VASOCONSTRICTOR ACTION OF ANGIOTENSIN-I CONVERTASE AND THE SYNTHETIC SUBSTRATE (PRO(11),D-ALA(12))-ANGIOTENSIN-I

A chymase (also referred to as angiotensin I-convertase) specific for the conversion of angiotensin (Ang) I to Ang II has been identified in human heart. This serine protease is also present in dog and marmoset vasculature. We examined the vasoconstrictor effects of Ang II putati vely generated from an angiotensin-converting enzyme (ACE)-resistant c onvertase synthetic substrate (SUB) in vivo and in vitro. In marmosets , SUB (7 to 700 mu g/kg IV) or Ang I (0.1 to 30 mu g/kg) caused simila r dose-dependent increases in mean arterial pressure (10 to 100 mm Hg) and decreases in heart rate. Presser effects of SUB were slightly att enuated at low (but not high) doses by captopril (CAP, 1 mg/kg IV) and blocked by losartan (5 mg/kg IV); in contrast Ang I pressor effects w ere substantially blocked by bath. In isolated canine superior mesente ric artery, Ang I-induced contraction was eliminated by losartan and r educed but not eliminated by 10 mu mol/L CAP. When combined with the s erine protease inhibitor chymostatin, CAP eliminated Ang I-induced con traction, but chymostatin alone had no effect. SUB-induced contraction was not blocked by CAP but was equally blocked by chymostatin (25 mu mol/L) alone or by the combination of CAP (10 mu mol/L) and chymostati n (25 mu mol/L); losartan (10 mu mol/L) eliminated SUB-induced respons es. Previous studies have suggested that Ang I-convertase is important for production of Ang II in the heart. Our results are consistent wit h a potential role for Ang I-convertase in the production of Ang II in the vasculature, resulting in Ang II-mediated vasoconstriction.