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

Cardiac myocytes express two types of nitric oxide (NO) synthase, eNOS and iNOS. eNOS activity is regulated by the contractile state of the heart, while iNOS expression is induced by cytokines. Nitric oxide induced by cytokines causes negative inotropic and lethal effects on cardiac myocytes. Expression of iNOS in the myocardium is increased in patients with dilated cardiomyopathy with clinical evidence of heart failure. Several neurohumoral factors activated in chronic heart failure augment cardiac iNOS expression and could cause cardiac dysfunction and cell damage.
 ...
PMID:Nitric oxide and cardiac failure. 937 19

Cardiac hypertrophy and heart failure are frequently accompanied by elevated plasma levels of tumor necrosis factor alpha (TNF alpha), the pathogenetic relevance of this finding being a matter of debate. In human acute septic cardiomyopathy, on the other hand, the negative inotropic impact of TNF alpha on the heart is well documented and frequently ascribed to the induction of inducible nitric oxide (NO) synthase (iNOS) and an enhanced production of NO in the heart. Yet the present study presents evidence that in cardiomyocytes TNF alpha in non-toxic concentrations specifically depresses contractile performance independent of NO. In spontaneously beating neonatal rat cardiomyocytes, TNF alpha in a low, pathophysiologically relevant concentration (10 U/ml, 1-3 days) does not alter basal pulsation amplitude, but blocks alpha- and beta-adrenoceptor-stimulated increase in contractility and beating irregularity and impairs the impact of high extracellular calcium on contractile performance. However, this low TNF alpha-concentration does not suffice to induce iNOS - documented by reverse transcriptase polymerase chain reaction - or enhance nitrite concentrations in the cell culture supernatants as a measure of cellular NO production, neither in the presence nor absence of dexamethasone (0.1 micro M). Only in high concentration - the specific proinflammatory action being documented by an enhanced release of interleukin-6 from cardiomyocytes - TNF alpha (1000 U/mol; 6, 24 h) weakly induces the mRNA for iNOS, with a consecutive moderate rise in cellular nitrite production. TNF alpha-incubation (10-1000 U/ml) does not alter the morphological appearance of the cells displayed by phase contrast microscopy or evoke gross cytotoxicity.
 ...
PMID:Tumor necrosis factor alpha (TNF alpha) is cardiodepressant in pathophysiologically relevant concentrations without inducing inducible nitric oxide-(NO)-synthase (iNOS) or triggering serious cytotoxicity. 940 66

Myocardial remodeling is a central feature in the progression of myocardial failure. This process, which can be stimulated by factors that are increased as a result of myocardial dysfunction such as mechanical stress, angiotensin, and norepinephrine, consists of a variety of molecular and cellular events that can lead to important changes in myocardial structure and function (or phenotype). These alterations include hypertrophy and cellular apoptosis of myocytes, changes in the molecular phenotype of the myocardium with reinduction of a fetal gene program, and alterations in the quantity and composition of the extracellular matrix. Agents that counteract these factors, such as vasodilators, angiotensin-converting enzyme inhibitors, and beta-adrenergic antagonists, slow the progression of myocardial failure and are of clinical value in the treatment of heart failure. Several additional mechanisms have recently been identified that could also be important in mediating myocardial remodeling. These include oxidative stress, inflammatory cytokines, nitric oxide, endothelin, and peptide growth factors. It is likely that additional strategies to inhibit these mechanisms will exert beneficial effects on the process of myocardial remodeling and the development of clinical heart failure.
 ...
PMID:Molecular and cellular mechanisms of myocardial failure. 941 39

The extra-adrenal sodium-retaining factor was first described in Circulation Research in 1964. This factor increases the responsiveness of the renal tubules to aldosterone in heart failure, and marked sodium retention occurs with resultant edema or ascites. Evidence for the extra-adrenal sodium-retaining factor is presented in two models of experimental heart failure in dogs and in dogs with thoracic caval constriction and a low cardiac output. Since the nature of this sodium-retaining factor remains unknown, several of the recently discovered factors that influence kidney function and that might alter the responsiveness of the renal tubules to a mineralocorticoid are described. These factors include atrial natriuretic peptide, nitric oxide, 11 beta-hydroxysteroid dehydrogenase activity, the endothelins, and the intrarenal tissue renin-angiotensin system. It is suggested that the nature and action of the sodium-retaining factor be reinvestigated in lieu of the new knowledge of kidney function. The applicability of newly developed experimental models of heart failure for study of the extra-adrenal factor is discussed; these include coronary artery ligation in rats, cardiac pacing in the dog, and application of transmyocardial direct current shock to local myocardial areas in dogs.
 ...
PMID:An extra-adrenal sodium-retaining factor in congestive heart failure. 942 Jun 48

