Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systolic hypertension is a major risk factor for cardiovascular disease. The determinants of systolic blood pressure are peripheral resistance and arterial compliance. Arterial vasoconstriction, vascular growth and fluid retention, induced by the renin-angiotensin system directly or indirectly by enhancing sympathetic nervous system activity, are important factors in increasing peripheral resistance, decreasing arterial compliance and, consequently, elevating systolic blood pressure. Selective blockade of the angiotensin II type 1 (AT1) receptor represents a novel mechanism for interrupting the renin-angiotensin system. This provides the additional benefit of blocking angiotensin II generated by non-angiotensin-converting-enzyme pathways without altering either bradykinin metabolism or the potential beneficial effects of AT2 receptor stimulation. Eprosartan is a potent (1.4 nmol/l) AT1 receptor antagonist that inhibits angiotensin-II-induced vascular contraction in a competitive manner. Eprosartan is effective in reducing disease progression in animal models of hypertension, heart failure, renal disease and stroke. Furthermore, eprosartan causes a large increase in arterial compliance in hypertensive rats fed high-salt and high-fat diets. Eprosartan also possesses sympathoinhibitory activity as demonstrated by an inhibition of the pressor responses induced by activation of sympathetic outflow through spinal cord stimulation in pithed rats. In contrast, other angiotensin II receptor antagonists, such as losartan, used at equivalent angiotensin II blocking activity, do not appear to alter sympathetic nervous system activity. Angiotensin II receptor antagonists, such as eprosartan, that have the ability to block both the direct effects of angiotensin II and the indirect effects mediated by enhanced sympathetic neurotransmission, may represent an important advance in the treatment of elevated systolic blood pressure.
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PMID:Pharmacological mechanism of angiotensin II receptor antagonists: implications for the treatment of elevated systolic blood pressure. 1046 64

Recently, we found that amlodipine can release nitric oxide (NO) from canine coronary microvessels, which raises the question of whether amlodipine can also promote coronary NO production in failing human hearts. The goal of this study was to define the effect of amlodipine on NO production in failing human hearts and to determine the role of kinins in the control of NO production induced by amlodipine. Six explanted human hearts with end-stage heart failure were obtained immediately at transplant surgery. Coronary microvessels were isolated as previously described, and nitrite, the stable metabolite of NO in aqueous solution, was measured using the Griess Reaction. Amlodipine (10(-10) to 10(-5) mol/L) significantly increased nitrite production in coronary microvessels in a dose-dependent manner. The increase in nitrite in response to the highest dose of amlodipine (79%) was similar in magnitude to either that of the angiotensin-converting enzyme inhibitor ramiprilat (74%) or the neutral endopeptidase inhibitors phosphoramidon (61%) and thiorphan (72%). Interestingly, the increase in nitrite production induced by amlodipine was entirely abolished by N(omega)-nitro-L-arginine methyl ester and also HOE-140 (a bradykinin-2 antagonist) and dichloroisocoumarin (a serine protease inhibitor that blocks kallikrein activity). These results indicate that amlodipine can promote coronary NO production in failing human hearts and that this effect is dependent on a kinin-mediated mechanism.
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PMID:Amlodipine promotes kinin-mediated nitric oxide production in coronary microvessels of failing human hearts. 1048 Apr 43

Angiotensin-(1-7) is a product of angiotensin processing that has been proposed to have vasodepressor effects, both on its own and in combination with bradykinin, which may be pathophysiologically and therapeutically important. Despite this, there has been very little examination of its effects in humans and none in heart failure patients or in other patients treated with ACE inhibitors. We therefore sought to determine the effects of angiotensin-(1-7) in patients with heart failure treated with an ACE inhibitor, as well as any interaction with the effects of bradykinin. A locally active dose of angiotensin-(1-7), alone and in combination with bradykinin, was infused into the nondominant brachial artery while forearm blood flow was measured by venous occlusion plethysmography in 8 patients with heart failure treated with ACE inhibitors. Although bradykinin on its own caused profound vasodilation, there was no effect of angiotensin-(1 to 7) on its own or any effect of angiotensin-(1-7) on the response to bradykinin. We conclude that angiotensin-(1-7) is biologically inactive in the forearm circulation of patients with heart failure treated with an ACE inhibitor. The contrast between these findings and previously reported preclinical findings calls into question the relevance of angiotensin-(1-7) to the hemodynamic effects of ACE inhibitors.
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PMID:Effect of angiotensin-(1-7) and bradykinin in patients with heart failure treated with an ACE inhibitor. 1048 93

