Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming

Abstract

Background: Cofactors contribute to the elicitation of anaphylaxis. β-Blockers and angiotensin-converting enzyme (ACE) inhibitors are widely used cardiovascular drugs. We specially designed a mouse model to further analyze the cofactor potential of these drugs.

Objective: We sought to test the hypothesis that β-blockers and ACE inhibitors alter the risk for severe anaphylaxis and to pinpoint the associated mechanism.

Methods: The risk factor potency of cardiovascular drugs on the severity of anaphylaxis in patients from German-speaking countries was analyzed. In vivo interaction of the cardiovascular drugs metoprolol (β-blocker) and ramipril (ACE inhibitor) with the anaphylactic response was determined. Mast cell (MC) mediators (histamine, serotonin, leukotriene C₄, prostaglandin D2, and mouse mast cell protease 1) were quantified in serum. Bone marrow-derived cultured MCs served to identify whether the therapeutics targeted MCs directly.

Results: Our anaphylaxis database indicated a higher risk of severe anaphylaxis after monotherapy with β-blockers or ACE inhibitors, which was more pronounced when both drugs were combined. This was confirmed in our mouse model. While single therapeutics had either no significant (ramipril) or a modestly aggravating (metoprolol) effect, their combined administration exacerbated anaphylactic symptoms potently and simultaneously enhanced MC mediators, hinting at MCs as direct targets. In fact, FcεRI-mediated MC histamine release was synergistically increased by metoprolol/ramipril or metoprolol/bradykinin (the latter increased after ACE inhibitor intake), whereas the substances had no significant effect on their own. MC priming was particularly pronounced when FcεRI aggregation was in the suboptimal range, reflecting common clinical settings.

Conclusion: β-Blockers and ACE inhibitors synergistically aggravate anaphylaxis at least partly by decreasing the threshold of MC activation.

Keywords: Anaphylaxis; angiotensin-converting enzyme inhibitor; cardiovascular medication; cofactor; mast cells; β-blocker.