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 approximately 100-fold less potent than ANG I, ANG II, and ANG III. PD-123319, an AT2-receptor antagonist, enhanced pressor responses to the four angiotensin peptides and to bradykinin but did not significantly change the pressor response to serotonin or to ventilatory hypoxia. DuP-753, an AT1-receptor antagonist, significantly decreased pressor responses to the four angiotensin peptides and enhanced the pressor responses to bradykinin but not to serotonin. Captopril and enalaprilat increased the pressor 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 AT1 receptors and that vasopressor responses of the angiotensin peptides may be modulated by activation of AT2 receptors. These results also suggest that responses to ANG IV are modulated by the release of vasodilator prostaglandins and nitric oxide and that AT2 receptors have little, if any, role in mediating or modulating the pressor response to ventilatory hypoxia.
Nossaman
B D
BD
Department of Anesthesiology, Tulane University Medical School, New Orleans, Louisiana 70112.
Feng
C J
CJ
Kaye
A D
AD
Kadowitz
P J
PJ
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure; D001920:Bradykinin / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D009569:Nitric Oxide; D008469:Meclofenamic Acid; D019808:Losartan; D001920:Bradykinin