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)

There is a wealth of data that suggests an important interaction between aspirin and angiotensin-converting enzyme inhibitors in patients with chronic stable cardiovascular disease. The interaction is less obvious in the postinfarction setting, possibly reflecting the fact that many patients stop their aspirin therapy within a few months of such an event. An interaction is biologically plausible, because there is considerable evidence that angiotensin-converting enzyme inhibitors exert important effects through increasing the production of vasodilator prostaglandins, whereas aspirin blocks their production through inhibition of cyclooxygenase, even at low doses. There is some evidence that low-dose aspirin may raise systolic and diastolic blood pressure. There is also considerable evidence that aspirin may entirely neutralize the clinical benefits of angiotensin-converting enzyme inhibitors in patients with heart failure. In addition, aspirin may have an adverse effect on outcome in patients with heart failure that is independent of any interaction with angiotensin-converting enzyme inhibitors, possibly by blocking endogenous vasodilator prostaglandin production and enhancing the vasoconstrictor potential of endothelin. The evidence is not sufficient to justify advising long-term aspirin therapy for patients with cardiovascular disease in general, and for those with heart failure in particular. Thus, the lack of evidence of benefit with aspirin in patients with heart failure and coronary disease, along with growing evidence that aspirin is directly harmful in patients with heart failure and that aspirin may negate the benefits of angiotensin-converting enzyme inhibitors suggest that, unless there is an opportunity to randomize the patient into a study of antithrombotic strategies, then aspirin should be withdrawn or possibly substituted with an anticoagulant or an antiplatelet agent that does not block cyclooxygenase. In contrast, there is fairly robust evidence for a benefit of both aspirin and angiotensin-converting enzyme inhibitors during the first 5 weeks after a myocardial infarction, with little evidence of an interaction. The combination of aspirin and angiotensin-converting enzyme inhibitors is warranted during this period, after which discontinuation or substitution of aspirin with another agent should be considered.
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PMID:Does aspirin attenuate the effect of angiotensin-converting enzyme inhibitors in hypertension or heart failure? 1149 56

Knowledge of transcription and translation has advanced our understanding of cardiac diseases. Here, we present the hypothesis that the stability of mRNA mediated by the 3'-untranslated region (3'-UTR) plays a role in changing gene expression in cardiovascular pathophysiology. Several proteins that bind to sequences in the 3'-UTR of mRNA of cardiovascular targets have been identified. The affected mRNAs include those encoding beta-adrenergic receptors, angiotensin II receptors, endothelial and inducible nitric oxide synthases, cyclooxygenase, endothelial growth factor, tissue necrosis factor (TNF-alpha), globin, elastin, proteins involved in cell cycle regulation, oncogenes, cytokines and lymphokines. We discuss: (a) the types of 3'-UTR sequences involved in mRNA stability, (b) AUF1, HuR and other proteins that bind to these sequences to either stabilize or destabilize the target mRNAs, and (c) the potential role of the 3'-UTR mediated mRNA stability in heart failure, myocardial infarction and hypertension. We hope that these concepts will aid in better understanding cardiovascular diseases and in developing new therapies.
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PMID:The role of 3'-untranslated region (3'-UTR) mediated mRNA stability in cardiovascular pathophysiology. 1169

In the adult mammalian kidney, high levels of cyclooxygenase (COX)-2 expression can be detected in the macula densa and associated cortical thick ascending limb cells and medullary interstitial cells. In the renal cortex, COX-2 expression increases in high renin states, and selective COX-2 inhibitors significantly decrease plasma renin levels. In the medullary region of the kidney, the expression of COX-2 increases in response to a high-salt diet and water deprivation. The most important prostanoids in the kidney are prostaglandin (PG)I(2), or prostacyclin, and PGE(2). PGE(2) diminishes sodium reabsorption; thereby, its inhibition results in sodium retention that can manifest clinically in a variety of ways, such as peripheral edema, increased blood pressure (mainly in treated hypertensive patients), weight gain, and occasionally deterioration of heart failure. PGI(2) increases potassium secretion. As such, its inhibition can result in hyperkalemia, particularly in patients with underlying renal insufficiency. PGI(2) is also a potent vasodilator and helps maintain renal perfusion in conditions of decreased actual or effective circulating volume; its inhibition in such patients can result in acute renal failure. A variety of studies has been conducted to examine the effects of celecoxib and rofecoxib on renal function. These incorporate various study designs directly, making it virtually impossible to compare data across studies. It is apparent from such studies, coupled with published case reports, that the impact of both celecoxib and rofecoxib on renal function (including development of edema and hypertension) is similar to that of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Studies comparing the 2 COX-2 inhibitors conflict in their interpretation. Overall, the data suggest similar effects on renal function among all NSAIDs when used at comparable doses.
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PMID:Cyclooxygenase-2 inhibition and renal physiology. 1190 56

