angiotensin I / Q000378:metabolism*; D000809:Angiotensins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002402:Cathepsin D; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism*; D004326:Drinking; D010450:Endopeptidases / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000378:metabolism; D012697:Serine Endopeptidases
D000809:Angiotensins; D000803:Angiotensin I; D002403:Cathepsins; D010450:Endopeptidases; D012697:Serine Endopeptidases; D056649:Cathepsin G; C534097:Ctsg protein, rat; D012083:Renin; D002402:Cathepsin D