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 determined 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 male volunteers (age 18 to 67 years). Changes in forearm blood flow (FBF) were registered with venous occlusion plethysmography. Arterial and venous blood samples were collected under steady-state conditions to quantify forearm fractional Ang I-to-II conversion. Ang I and II exerted the same maximal effect (mean+/-SEM 71+/-4% and 75+/-4% decrease in FBF, respectively), with similar potencies (mean EC(50) [range] 5.6 [0.30 to 12.0] nmol/L for Ang I and 3.6 [0.37 to 7.1] nmol/L for Ang II). Forearm fractional Ang I-to-II conversion 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%), thereby 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, the 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 vasoconstriction than circulating Ang II. Local Ang II generation in the forearm depends on ACE exclusively and results in vasoconstriction via Ang II type 1 receptors.
Saris
J J
JJ
Departments of Pharmacology and Internal Medicine I, Erasmus University Rotterdam, Rotterdam, The Netherlands.
van Dijk
M A
MA
Kroon
I
I
Schalekamp
M A
MA
Danser
A H
AH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000803:Angiotensin I / Q000008:administration & dosage* / Q000097:blood; D000804:Angiotensin II / Q000008:administration & dosage* / Q000096:biosynthesis* / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001916:Brachial Artery / Q000502:physiology; D015773:Enalaprilat / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D019808:Losartan / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D012039:Regional Blood Flow; D014661:Vasoconstriction / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat; D019808:Losartan