To determine the short-term effects of angiotensin-converting enzyme (ACE) inhibition on hemodynamics and circulating levels of norepinephrine, angiotensin, and bradykinin, responses to enalaprilat and perindoprilat were examined at doses of 0.03, 0.3, and 1 mg/kg in permanently instrumented conscious dogs with pacing-induced heart failure (right ventricular pacing, 240-250 beats/min, 3 weeks). All doses of the two inhibitors produced similar decrease in mean aortic pressure and increase in cardiac output. Neither inhibitor affected plasma norepinephrine level. Both compounds induced a similar 60-80% decrease in blood angiotensin II level, a similar two- to eightfold increase in blood angiotensin I level, and a 80-95% decrease in the angiotensin II/angiotensin I ratio. There were also a fourfold to 10-fold increase in blood bradykinin-(1-9) level, a twofold increase in blood bradykinin-(1-7) level, and a 70-85% decrease in bradykinin-(1-7)/bradykinin-(1-9) ratio. In addition, the changes in total peripheral resistance induced by the two ACE inhibitors were weakly but significantly correlated with the changes in blood angiotensin II or blood bradykinin-(1-9). Thus whatever the specificity of enalaprilat and perindoprilat, both inhibitors produced similar acute hemodynamic effects in dogs with heart failure, which was associated with marked decrease in circulating angiotensin II level and increase in bradykinin-(1-9) level. This study, which measures for the first time in heart failure the blood bradykinin level after ACE inhibitors, indicates, in concert with angiotensin II reduction, a role for increased bradykinin-(1-9) level in mediating short-term hemodynamic effects of ACE inhibition in this model of heart failure.
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PMID:Increased bradykinin levels accompany the hemodynamic response to acute inhibition of angiotensin-converting enzyme in dogs with heart failure. 1054 87

Chronic mitral regurgitation (MR) in dogs results in pulmonary congestion and increased cardiac angiotensin-converting enzyme (ACE) activity and angiotensin (ANG) II levels. ACE could contribute to altered pulmonary vasomotion in heart failure, and ACE inhibitor (ACEI) therapy may normalize pulmonary vasomotion. We evaluated pulmonary artery (PA) responses to ANG II and bradykinin (BK) in control dogs, in dogs with 4 mo of MR, in MR dogs treated with the ACEI ramipril (MR + R), and in control dogs treated with ramipril (C + R). Mean PA systolic pressure increased in MR dogs (21 +/- 4 mmHg) but was normal in MR + R dogs (13 +/- 1 mmHg). Constriction of PA rings to ANG II was depressed in MR dogs. ACEI treatment (MR + R) restored ANG II responsiveness, but peak ANG II response (3.6 +/- 0.2 g) in MR + R dogs remained lower than in C + R dogs (4.7 +/- 0.2 g). Endothelium-dependent relaxation to BK was decreased (-87 +/- 4% C, -65 +/- 4% MR; P < 0.05). Ramipril (MR + R) restored relaxation to BK. This demonstrates that pulmonary congestion results in impaired pulmonary vasomotion to ANG II and BK, which ACEIs could normalize, supporting the use of ACEIs in clinical management of chronic congestive heart failure.
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PMID:ACE inhibitors in HF restore canine pulmonary endothelial function and ANG II vasoconstriction. 1056 48

Angiotensin II plays a significant role in cell growth and proliferation in model systems and in humans. In addition, angiotensin II appears to facilitate sympathetic activation and the release of endothelin-1, and also to promote apoptosis. The use of angiotensin-converting enzyme (ACE) inhibitors has provided beneficial effects on left ventricular hypertrophy (LVH) regression and on cardiac remodelling in the presence of heart failure. Data from experimental models as well as studies in humans suggest that the increase of bradykinin mediated by ACE inhibitors provides most of the beneficial effects of ACE inhibitors. The new class of angiotensin receptor blocker appears to provide cardioprotective effects that are similar to those of the ACE inhibitors. Most of the beneficial effects provided by these agents appear to be related to a more complete blockade of angiotensin II type 1 (AT1) receptor. However, costimulation of the angiotensin II type 2 (AT2) receptor appears to increase nitric oxide and thus to cause some bradykinin-like effects. Evidence for the role of angiotensin II in promoting LVH and cardiac failure as well as for abnormal regulations of the angiotensin signal transduction pathways in model systems and in humans are reviewed. Second, the mechanisms for the beneficial effects of angiotensin II modulation by ACE inhibitors versus angiotensin II antagonists studied in model systems are presented. Finally, results from pivotal phase II studies such as Evaluation of Losartan In The Elderly (ELITE), as well as an overview of the ongoing phase III trials involving the use of ARB in high risk patients are presented.
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PMID:Cardioprotective effect of angiotensin II receptor antagonists. 1057 47

