Functional evidence for alternative ANG II-forming pathways in hamster cardiovascular system.
Like human chymase, hamster chymase is an ANG II-forming enzyme, but pathophysiological roles of chymase are still unknown. We determined the functional conversion of ANG I and [Pro11, D-Ala12]ANG I, a chymase-selective substrate, to ANG II in the hamster cardiovascular system. ANG I and [Pro11, D-Ala12]ANG I produced similar dose-dependent pressor responses in conscious hamsters. Captopril and CV-11974, an ANG II type 1 (AT1)-receptor antagonist, inhibited the responses to ANG I; in contrast, the pressor responses to [Pro11, D-Ala12]ANG I were suppressed only by CV-11974. In the isolated aorta, captopril suppressed ANG I-induced contraction by 84%; administration of captopril with either chymostatin or aprotinin eliminated the contraction. [Pro11, D-Ala12]ANG I-induced contraction was not affected by captopril but was attenuated by chymostatin (71%) and aprotinin (57%). CV-11974 abolished the responses to both substrates, whereas PD-123319, an AT2-receptor antagonist, had no effect. In homogenates of the aorta and heart, soybean trypsin inhibitor-inhibitable ANG II formation predominated over captopril- or aprotinin-inhibitable ANG II formation. These data suggest that [Pro11,D-Ala12]ANG I and part of ANG I were functionally converted to ANG II by chymase and other serine protease(s) in hamster vessels, inducing AT1-receptor-mediated vasoconstriction. Biochemical data supported a role for chymase in the alternative pathway.
Nishimura
H
H
Third Department of Internal Medicine, Osaka Medical College, Takatsuki 569, Japan.
Buikema
H
H
Baltatu
O
O
Ganten
D
D
Urata
H
H
D000803:Angiotensin I / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology*; D000804:Angiotensin II / Q000096:biosynthesis*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007611:Aprotinin / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D002216:Captopril / Q000494:pharmacology; D053818:Chymases; D006224:Cricetinae; D006352:Heart Ventricles; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity; D013777:Tetrazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D009842:Oligopeptides; D013777:Tetrazoles; D000804:Angiotensin II; D000803:Angiotensin I; C002101:chymostatin; D007611:Aprotinin; D002216:Captopril; D012697:Serine Endopeptidases; D053818:Chymases; C081643:candesartan