Exploring the Difference Between Angiotensin Converting Enzyme Inhibitors and Angiotensin II-Receptor Antagonists. A Focus on Bradykinin

Barnes, Colin C.

doi:10.1007/978-1-4615-5743-2_15

Progress in Experimental Cardiology

1998

DOI: 10.1007/978-1-4615-5743-2_15

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Exploring the Difference Between Angiotensin Converting Enzyme Inhibitors and Angiotensin II-Receptor Antagonists. A Focus on Bradykinin

Colin C. Barnes

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2001

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“…3 ACE inhibitors increase the short half-life of BK because ACE is a nonspecific kininase that degrades BK in addition to cleaving the Ang I decapeptide. 20 This suggests that ACE inhibitors and ARBs may potentiate each other in increasing BK levels through independent pharmacological mechanisms. To test this hypothesis, we devised experiments in conscious rats during sodium restriction (a condition known to activate the RAS) to quantify the individual or combined effects of AT 1 receptor blockade with valsartan, ACE inhibition with benazeprilate, and specific AT 2 receptor blockade with PD 123,319 on RIF BK and cGMP.…”

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Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP

et al. 2001

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Abstract-Angiotensin (Ang) receptor blockers (ARBs) increase bradykinin (BK) by antagonizing Ang II at its type 1 (AT 1 ) receptors and diverting Ang II to its counterregulatory type 2 (AT 2 ) receptors. Because the effect of ARBs on BK is constrained by the short half-life of BK and because ACE inhibitors block the degradation of BK, this study was designed to test the hypothesis that an ACE inhibitor can potentiate ARB-induced increases in renal interstitial fluid (RIF) BK levels. We used a microdialysis technique to recover BK and cGMP in vivo from the RIF of sodium-depleted, conscious Sprague-Dawley rats infused for 60 minutes with the AT 1 receptor blocker valsartan (0.17 mg/kg per minute), with the active metabolite of the ACE inhibitor benazepril (benazeprilate, 0.05 mg/kg per minute), or with the specific AT 2 receptor blocker PD 123,319 (50 g/kg per minute) alone or combined. Each animal served as its own control. RIF BK and cGMP levels increased significantly over 1 hour in response to valsartan, benazeprilate, or both but not to a vehicle control (PϽ0.01). The combined benazeprilate-valsartan effect was greater than the sum of their individual effects, suggesting potentiation rather than addition, and was abolished by PD 123,319. We demonstrate for the first time that an ACE inhibitor (benazepril) and an ARB (valsartan) potentiate each other, and we postulate that such combinations may be beneficial in clinical states marked by Ang II elevation, such as chronic heart failure, postinfarction left ventricular dysfunction, and hypertension. Key Words: angiotensin-converting enzyme inhibitors Ⅲ receptors, angiotensin II Ⅲ bradykinin Ⅲ rats Ⅲ cyclic GMP T he renin-angiotensin system (RAS) exerts paracrine and autocrine effects on the heart, vasculature, adrenal glands, kidneys, and brain in addition to its endocrine role in maintaining systemic perfusion and renal function. 1 Prolonged RAS activation in conjunction with other growth promoters may contribute to cardiovascular hypertrophy and hyperplasia. Angiotensin (Ang) II, the principal effector of the RAS, produces both physiological and detrimental effects via its ubiquitously distributed type 1 (AT 1 ) receptors. 2 Although the functions of the less expressed type 2 (AT 2 ) receptors have not been fully elucidated, initial studies have suggested that these receptors mediate counterregulatory homeostatic effects (eg, vasodilation, inhibition of cell proliferation, increased apoptosis, and differentiation) in a yinyang relationship with the AT 1 receptors. 3,4 Studies from our laboratory have indicated that AT 2 receptor stimulation is associated with increased bradykinin (BK), 5 NO,6,7 and cGMP levels in renal interstitial fluid (RIF). 8 BK is a vasoactive peptide hormone that serves as an intermediate in a cascade mediated by AT 2 receptors in opposition to actions initiated at AT 1 receptors. 7 Intrarenal generation of BK modulates NO production, 9 which in turn leads to the activation of cGMP, 10 the final link in the biochemical cascade set in moti...

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Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP

et al. 2001

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Exploring the Difference Between Angiotensin Converting Enzyme Inhibitors and Angiotensin II-Receptor Antagonists. A Focus on Bradykinin

Cited by 1 publication

References 33 publications

Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP

Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP

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