Elevation of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors (original) (raw)
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Background: The commercially available synthetic angiotensin-I-converting enzyme (ACE) inhibitors are known to exert negative side effects which have driven many research groups globally to discover the novel ACE inhibitors. Method: Literature search was performed within the PubMed, ScienceDirect.com and Google Scholar. Results: The presence of proline at the C-terminal tripeptide of ACE inhibitor can competitively inhibit the ACE activity. The effects of other amino acids are less studied leading to difficulties in predicting potent peptide sequences. The broad specificity of the enzyme may be due to the dual active sites observed on the somatic ACE. The inhibitors may not necessarily competitively inhibit the enzyme which explains why some reported inhibitors do not have the common ACE inhibitor characteristics. Finally, the in vivo assay has to be carried out before the peptides as the antihypertensive agents can be claimed. The peptides must be absorbed into circulation without being degraded, which will affect their bioavailability and potency. Thus, peptides with strong in vitro IC50 values do not necessarily have the same effect in vivo and vice versa. Conclusion: The relationship between peptide amino acid sequence and inhibitory activity, in vivo studies of the active peptides and bioavailability must be studied before the peptides as antihypertensive agents can be claimed.
African journal of traditional, complementary, and alternative medicines : AJTCAM, 2017
The commercially available synthetic angiotensin-I-converting enzyme (ACE) inhibitors are known to exert negative side effects which have driven many research groups globally to discover the novel ACE inhibitors. Literature search was performed within the PubMed, ScienceDirect.com and Google Scholar. The presence of proline at the C-terminal tripeptide of ACE inhibitor can competitively inhibit the ACE activity. The effects of other amino acids are less studied leading to difficulties in predicting potent peptide sequences. The broad specificity of the enzyme may be due to the dual active sites observed on the somatic ACE. The inhibitors may not necessarily competitively inhibit the enzyme which explains why some reported inhibitors do not have the common ACE inhibitor characteristics. Finally, the in vivo assay has to be carried out before the peptides as the antihypertensive agents can be claimed. The peptides must be absorbed into circulation without being degraded, which will af...
The renin-angiotensin system and its blockers
Srpski arhiv za celokupno lekarstvo, 2014
Research on the renin-angiotensin system (RAS) has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE) metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS) and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well.
Hypertension, 2001
N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits not only hematopoietic cell proliferation but also fibroblast proliferation and collagen synthesis in vitro. Ac-SDKP also prevents collagen deposition and cell proliferation in the left ventricle (LV) in rats with renovascular hypertension (renin dependent). However, it is not clear whether Ac-SDKP has similar effects in a model of renin-independent hypertension (aldosterone-salt). Using a hypertensive rat model of cardiac and renal fibrosis created by chronic elevation of circulating aldosterone (ALDO) levels, we examined the effect of Ac-SDKP on blood pressure, cardiac and renal fibrosis and hypertrophy, and proliferating cell nuclear antigen (PCNA) expression in the LV and left kidney. Uninephrectomized rats were divided into 4 groups: (1) controls that received tap water, (2) rats that received ALDO (0.75 g/h SC) and 1% NaCl/0.2% KCl in drinking water (ALDO-salt), (3) rats that received ALDO-salt plus Ac-SDKP 400 g · kg Ϫ1 · day Ϫ1 SC, and (4) rats that received ALDO-salt plus Ac-SDKP 800 g · kg Ϫ1 · d Ϫ1 SC. After 6 weeks of treatment, the ALDO-salt group was found to have significantly increased blood pressure with decreased body weight and plasma renin concentration (PϽ0.05), LV and renal hypertrophy as well as renal injury, significantly increased collagen content in both ventricles and kidney as well as increased collagen volume fraction in the LV (PϽ0.0001), and significantly increased interstitial and perivascular PCNA-positive cells in the LV and kidney (PϽ0.0001). Ac-SDKP at 800 g · kg Ϫ1 · d Ϫ1 markedly prevented cardiac and renal fibrosis (PϽ0.005) without affecting blood pressure or organ hypertrophy. It also suppressed PCNA expression in the LV and kidney in a dose-dependent manner. We concluded that Ac-SDKP prevents increased collagen deposition and cell proliferation in the heart and kidney in ALDO-salt hypertensive rats. Because ACE inhibitors increase plasma and tissue Ac-SDKP and decrease cardiac and renal fibrosis, we speculate that Ac-SDKP may participate in the antifibrotic effect of ACE inhibitors. (Hypertension. 2001;37[part 2]:794-800.)
Pharmacological properties of angiotensin II antagonists: examining all the therapeutic implications
Journal of the renin-angiotensin-aldosterone system : JRAAS, 2001
Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), exerts a variety of actions in physiological blood pressure and body fluid regulation, and is implicated as a major pathogenic factor in the development of cardiovascular disease. Inhibition of the RAS, via treatment with the angiotensin-converting enzyme inhibitors (ACE-I), or more recently the Ang II AT 1-receptor blockers (ARBs), has been used as a therapeutic approach to the treatment of hypertension and other cardiovascular dysfunction. Evidence from animal and clinical studies shows that the antihypertensive and overall organ-protective actions of the ARBs are similar to those of ACE-I. However, as the ARBs selectively block the AT 1-receptor, which is responsible for the known cardiovascular actions of Ang II, leave the AT 2-receptor unopposed and do not interfere with the breakdown of bradykinin, there is the potential for beneficial effects in hypertensive patients with cardiovascular diseases such as left ventricular hypertrophy. Furthermore, there may be additional benefits when the ARBs are combined with ACE-I in such patients. Animal studies contribute to the elucidation and understanding of the role of AT 1-and AT 2-receptors in the cardiovascular system, and may help in the design of clinical studies aimed at investigating the effects of ACE-I, ARBs, and their combination, on cardiovascular outcomes in hypertensive patients.
Rethinking the renin-angiotensin system and its role in cardiovascular regulation
Cardiovascular Drugs and Therapy, 2005
Angiotensin-converting enzyme (ACE) plays a pivotal role in the renin-angiotensin system (RAS) and ACE-inhibitors are widely used in several clinical conditions, including hypertension and heart failure. Recently, a homologue of ACE, ACE 2 has been discovered. Both ACE and ACE 2 are emerging as key enzymes of the RAS, where ACE 2 may play a role as negative regulator of ACE. Moreover, ACE 2 appears to be an important enzyme outside the classical RAS, as it hydrolyzes apelins, dynorphin A 1-13, des-Arg-bradykinin and other peptide substrates. The precise interplay between tissue ACE, ACE 2 , and their substrates and by-products are presently still unclear.
Beyond ACE inhibition: new developments in drug therapy for hypertension
Medical Journal of Australia, 1995
The growing list of vasoactive substances known to be involved in blood pressure control provides new targets for antihypertensive drugs. Currently under development are alternative strategies for blockade of the renin-angiotensin system (e.g., renin inhibition and angiotensin /I receptor antagonism) that may have fewer side effects than angiotensin-converting-enzyme inhibition, and antagonists to other vasocontrictor peptides, such as endothelin and vasopressin. Novel strategies to enhance the effects of endogenous vasodilators, such as natriuretic peptides and nitric oxide, are also being explored.