Although the influence of the adrenergic system has been studied in the presence of heart failure, controversies still exist. Since cyclooxygenase derivatives appear to modulate coronary and cardiac adaptation in the failing heart, we hypothesized that cyclooxygenase derivatives may participate in the altered adrenergic responses in this situation. Isolated hearts from cardiomyopathic (UM-X7.1 subline) and normal hamsters, aged > 240 days, were utilized. Coronary and cardiac response to alpha1-, beta1-, and beta2-adrenergic stimulations was observed before and after pretreatment with indomethacin, a cyclooxygenase inhibitor. Reduction of coronary flow elicited by alpha1-adrenergic stimulation was unchanged in the presence of heart failure, while beta1- and beta2-induced vasodilatations were reduced. Inotropic response to alpha1 and beta1 stimulations were also reduced in failing hearts, while beta2-adrenergic action was unchanged. Pretreatment with indomethacin exacerbated coronary flow reduction observed with alpha1 stimulation in failing hearts only. Beta2-induced coronary vasodilatation and inotropic response to alpha1 and beta2 stimulations were impaired similarly in the presence of indomethacin in normal and failing hearts. The results suggest a complex interaction between adrenergic and cyclooxygenase activation.
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PMID:Altered coronary and cardiac adrenergic response in the failing hamster heart: role of cyclooxygenase derivatives. 1199 Dec 33

Prostaglandins released from blood vessels modulate vascular tone, and inhibition of their production during exogenous infusions of catecholamines causes increased venoconstriction. To determine the influence of prostaglandin production on venoconstriction during physiological stimuli known to cause sympathetic activation, and to assess its importance in chronic heart failure (CHF), we studied 11 normal subjects (62 +/- 4 yr) and 14 patients with CHF (64 +/- 2 yr, left ventricular ejection fraction 23 +/- 1%, New York Heart Association classes II and III) (means +/- SE). Dorsal hand vein distension was measured during mental arithmetic (MA), cold pressor test (CPT), and lower body negative pressure (LBNP; -10 and -40 mmHg), with saline infusion in one hand and local indomethacin (cyclooxygenase inhibitor) infusion (3 microg/min) in the other. Acetylcholine (0.01-1 nmol/min) dilated veins preconstricted with PGF(2alpha) in normals but, consistent with endothelial dysfunction, barely did so in CHF patients (P = 0.001). Nonendothelial venodilation to sodium nitroprusside (0.3-10 nmol/min) was not different between normals and CHF patients. Resting venous norepinephrine levels were higher in CHF patients (2,812 +/- 420 pmol/l) than normals (1,418 +/- 145 pmol/l, P = 0.007). In normals, indomethacin caused increased venoconstriction to MA (from 4.9 +/- 1.5 to 19.2 +/- 4.5%, P = 0.022) and CPT (from 2.9 +/- 3.8 to 17.6 +/- 4.2%, P = 0.007). In CHF, indomethacin caused increased venoconstriction to MA (from 6.6 +/- 3.9% to 19.0 +/- 4.5%, P = 0.014), CPT (from 9.6 +/- 2.1% to 20.1 +/- 3.7%, P = 0.001), and -40 mmHg LBNP (from 10.7 +/- 3.0% to 23.2 +/- 3.8%, P = 0.041). Control responses for all tests were not different between normals and CHF patients. The effects of indomethacin on venoconstriction to MA and CPT were not different between normals and CHF patients, but venoconstriction to -40 mmHg LBNP was accentuated in CHF patients (P = 0.036). Inhibition of prostaglandins by indomethacin significantly enhances hand vein constriction to physiological stimuli in both normals and CHF patients, although a differential effect exists for LBNP.
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PMID:Prostaglandin modulation of venoconstriction to physiological stress in normals and heart failure patients. 1257 11

