Corcoran Lecture. Angiotensin-converting enzyme inhibition and the heart.

Gavras, Haralambos

doi:10.1161/01.hyp.23.6.813

Cited by 49 publications

(26 citation statements)

References 98 publications

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“…Even if these findings are verified in other populations, they would not indicate whether excess ACE is a causative factor or merely a marker of coronary risk, and, if causative, whether its effects are due to abundant formation of angiotensin II or to excessive degradation of bradykinin. 52 These data illustrate the problems with attributing a causal role to genetic variants identified via statistical analysis of affected versus normal populations. Various strategies are employed to further dissect these findings.…”

Section: Molecular Genetics Of Essential Hypertensionmentioning

confidence: 94%

Genetic epidemiology of essential hypertension

1999

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This review article is intended to introduce the uninitiated clinician to the basic concepts, aims and early findings of the genetic epidemiology of hypertension. It separates the rare monogenic 'Mendelian' hypertensive disorders from the vast majority of patients with essential hypertension, which is a complex, polygenic, multifactorial disorder resulting from interaction of several genes with each other and with the environment. Hypertensive phenotypesEssential hypertension results from the interaction of hereditary and environmental factors and is one of the leading causes of premature cardiovascular morbidity and mortality. Blood pressure levels are highly correlated among family members, a fact attributable to either common genetic background or shared environment and lifestyle habits, or both. Studies of familial aggregation and rates of concordance among monozygotic and dizygotic twins suggest that genes may contribute as much as 40% of the risk to this disorder.1 High blood pressure, defined as systolic pressure у140 mm Hg and diastolic у90 mm Hg, is characterised by a high but variable prevalence rate of 15-25% among populations.2 But blood pressure does not have a bimodal distribution into normal and abnormal groups. Rather, it is a quantitative trait with wide phenotypic variation and a continuous distribution, where an arbitrary cutoff line at some point of the Gaussian curve separates normal from abnormal. This indicates that hypertension is a complex trait, ie, a phenotype that does not follow the classic Mendelian rules of dominant or recessive inheritance attributable to a single gene locus.3 More likely, it is a polygenic and multifactorial disorder, in which

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Section: Molecular Genetics Of Essential Hypertensionmentioning

confidence: 94%

Genetic epidemiology of essential hypertension

1999

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“…2 The role of BK in cardiovascular regulation under physiological and pathological conditions attracted the interest of clinicians with the advent of angiotensinconverting enzyme (ACE) inhibitors, which in the last two decades have become standard therapy for hypertension, ischemic heart disease and heart failure. 3 In recent years the work of many investigators has produced a lot of new information regarding the role of kinins in the pathophysiology of hypertension and the prevention of its end-organ complications. …”

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Cardioprotective properties of bradykinin: role of the B2 receptor

