ANALYSIS OF RESPONSES TO ANG-IV - EFFECTS OF PD-123319 AND DUP-753 IN THE PULMONARY CIRCULATION OF THE RAT

Pulmonary vasoconstrictor responses to angiotensin (ANG) IV, the 3-8 amino acid fragment of ANG II, were compared with responses to ANG I, ANG II, and ANG III and to other vasoactive peptides in the isolated blood perfused rat lung. In terms of relative activity, ANG IV was similar in potency to bradykinin and serotonin but was similar to 100-fold less potent than ANG I, ANG II, and ANG III. PD-123319, an AT(2)-receptor antagonist, enhanced presser responses to the four angiotensin peptides and to bradykinin but did not significantly change the presser response to serotonin or to ventilatory hypoxia. DuP-753, an AT(1)-receptor antagonist, significantly decreased presser responses to the four angiotensin peptides and enhanced the presser responses to bradykinin but not to serotonin. Captopril and enalaprilat increased the presser response to ANG IV. Meclofenamate and N-omega-nitro-L-arginine methyl ester shifted the dose-response curve for ANG IV to the left in a manner similar to that observed with ANG II and ANG III. These data show that ANG IV has significant vasoconstrictor activity and suggest that responses are mediated by the activation of AT(1) receptors and that vasopressor responses of the angiotensin peptides may be modulated by activation of AT(2) receptors. These results also suggest that responses to ANG IV are modulated by the release of vasodilator prostaglandins and nitric oxide and that AT(2) receptors have little, if any, role in mediating or modulating the presser response to ventilatory hypoxia.