(1) Increased vascular resistance in chronic heart failure (CHF) has been attributed to stimulated neurohumoral systems. However, local mechanisms may also importantly contribute to set arterial tone. Our aim, therefore, was to test whether pressure-induced myogenic constriction of resistance arteries in vitro--devoid of acute effects of circulating factors--is increased in CHF and to explore underlying mechanisms. (2) At 12 weeks after coronary ligation-induced myocardial infarction or SHAM-operations in rats, we studied isolated mesenteric arteries for myogenic constriction, determined as the active constriction (% of passive diameter) in response to stepwise increase in intraluminal pressure (20 - 160 mmHg), in the absence and presence of inhibitors of potentially involved modulators of myogenic constriction. (3) We found that myogenic constriction in mesenteric arteries from CHF rats was markedly increased compared to SHAM over the whole pressure range, the difference being most pronounced at 60 mmHg (24+/-2 versus 4+/-3%, respectively, P<0.001). (4) Both removal of the endothelium as well as inhibition of NO production (L-N(G)-monomethylarginine, 100 micro M) significantly increased myogenic constriction (+16 and +25%, respectively), the increase being similar in CHF- and SHAM-arteries (P=NS). Neither endothelin type A (ET(A))-receptor blockade (BQ123, 1 micro M) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin, 100 nM) affected the myogenic response in either group. (5) Interestingly, increased myogenic constriction in CHF was fully reversed after angiotensin II type I (AT(1))-receptor blockade (candesartan, 100 nM; losartan, 10 micro M), which was without effect in SHAM. In contrast, neither angiotensin-converting enzyme (ACE) inhibition (lisinopril, 1 micro M; captopril, 10 micro M) or AT(2)-receptor blockade (PD123319, 1 micro M), nor inhibition of superoxide production (superoxide dismutase, 50 U ml(-1)), TXA(2)-receptor blockade (SQ29,548, 1 micro M) or inhibition of cyclooxygenase-derived prostaglandins (indomethacin, 10 micro M) affected myogenic constriction. (6) Sensitivity of mesenteric arteries to angiotensin II (10 nM - 100 micro M) was increased (P<0.05) in CHF (pD(2) 7.1+/-0.4) compared to SHAM (pD(2) 6.2+/-0.3), while the sensitivity to KCl and phenylephrine was not different. (7) Our results demonstrate increased myogenic constriction in small mesenteric arteries of rats with CHF, potentially making it an important target for therapy in counteracting increased vascular resistance in CHF. Our results further suggest active and instantaneous participation of AT(1)-receptors in increased myogenic constriction in CHF, involving increased sensitivity of AT(1)-receptors rather than apparent ACE-mediated local angiotensin II production.
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PMID:Myogenic constriction is increased in mesenteric resistance arteries from rats with chronic heart failure: instantaneous counteraction by acute AT1 receptor blockade. 1289 Jul 11

Increased understanding of pathophysiological mechanisms of cardiovascular diseases has shown that the renin-angiotensin-aldosterone system (RAAS) is activated in this setting and suggests a central role for the angiotensin-converting enzyme (ACE). ACE transforms angiotensin I (Ang I) to angiotensin II (Ang II), and also promotes the degradation of bradykinin into inactive metabolites. These bradykinins stimulate nitric oxide synthesis and vasodilatator prostaglandin synthesis via a cyclooxygenase (COX) pathway. COX inhibitors may therefore be deleterious in cardiovascular disease and/or counteract part of ACE inhibitor (ACE-I) efficacy. This has been clearly demonstrated with non-steroidal anti-inflammatory drugs (NSAIDs), including high-dose aspirin, in hypertension, coronary artery disease and chronic heart failure (CHF); most guidelines recommend avoiding their use in such patients. Theoretically, this effect is dose-mediated and the existence of an identical deleterious effect with low-dose aspirin has been an area of intense debate. In this article, we review studies, most of them conducted in CHF, that pointed out such a possible deleterious effect and a counteraction of ACE-Is with low-dose aspirin, using various criteria of assessment. However, there are no prospective long-term studies that have validated such an effect, and the role of other anti-aggregating agents has not been evaluated. Until such studies are published, the use of low-dose aspirin (100 mg/day) in such patients can be recommended.
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PMID:Interaction between cyclooxygenase and the renin-angiotensin-aldosterone system: rationale and clinical relevance. 1460 18