ACE inhibitors are a widely prescribed class of drug for the management of hypertension. Their therapeutic role in the treatment of heart failure, diabetic nephropathy and post myocardial infarction with left ventricular dysfunction is steadily increasing. Although ACE inhibitors have a similar mechanism of action--namely, inhibition of circulatory ACE, thereby decreasing the formation of angiotensin II--individual members differ in their physicochemical properties, enzyme-binding kinetics, pharmacokinetic profile, organ-specific affinity and selectivity, as well as in their bradykinin potentiating effect. These factors play an important part in influencing the pharmacological profile of an agent and its clinical efficacy, especially in the treatment of hypertension. It is therefore prudent to take into account the existing pharmacological and clinically relevant differences between the individual members of this drug class before making the decision to select a particular ACE inhibitor for the long-term management of arterial hypertension.
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PMID:Management of hypertension and its sequelae with ACE inhibitors: biochemical, pharmacological and clinical aspects. 1062 92

Using Brown Norway Katholiek (BNK) rats, which are deficient in kininogen (kinin precursor) due to a mutation in the kininogen gene, we examined the role of endogenous kinins in 1) normal cardiac function; 2) myocardial infarction (MI) caused by coronary artery ligation; 3) cardiac remodeling in the development of heart failure (HF) after MI; and 4) the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEI) on HF after MI. Two months after MI, rats were randomly treated with vehicle or the ACEI ramipril for 2 mo. Brown Norway rats (BN), which have normal kininogen, were used as controls. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and ejection fraction (EF) as well as myocardial infarct size (IS), interstitial collagen fraction (ICF), cardiomyocyte cross-sectional area (MCA), and oxygen diffusion distance (ODD) were measured. We found that 1) cardiac hemodynamics, function, and histology were the same in sham-ligated BN and BNK rats; 2) IS was similar in BN and BNK; 3) in rats with HF treated with vehicle, the decrease in LVEF and the increase in LVEDV, LVESV, LVEDP, ICF, MCA, and ODD did not differ between BNK and BN; and 4) ACEI increased EF, decreased LVEDV and LVESV, and improved cardiac remodeling in BN-HF rats, and these effects were partially blocked by the bradykinin B(2) receptor antagonist icatibant (HOE-140). In BNK-HF rats, ACEI failed to produce these beneficial cardiac effects. We concluded that in rats, lack of kinins does not influence regulation of normal cardiac function, myocardial infarct size, or development of HF; however, kinins appear to play an important role in the cardioprotective effect of ACEI, since 1) this effect was significantly diminished in kininogen-deficient rats and 2) it was blocked by a B(2) kinin receptor antagonist in BN rats.
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PMID:Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats. 1066 82

The renin angiotensin system (RAS) is now recognized as the body's most powerful hormone system for controlling renal hemodynamics and sodium excretion and, therefore, body fluid volumes and arterial pressure. The discovery of angiotensin converting enzyme inhibitors (ACEi) was a keystone for the understanding of the significance of the RAS since ACEi proved to be effective in controlling hypertension and heart failure and in preventing the development of the vascular injury of chronic diseases like scleroderma and diabetes mellitus. The success of ACEi stimulated the research into inhibitors of other actors of the RAS like renin or angiotensin receptor antagonists. It is not often realized that the discovery of ACEi owes a great deal to basic research in which the venom of a Brazilian viper, Bothrops Jararaca, was instrumental for the discovery of bradykinin by Rocha e Silva and the bradykinin potentiating factor. This article reviews the contribution of the converting enzyme inhibitors for the demonstration of the relevance of the RAS to several human pathologies.
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PMID:Angiotensin converting enzyme: history and relevance. 1070 50

The cardiac mechano- and chemoreceptors are broadly distributed in the myocardium and coronary vessels. A portion of these receptors extends over the epicardium and pericardium and therefore can be excited by mechanical or chemical stimuli directly applied to the surface of the heart. Excitation of epicardial receptors by topical application of chemical compounds elicits a variety of reflex cardiovascular responses, without the vascular or systemic effects of the drug administered systemically. A considerable number of studies has used the epicardial sensory field as a tool to delineate the functional characteristics of the cardiac afferent neurones in normal as well as in pathological conditions. In this review we analyze the cardiovascular reflex responses induced by epicardial application of a variety of substances like bradykinin, nicotine, muscarine, isoprenaline, adenosine, potassium chloride, capsaicin, prostaglandins or substance P in physiological models and also in models with acute myocardial ischemia or heart failure. The data highlight the contribution of the epicardial sensory neurites to the overall control of the cardiovascular system and, on the other hand, strengthen the need for further investigations directed to better elucidate the reflex cardiovascular responses that may develop in patients with pericardial abnormalities.
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PMID:Cardiovascular reflex responses induced by epicardial chemoreceptor stimulation. 1072 29


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