et al. 2010

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Following the introduction of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension and ischemic heart disease, there has been increasing interest in the bradykinin-mediated aspects of ACE inhibition. Several preclinical and clinical studies have been conducted using genetically engineered animals or pharmacological agonists and antagonists of the two receptors of bradykinin, B 1 R and B 2 R. The results have mostly indicated that the B 1 R, whose expression is induced by tissue damage, seem to have mostly noxious effects, whereas the constitutively expressed B 2 R, when activated, exert mostly beneficial actions. Accumulating evidence in the recent literature suggests that the B 2 R have an important role in the process of ischemic post-conditioning that limits the ischemia/reperfusion injury of the myocardium. In this article, we describe a series of experiments conducted on mice submitted to acute myocardial infarct and treated either with ACE inhibition (which produces potentiation of bradykinin resulting in non-selective B 1 R and B 2 R activation) or with a potent and highly selective B 2 R agonist. These data suggest that this latter pharmacological approach offers functional and structural benefits and is therefore a promising cardioprotective therapeutic modality against acute ischemic events. INTRODUCTIONThe possible role of bradykinin (BK) in cardiovascular regulation has intrigued scientists for many years. A member of the kinin system discovered in the late 1920s, BK is a nonapeptide whose existence was first recognized by Roha e Silva et al. 1 from its effects on intestinal smooth muscle. Since then, several other actions of BK were described, including vascular contraction and relaxation, participation in the process of inflammatory reactions, interaction with central and peripheral neural structures, stimulation of synthesis and release of various vasoactive substances, enhanced insulin-dependent glucose transport and utilization, etc.Circulatory homeostasis is the result of a constant equilibrium between vasoconstrictors (e.g., pressor neurohormonal factors like angiotensin II, catecholamines, vasopressin, endothelin) and vasodilators (like kinins, prostaglandins, NO, etc.). Bradykinin, a tissue hormone that regulates the regional blood flows of vital organs, is an important member of the latter group. 2 The role of BK in cardiovascular regulation under physiological and pathological conditions attracted the interest of clinicians with the advent of angiotensinconverting enzyme (ACE) inhibitors, which in the last two decades have become standard therapy for hypertension, ischemic heart disease and heart failure. 3 In recent years the work of many investigators has produced a lot of new information regarding the role of kinins in the pathophysiology of hypertension and the prevention of its end-organ complications.

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“…9 Ang I and BK are among the physiologically important substrates of Ang I-converting enzyme (kininase II; ACE); thus ACE inhibitors have dual actions in blocking hydrolysis of both peptides. [15][16][17][18] The molecular cloning and sequencing of the complementary DNA for human and animal ACE revealed that ACE (somatic ACE) has two homologous domains, 19 -21 each containing an active center. According to their position in the N-terminal half or in the C-terminal half of the single chain protein, they are designated N-or C-domain, which will be referred to here as N-ACE and C-ACE.…”

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N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

et al. 1998

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Abstract-We used the isolated N-and C-domains of the angiotensin I-converting enzyme (N-ACE and C-ACE; ACE; kininase II) to investigate the hydrolysis of the active 1-7 derivative of angiotensin (Ang) II and inhibition by 5-S-5-benzamido-4-oxo-6-phenylhexanoyl-L-proline (keto-ACE). Ang-(1-7) is both a substrate and an inhibitor; it is cleaved by N-ACE at approximately one half the rate of bradykinin but negligibly by C-ACE. It inhibits C-ACE, however, at an order of magnitude lower concentration than N-ACE; the IC 50 of C-ACE with 100 mol/L Ang I substrate was 1.2 mol/L and the K i was 0.13. While searching for a specific inhibitor of a single active site of ACE, we found that keto-ACE inhibited bradykinin and Ang I hydrolysis by C-ACE in approximately a 38-to 47-times lower concentration than by N-ACE; IC 50 values with C-ACE were 0.5 and 0.04 mol/L. Furthermore, we investigated how Ang-(1-7) acts via bradykinin and the involvement of its B 2 receptor. Ang-(1-7) was ineffective directly on the human bradykinin B 2 receptor transfected and expressed in Chinese hamster ovary cells. However, Ang-(1-7) potentiated arachidonic acid release by an ACE-resistant bradykinin analogue (1 mol/L), acting on the B 2 receptor when the cells were cotransfected with cDNAs of both B 2 receptor and ACE and the proteins were expressed on the plasma membrane of Chinese hamster ovary cells. Thus like other ACE inhibitors, Ang-(1-7) can potentiate the actions of a ligand of the B 2 receptor indirectly by binding to the active site of ACE and independent of blocking ligand hydrolysis. This potentiation of kinins at the receptor level can explain some of the well-documented kininlike actions of Ang-(1-7).(Hypertension. 1998;31:912-917.)

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Corcoran Lecture. Angiotensin-converting enzyme inhibition and the heart.

Cited by 49 publications

References 98 publications

Genetic epidemiology of essential hypertension

Genetic epidemiology of essential hypertension

Cardioprotective properties of bradykinin: role of the B2 receptor

N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

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