Functional importance of angiotensin-converting enzyme-dependent in situ angiotensin II generation in the human forearm

To assess the importance for vasoconstriction of in situ angiotensin (Ang) II generation, as opposed to Ang II delivery via the circulation, we determ ined forearm vasoconstriction in response to Ang I (0.1 to 10 ng . kg(-1) . min(-1)) and Ang II (0.1 to 5 ng . kg(-1) . min(-1)) in 14 normotensive ma le volunteers (age 18 to 67 years). Changes in forearm blood flow (FBF) wer e registered with venous occlusion plethysmography. Arterial and venous blo od samples were collected under steady-state conditions to quantify forearm fractional Ang I-to-II conversion. Ang I and II exerted the same maximal e ffect (mean+/-SEM 71+/-4% and 75+/-4% decrease in FBF, respectively), with similar potencies (mean ECS50 [range] 5.6 [0.30 to 12.0] nmol/L for Ang I a nd 3.6 [0.37 to 7.1] nmol/L for Ang II). Forearm fractional Ang I-to-II con version was 36% (range 18% to 57%). The angiotensin-converting enzyme (ACE) inhibitor enalaprilat (80 ng . kg(-1) . min(-1)) inhibited the contractile effects of Ang I and reduced fractional conversion to 1% (0.1% to 8%), the reby excluding a role for Ang I-to-II converting enzymes other than ACE (eg , chymase). The Ang II type 1 receptor antagonist losartan (3 mg . kg(-1) . min(-1)) inhibited the vasoconstrictor effects of Ang II. In conclusion, t he similar potencies of Ang I and II in the forearm, combined with the fact that only one third of arterially delivered Ang I is converted to Ang II, suggest that in situ-generated Ang II is more important for vasoconstrictio n than circulating Ang II. Local Ang II generation in the forearm depends o n ACE exclusively and results in vasoconstriction via Ang II type 1 recepto rs.