FUNCTIONAL EVIDENCE FOR ALTERNATIVE ANG II-FORMING PATHWAYS IN HAMSTER CARDIOVASCULAR-SYSTEM

Like human chymase, hamster chymase is an ANG II-forming enzyme, but p athophysiological roles of chymase are still unknown. We determined th e functional conversion of ANG I and [Pro(11), D-Ala(12)]ANG I, a chym ase-selective substrate, to ANG II in the hamster cardiovascular syste m. ANG I and [Pro(11), D-Ala(12)]ANG I produced similar dose-dependent presser responses in conscious hamsters. Captopril and CV-11974, an A NG II type 1 (AT(1))-receptor antagonist, inhibited the responses to A NG I; in contrast, the presser responses to [Pro(11),D-Ala(12)]ANG I w ere suppressed only by CV-11974. In the isolated aorta, captopril supp ressed ANG I-induced contraction by 84%; administration of captopril w ith either chymostatin or aprotinin eliminated the contraction. [Pro(1 1), D-Ala(12)]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 AT(2 )-receptor antagonist, had no effect. In homogenates of the aorta and heart, soybean trypsin inhibitor-inhibitable ANG II formation predomin ated over captopril- or aprotinin-inhibitable ANG II formation. These data suggest that [Pro(11),D-Ala(12)]ANG I and part of ANG I were func tionally converted to ANG II by chymase and other serine protease(s) i n hamster vessels, inducing AT(1)-receptor-mediated vasoconstriction. Biochemical data supported a role for chymase in the alternative pathw ay.