Alternative angiotensin II formation in rat arteries occurs only at very high concentrations of angiotensin I.
Contrary to previous reports, recent enzymatic assays showed the predominance of chymase-like activity in rat arteries. We determined the existence and significance of such alternative pathways in rat carotid arteries by measuring contraction of arterial rings in organ baths and blood pressure in conscious rats. Hamster aorta served as a positive control for chymase. Temocapril (30 micromol/L) inhibited the contractions to angiotensin (Ang) I (10(-9) to 10(-5) mol/L) except at high concentrations of Ang I (>10(-7) mol/L). Addition of chymostatin (100 micromol/L) to temocapril exerted a synergistic inhibitory effect. Hamster aorta gave similar results, except that temocapril was 30-fold less effective than in rat arteries. [Pro(11), D-Ala(12)]Ang I (10(-8) to 10(-5) mol/L), a chymase-specific substrate, provoked similar responses in rat and hamster arteries; chymostatin, but not temocapril, attenuated the responses. CV 11974 (30 micromol/L), an Ang II type 1 receptor antagonist, abolished the responses to both peptides. In conscious rats, Ang I (0.03 to 30 microg/kg) and [Pro(11),D-Ala(12)]Ang I (7 to 700 microg/kg) produced similar pressor responses. Not only CV 11974 (1 mg/kg) but also temocapril (2 mg/kg) abolished Ang I-induced responses in vivo. CV 11974, but not temocapril, inhibited responses to [Pro(11), D-Ala(12)]Ang I. Our results showed the presence of the alternative pathway in rat arteries, but it did not play a major role. Arteries with the opposing characteristics of chymase responded equally to [Pro(11),D-Ala(12)]Ang I. These findings suggest that biochemical and [Pro(11),D-Ala(12)]Ang I-derived results may not reflect the functional significance of chymase.
Inoue
K
K
Third Department of Internal Medicine, Osaka Medical College, Takatsuki City, Osaka, Japan.
Nishimura
H
H
Kubota
J
J
Kawamura
K
K
D000803:Angiotensin I / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000804:Angiotensin II / Q000187:drug effects / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001158:Arteries / Q000187:drug effects / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism*; D006224:Cricetinae; D008297:Male; D008647:Mesocricetus; D011311:Pressoreceptors / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D015842:Serine Proteinase Inhibitors; D013777:Tetrazoles; C087635:angiotensin I, Pro(11)-Ala(12)-; D000804:Angiotensin II; D000803:Angiotensin I; C081643:candesartan