Ace inhibitor bradykinin
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The Role of Bradykinin in ACE Inhibitor Activity
Introduction to ACE Inhibitors and Bradykinin
Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of hypertension and heart failure. These medications primarily function by inhibiting the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. However, ACE inhibitors also prevent the degradation of bradykinin, a peptide that plays a significant role in vasodilation and other cardiovascular effects .
Bradykinin's Mechanism of Action
Vasodilation and Cardiovascular Benefits
Bradykinin is an endogenous vasodilator that contributes to the systemic hemodynamic effects of ACE inhibitors. It promotes vasodilation, natriuresis, and reduces oxidative stress, fibrinolysis, inflammation, and apoptosis . The affinity of ACE for bradykinin is higher than for angiotensin I, suggesting that ACE inhibitors may be more effective at preventing bradykinin degradation than at reducing angiotensin II production . This mechanism is particularly significant in the endothelium, where bradykinin signaling is a major target of ACE inhibition.
Hemodynamic Effects in Heart Failure
In patients with chronic heart failure, bradykinin significantly contributes to the hemodynamic effects of long-term ACE inhibition. Studies have shown that bradykinin receptor antagonism can attenuate the beneficial effects of ACE inhibitors on blood pressure and vascular resistance, indicating that bradykinin plays a crucial role in these processes .
Clinical Implications of Bradykinin Potentiation
Blood Pressure Regulation
The coadministration of bradykinin receptor antagonists, such as icatibant, with ACE inhibitors has been shown to attenuate the blood pressure-lowering effects of ACE inhibitors. This suggests that bradykinin significantly contributes to the short-term hypotensive effects of ACE inhibition . In normotensive and hypertensive subjects, the attenuation of blood pressure response by bradykinin receptor blockade further supports this role .
Angioedema and Bradykinin Receptor Antagonism
ACE inhibitor-associated angioedema is a known adverse effect, primarily mediated by increased bradykinin levels. However, clinical trials have shown that bradykinin B2 receptor antagonism with icatibant does not significantly reduce the time-to-resolution of angioedema symptoms, indicating that other pathways may also be involved.
Molecular Interactions and Receptor Sensitization
ACE and Bradykinin Receptor Crosstalk
ACE inhibitors not only prevent bradykinin degradation but also potentiate its effects by inhibiting receptor desensitization. This crosstalk between ACE and bradykinin receptors enhances the vasodilatory effects of bradykinin, independent of its metabolism . Studies in isolated cells and porcine arteries have demonstrated that ACE inhibitors can resensitize desensitized bradykinin receptors, further amplifying bradykinin's effects .
Selectivity of ACE Inhibitors
Different ACE inhibitors exhibit varying selectivity for bradykinin versus angiotensin I binding sites. For instance, perindoprilat has a higher selectivity for bradykinin degradation sites compared to other ACE inhibitors, which may influence their efficacy in cardiovascular disease treatment.
Conclusion
Bradykinin plays a pivotal role in the therapeutic effects of ACE inhibitors, particularly in vasodilation and blood pressure regulation. The potentiation of bradykinin's effects through ACE inhibition contributes significantly to the cardiovascular benefits of these drugs. Understanding the intricate interactions between ACE, bradykinin, and their receptors can help optimize the use of ACE inhibitors in clinical practice and potentially lead to the development of new therapeutic strategies.
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