chymostatin and rentiapril

The functional role of the endothelium in conversion of angiotensin (Ang) I to Ang II was studied in helical strips of dog renal arteries. In the arteries precontracted with PGF2 alpha, Angs I and II caused a moderate relaxation, which was abolished by treatment with saralasin and reversed to a contraction by indomethacin. Removal of the endothelium attenuated the response to Ang I but did not abolish it. The Ang I-induced relaxation in the arteries without endothelium was not significantly attenuated by an Ang-converting enzyme inhibitor, SA446, but was markedly suppressed by chymostatin. On the other hand, in the arteries with endothelium, the relaxation was suppressed but not abolished by SA446, and the remaining relaxation was abolished by additional treatment with chymostatin. Relaxation induced by prostaglandin I2 was unaffected by these enzyme inhibitors. These results strongly suggest that the conversion of Ang I to Ang II is due mainly to the Ang-converting enzyme in the endothelium and to the chymostatin-sensitive Ang II-generating enzyme in subendothelial tissues.

Topics: 3-Mercaptopropionic Acid; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Dinoprost; Dogs; Endothelium, Vascular; Female; In Vitro Techniques; Indomethacin; Isometric Contraction; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Oligopeptides; Peptidyl-Dipeptidase A; Renal Artery; Serine Endopeptidases; Thiazolidines; Tranylcypromine

An inhibitor of angiotensin I (ANG I) converting enzyme, SA446, reduced the response to ANG I of blood vessels isolated from dogs and monkeys, but did not abolish the response even at high concentrations. The residual action of ANG I in the presence of high concentrations of SA446 could be abolished by (Sar1, Ala8)-ANG II. Vascular strips and crude extracts of vessels and lungs possessed the enzymic activity generating ANG II from ANG I, or hippuric acid from hippuryl-histidyl-leucine (HHL). The HHL-hydrolysing activity of the crude extracts was completely inhibited by SA446 (10(-7) mol/l) and/or Na2-EDTA (10(-3) mol/l). However, the octapeptide generation was not abolished despite the combined treatment with SA446 (5 X 10(-4) mol/l) and Na2-EDTA (5 x 10(-3) mol/l). The residual activity forming ANG II was inhibited by chymostatin and soybean trypsin inhibitor, which however did not affect the HHL-hydrolysis. Combined treatment with SA446 (10(-5) mol/l) and chymostatin (2.5 X 10(-5) mol/l) abolished the vascular action of ANG I but did not alter the action of ANG II. These results strongly suggest that besides the ANG I converting enzyme, another enzyme which generates ANG II is present in vascular tissues and lungs, and may play an important role in the local generation of ANG II, which possibly regulates the regional vascular tone.

Topics: 3-Mercaptopropionic Acid; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Blood Vessels; Dogs; Female; In Vitro Techniques; Macaca; Male; Muscle Contraction; Muscle, Smooth, Vascular; Oligopeptides; Sulfhydryl Compounds; Thiazolidines