Aggregate anaphylaxis and carboxypeptidase N.
Bradykinin (BK) is widely believed to play a role in the pathogenesis of anaphylaxis. To help clarify any such roles, we examined for effects of inhibitors of kininase II (angiotensin converting enzyme, ACE) and "kininase I" (carboxypeptidase N, CPN), on the early course of egg albumin-induced aggregate anaphylaxis in anesthetized guinea pigs. In this model, pulmonary and systemic arterial blood pressure (BP) rise (unless pulmonary fibrillation occurs), lung wgt increases by approximately 60% and pulmonary microvessels are occluded by cell-rich thrombi, all within 5 min of i.v. antigen. The 30 min mortality rate is approximately 2%. ACE inhibitors (BPP9a, Captopril and MK 422; doses up to 140 mumol/kg) do not make anaphylaxis more nor less severe in terms discernible by changes in BP, lung wgt, EKG or intravascular coagulation. In marked contrast, an inhibitor of CPN (2-mercaptomethyl-3-guanidinoethylthiopropionic acid, 2-MGP; 8-16 mumol/kg) increases the 30 min mortality rate to 94% and lung wgt to 180% of control. The animals die in ventricular fibrillation. Given the enormous BK potentiating effects of BPP9a, Captopril and MK 422, it seems likely that little if any BK is formed in the early min of anaphylaxis. 2-MGP does not potentiate BP effects of BK but markedly potentiates effects of C3a anaphylatoxin. Thus, our data support the views that BK is neither a primary nor secondary mediator of aggregate anaphylaxis, and the adverse effects of 2-MGP are best explained in terms of preservation of anaphylatoxins and not in terms of preservation of kinins.
D015097:3-Mercaptopropionic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D000707:Anaphylaxis; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D004656:Enalapril / Q000031:analogs & derivatives / Q000494:pharmacology; D015773:Enalaprilat; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000503:physiopathology* / Q000648:ultrastructure; D001121:Lysine Carboxypeptidase / Q000037:antagonists & inhibitors*; D010047:Ovalbumin; D013438:Sulfhydryl Compounds
D000806:Angiotensin-Converting Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D004656:Enalapril; C029729:2-mercaptomethyl-3-guanidinoethylthiopropionic acid; D010047:Ovalbumin; D002216:Captopril; D015097:3-Mercaptopropionic Acid; D002268:Carboxypeptidases; D001121:Lysine Carboxypeptidase; D015773:Enalaprilat