Angiotensin-converting enzyme inhibitors bradykinin

Brown NJ, Ryder D, Gainer JV Morrow JD, Nadeau J. Differential effects of angiotensin converting enzyme inhibitors on the vasodepressor and prostacyclin responses to bradykinin.J Pharmacol Exp Ther 1996 279 703-712. 

Mukae S, Aoki S, Itoh S, Iwata T, Ueda H, Katagiri T. Bradykinin B(2) receptor gene polymorphism is associated with angiotensin-converting enzyme inhibitor-related cough. Hypertension 2000 36(1) 127-31. 

Figure 11-4. Actions of angiotensin-converting enzyme inhibitors and AT receptor blockers. The enzyme is responsible for activating angiotensin by conversion of angiotensin I to angiotensin II and for inactivating bradykinin, a vasodilator normally present in very low concentrations. Block of the enzyme thus decreases the concentration of a vasoconstrictor and increases the concentration of a vasodilator. The AT, receptor antagonists lack the effect on bradykinin levels, which may explain the lower incidence of cough observed with these agents.

C. Clinical Role Although it has no therapeutic application, bradykinin may play a role in the antihypertensive action of angiotensin-converting enzyme inhibitors, as previously noted (Chapter 11 Figure 11-4). At present there are no clinically important bradykinin antagonists. 

Hornig, B., Kohler, C., Drexler, H. Role of bradykinin in mediating vascular effects of angiotensin converting enzyme inhibitors in humans. CirKulation 1997 95 482b6. 

Angiotensin converting enzyme (ACE) plays a central role in cardiovascular hemostasis. Its major function is the generation of angiotensin (ANG) II from ANGI and the degradation of bradykinin. Both peptides have profound impact on the cardiovascular system and beyond. ACE inhibitors are used to decrease blood pressure in hypertensive patients, to improve cardiac function, and to reduce work load of the heart in patients with cardiac failure. 

Figure 17.5 The dual vasodilatoiy effect of inhibitors of the angiotensin-converting enzyme (ACE). The ACE inhibitors not only inhibit ACE but also the kininase which degrades bradykinin. (See also Chapter 22).

Figure 22.16 Regulation of vasoconstriction/vasodilation by angiotensin-II and bradykinin. The mechanism by which angiotensin-II stimulates vasoconstriction is shown in Figure 22.15. Angiotensin-converting enzyme is also responsible for bradykinin inactivation. Bradykinin stimulates endothelial cells to produce and secrete nitric oxide and prostacyclin, both of which are vasodilators. Consequently the effect of an ACE inhibitor is to decrease the concentration of angiotensin-II, which lowers blood pressure, and to increase the concentration of bradykinin, which also lowers blood pressure.

Maruyama, S., Nakagomi, K., Tomizuka, N., and Suzuki, H. 1985. Angiotensin I-converting enzyme inhibitor derived from an enzymatic hydrolysate of casein. II. Isolation and bradykinin-potentiating activity on the uterus and the ileum of rats. Agric. Biol. Chem. Tokyo 49, 1405-1409. 

ACE inhibitors (ACEIs) (e.g., captopril) inhibit kininase II (angiotensin-converting enzyme), blocking the formation of angiotensin II and preventing its activation of AT-1 receptors in the adrenal cortex —> 4, aldosterone and its effect on vasculature, thereby i vasoconstriction. ACEIs also inhibit the metabolism of bradykinin (BK), which causes NO/EDRF-mediated vasodilation - l TPR. 

Angiotensin converting enzyme (ACE) inhibitor. ACE is a dipep-tidylaminopeptidase (EC 3.4.15.1) which cleaves dipeptides from the C-terminus of peptides. It converts angiotensin I to the potent vasoconstrictor, angiotensin II, and inactivates the vasodilator, bradykinin. The dodecapep-tide, H.Phe.Phe.Val.Ala.Pro.Phe.Pro.Glu.Val.Phe.Gly.Lys, i.e. a i-CN f23-34, from tryptic hydrolysates of casein inhibits ACE. The C-terminal sequence of aji-casein, H.Thr.Thr.Met.Pro.Leu.Tyr, a j-CN fl94-199, also has ACE inhibitory activity. Peptides from the sequence 39-52 of human )8-casein, especially H.Ser.Phe.Gln.Pro.Gln.Pro.Leu.Ile.Tyr.Pro (j8-CN f43-52), also have ACE inhibitory activity. 

---