Besides cyclooxygenase and NO-synthase, another distinct endothelial pathway, endothelium-dependent hyperpolarization (EDHF), is involved in the relaxation of the vascular smooth muscle cells. EDHF has been demonstrated unequivocally in various blood vessels from different species, including human, and is likely to play an important role in cardiovascular physiology. This alternative pathway involves the activation of two populations of endothelial potassium channels, the small conductance and intermediate conductance calcium-activated potassium channels (SK(Ca) and IK(Ca), respectively). EDHF-mediated responses are clearly altered in various pathological conditions (ageing, hypertension, atherosclerosis, hypercholesterolemia, heart failure, ischemia-reperfusion, angioplasty, eclampsia, diabetes, sepsis). Therapeutic or adjutant interventions (angiotensin converting enzyme inhibitors, antagonist of the angiotensin receptor, estrogen, omega-3 polyunsaturated fatty acids, polyphenol derivatives, potassium and/or calcium intake) can restore these responses, suggesting that the improvement of the EDHF pathway contributes to the observed beneficial effect of these various substances. However, the improvement or restoration of EDHF responses has not been, yet, the direct purpose of any pharmaceutical effort. Activating endothelial IK(Ca) and/or SK(Ca) or increasing their expression as well as improving myo-endothelial communication, for instance by increasing the expression of connexin(s), could become interesting therapeutic targets.
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PMID:EDHF: new therapeutic targets? 1502 34

Previous studies have shown that chronic hyperhomocysteinemia is associated with an adverse cardiac remodeling and heart failure. This study, which utilized coronary-perfused hearts and superfused papillary muscle, was designed to determine whether homocysteine acts acutely to alter cardiac contractile function. Left ventricular developed pressure was used as a measure of systolic function in the Langendorff-perfused heart, whereas isometric developed tension was used in papillary muscle. All preparations were bathed in physiological buffer and paced electrically. Initial results showed that homocysteine elicits a relatively rapid onset (maximum effect observed within 5 min), concentration-dependent (10-300 microM), and moderate negative inotropic action (maximum decrease in tension was approximately 15% of control values) in Langendorff-perfused hearts but not in papillary muscle. In contrast, effluent from homocysteine-treated hearts decreased contractility in papillary muscle, and all inotropic actions were largely eliminated when brief Triton X-100 treatment was utilized to inactivate the coronary endothelium in the intact heart. The homocysteine-induced decrease in contractile function was not antagonized by N(omega)-nitro-l-arginine, a nitric oxide synthase inhibitor, or the cyclooxygenase inhibitor indomethacin. Thus data suggest that pathophysiological concentrations of homocysteine elicit an acute negative inotropic effect on ventricular myocardium that is mediated by a coronary endothelium-derived agent other than nitric oxide or products of cyclooxygenase. Future studies are required to elucidate the mechanism by which homocysteine acts to elicit the release of the proposed endothelial mediator, the identity of the proposed paracrine agent, and the mechanism of its negative inotropic action.
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PMID:Acute negative inotropic effects of homocysteine are mediated via the endothelium. 1507 57

This review provides an overview of gender-specific differences in the incidence and development of cardiovascular diseases, including hypertension, atherosclerosis, heart failure and the corresponding myocardial remodeling. The review discusses the possible mechanisms by which estrogen affords a beneficial effect on cardiovascular function via genomic vs non genomic regulation; estrogen receptor-dependent vs estrogen receptor-independent pathways, specific signal transduction cascades, especially those involving protein kinase B (Akt) and mitogen activated protein kinase (MAPK), as well as their downstream targets, such as nitric oxide synthase, cyclooxygenase, cytochrome P450 (CYP), NADPH oxidase and superoxide dismutase. Having considered the essential role of the microcirculation in the control of vascular resistance in vivo, estrogen-related regulation of microvascular function and blood pressure is highlighted. Attention is focused on the effects of estrogen on pressure (myogenic)-dependent and flow/shear stress-dependent mechanisms of arterioles, which contribute significantly to the control of local blood flow and peripheral resistance via alterations in the release of endothelial mediators, such as nitric oxide, prostaglandins and endothelium-derived hyperpolarizing factor.
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PMID:Gender-specific regulation of cardiovascular function: estrogen as key player. 1528 95


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