Bradykinin metabolism

Brown NJ, Blais C Jr, Gandhi SK, Aam A. ACE insertion/deletion genotype affects bradykinin metabolism. J Cardio-vasc Pharmacol 1998 32 373-377. 

ACE inhibitors not only block the conversion of Ang I to Ang II but also inhibit the degradation of other substances, including bradykinin, substance P, and enkephalins. The action of ACE inhibitors to inhibit bradykinin metabolism contributes significantly to their hypotensive action (see Figure 11-5) and is apparently responsible for some adverse side effects, including cough and angioedema. 

The synthesis of kinins can be inhibited with the kallikrein inhibitor aprotinin. Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin. Conversely, the actions of kinins can be enhanced with ACE inhibitors, which block the degradation of the peptides. Indeed, as noted above, inhibition of bradykinin metabolism by ACE inhibitors contributes significantly to their antihypertensive action. 

The angiotensin I-converting enzyme (ACE), designated peptidyl-dipeptidase A (E.C.3.4.15.1), is identical to the bradykinin-metabolizing enzyme kininase II (38). Its early history and initial characterizations have been reviewed (51-54). It was discovered by Skeggs and co-workers (55), and in their pioneering work they showed it to be inhibited by ethylene-diaminetetraacetic acid (EDTA) (37), to remove a dipeptide from the carboxyl terminus of angiotensin I (then called hypertensin I [56]) and to be activated by sodium chloride (55). The fact that ACE is a Zn2+-contain-ing peptidase was first reported by Das and Sofler in 1975 (57). 

Studies with BPF were continued by Ferreira in the laboratories of J. R. Vane, where it was also shown to increase the in vivo stability of bradykinin (76). Importantly, Ng and Vane established BPF as a potent inhibitor of angiotensin I conversion in the lung (77), and Bakhle in Vane s department demonstrated that BPF blocked the formation of angiotensin II from angiotensin I in vitro (78). Subsequently, Erdos and co-workers (35) established the identity of the bradykinin-metabolizing enzyme kininase II with the ACE. 

Taylor-McCabe KJ, Erasahin C, Simmons WH. 2001. Bradykinin metabolism in the isolated perfused rabbit heart. J. Hypertens. 19 1295-99... 

ACEIs block formation of All and inhibit bradykinin metabolism —aldosterone —fluid retention —vasodilation —>4- preload and afterload. 

As discussed earlier, CatA is strongly involved in urinary bradykinin metabolism in rat and humans. Therefore, elevated bradykinin levels after CatA inhibition should result in increased diuresis. Based on these considerations, the group of Majima investigated effects on urinary kinin levels, natriuresis, and diuresis after administration of the CatA inhibitor ebelactone B to rats [48,49]. Using a sophisticated experimental protocol with cannulated ureters in anesthetized animals. 

Ramirez-Molina, C., Heudi, O., Pullen, M and Marshall, P.S. (2006) Study of bradykinin metabolism by rat lung tissue membranes and rat kidney brush border membranes with inductively coupled plasma-mass spectormetry and orthogonal acceleration time-of-flight mass spectrometry. Jourruil of Peptide Science, 12, 220-226. 

Murphey LJ, Gainer JV, Vaughan DE, Brown NJ. Angiotensin-converting enzyme insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinin. Circulation. 2000 102 829-832. 

The pathway for the formation and metabolism of kinins is shown in Figure 17-4. Three kinins have been identified in mammals bradykinin, lysylbradykinin (also known as kallidin), and methionyllysylbradykinin. Each contains bradykinin in its structure. 

In contrast to the adverse physiologies associated with bradykinin release, there is a growing body of literature that implicates bradykinin as a protective agent during periods of cardiac or renal stress [14-16]. In this regard there is substantial evidence that the cardioprotective effects afforded by ACE-inhibitor treatment are a result of metabolically preserving bradykinin and are therefore mediated by bradykinin B2 (and possibly 1) receptors [17-18]. These results point to a possible therapeutic role for a kinin receptor agonist. 

ANTI HYPERTENSIVES AND HEART FAILURE DRUGS NS AIDs 1 hypotensive effect, especially with indometacin. The effect is variable amongst different ACE inhibitors and NSAIDs, but is most notable between captopril and indometacin NSAIDs cause sodium and water retention and raise BP by inhibiting vasodilating renal prostaglandins. ACE inhibitors metabolize tissue kinins (e.g. bradykinin) and this may be the basis for indometacin attenuating hypotensive effect of captopril Monitor BP at least weekly until stable. Avoid co administering indometacin with captopril... 

Naftidrofuryl is a complex acid ester of diethylaminoetha-nol, with direct vasodilatory properties and antagonistic effects on 5-HT (via 5-HT2 receptors) and bradykinin. It also causes an intracellular increase in ATP concentrations, improves cellular oxidative metabolism (by activating succinate dehydrogenase), and reduces blood and plasma viscosity and fibrinogen concentrations. 

Non-IgE-mediated anaphylactic reactions to polyacrylonitrile membranes have been reported (2,3). The effects are enhacing in those using ACE inhibitors (4,5), perhaps because of an effect of bradykinin (6), which is released by the membranes (2,8,9) and whose metabolism is inhibited by ACE inhibitors. The effects also occur to a lesser extent in those taking angiotensin receptor antagonists (7) and in those with Cl esterase inhibitor deficiency (10). Treating the membranes with polyethyleneimine prevents bradykinin release (11). 

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