The endothelin peptide family consists of the 21 amino acid isoforms endothelin-1, endothelin-2, endothelin-3, and sarafotoxin (a snake venom). Endothelin-1 has been isolated from the supernatant of endothelial cells and has subsequently been shown to be the most potent vasoconstrictor known to date and to be positively inotropic. This review summarizes some of the current literature pertaining to circulatory and myocardial effects of endothelins. Exogenously administered endothelin-1 has been demonstrated to increase peripheral resistance and blood pressure in a dose-dependent manner. However, during the first minutes of intravenous administration endothelins also decrease peripheral resistance and blood pressure, presumably due to the release of vasodilatory compounds such as nitric oxide, prostacyclin, and atrial natriuretic peptide. Endothelins appear to be involved in the pathogenesis of salt-dependent and renovascular animal models of experimental hypertension. Although endothelins appear to contribute to basal vascular tone, the role of endothelins in the pathophysiology of human hypertension remains unclear. In addition, a role has been suggested for endothelins in specific vascular lesions and inflammatory conditions (e.g., restenosis after coronary angioplasty, atherosclerotic coronary lesions, acute myocardial infarction, and vasculitis, glomerulonephritis). Endothelins are positively inotropic peptides in cardiac myocyte and papillary muscle preparations. They have also been demonstrated to induce hypertrophy of cardiac myocyte and may play an important role in ventricular processes that lead to chronic cardiac failure. The pathophysiological relevance of the endothelin system in human disease states is elucidated using selective (ET[A]) and nonselective (ET[A/B]) inhibitors of the endothelin receptors.
 ...
PMID:Circulatory and myocardial effects of endothelin. 942 21

The endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium-derived relaxing factors (EDRFs) under basal conditions. In addition, the endothelium can increase the release of EDRFs in response to humoral stimulation by vasoactive substances such as acetylcholine or bradykinin. Under physiological conditions, the most important stimulus to the release of EDRFs is an increase in blood flow leading to increased shear stress on endothelial cells. Recent experimental studies raised the possibility that bradykinin plays an important role in the regulation of vascular tone at rest and during flow-stimulated conditions. Bradykinin is a very potent vasodilator that exerts its vasodilatory actions by causing endothelial release of nitric oxide, prostacyclin and/or a hyperpolarising factor [endothelium-derived hyperpolarising factor (EDHF)]. This concept is also supported by recent studies in humans demonstrating that bradykinin contributes to the regulation of coronary vascular tone under resting and flow-stimulated conditions. This mechanism has now been shown to be important in both human peripheral and coronary arteries. Angiotensin converting enzyme (ACE) inhibitors not only reduce angiotensin II, but also increase bradykinin levels, since the angiotensin converting enzyme is identical to kininase II, an enzyme that degrades bradykinin. This raises the possibility that beneficial vascular effects of ACE inhibitors may be related to increased availability of bradykinin. Indeed, we have recently shown that ACE inhibition improves flow-dependent, endothelium-mediated vasodilation and that this beneficial effect of ACE inhibition is bradykinin dependent. These findings raise the possibility that the beneficial effects of ACE inhibition in heart failure and coronary artery disease might be partly due to improved endothelial function.
 ...
PMID:Endothelial function and bradykinin in humans. 942 44

The endothelins (ET) are a family of contractile peptides made up of 21 amino acids. They are synthesised from larger precursors and they are expressed in different tissues. ET-1 is synthesised in endothelial cells by means of a specific endothelin converting enzyme and it is assumed that most of it is secreted into the basolateral compartment. It acts in a paracrine manner on the ETA and ETB2 receptors located on the surface of the vascular smooth muscle to elicit an increase in intracellular calcium and vasoconstriction. The circulating ET-1 can also activate endothelial ETC and ETB1 receptors releasing vascular smooth muscle relaxing factors, such as nitric oxide and prostacyclin. At present, it is generally accepted that ET-1 is a vasodilator in physiological conditions acting on endothelium ETB1 receptors. Nevertheless, in pathological situations such as hypertension, heart failure, acute myocardial infarction, acute renal failure and vasospastic conditions (Raynaud's disease and subarachnoid haemorrhage), ET-1 levels increase and it binds to the receptors present in vascular smooth muscle in such a way that its vasoconstrictor effect is manifested. Currently, experimental and clinical evidence exists to support the importance of the development of drugs that block the production or actions of ET for use in cardiovascular medicine, particularly in conditions in which these peptides are clearly implicated.
 ...
PMID:Highlights on endothelins: a review. 944 24

The goal of this study was to understand the mechanisms behind the changes in plasma NOx during heart failure. Heart failure is associated with an increase in plasma nitrate levels, and yet most experimental evidence demonstrates a reduction in endothelial nitric oxide production during heart failure. Dogs were chronically instrumented for measurement of systemic hemodynamics and left ventricular (LV) dimensions. Hearts were paced at 210 bpm for 3 weeks (n = 14) and then 240 bpm for 1 week (n = 7). Hemodynamics, arterial blood gases, plasma NOx, and creatinine levels were monitored weekly. Heart failure was evidenced by cachexia, ascites, and hemodynamic alterations. Resting heart rate rose (94 +/- 6 to 135 +/- 9 bpm), and LV dP/dt fell (2810 +/- 82 to 1471 +/- 99 mm Hg/s), while LV end diastolic pressure quadrupled (5.8 +/- 0.7 to 25 +/- 0.8 mm Hg), and diastolic wall stress quadrupled (11 +/- 1.3 to 43 +/- 6.0 g/cm2, all P < 0.05). These changes occurred during a doubling in plasma NOx (5.5 +/- 1.5 to 10 +/- 1.6 microM, P < 0.05). There were no changes in plasma NOx through 3 weeks of pacing. Plasma creatinine levels increased 450% (from 0.27 +/- 0.32 to 1.21 +/- 0.63 mg%). Stimulated nitrite production by agonists in sieved coronary microvessels was unchanged after 3 weeks of pacing but was reduced after heart failure. Plasma NOx did not correlate with LV dP/dt or systolic wall stress but correlated directly with LV EDP or diastolic wall stress and inversely with cardiac work. Plasma NOx rose in direct relation to plasma creatinine levels (Y = 4.8X + 2.8, r2 = 0.84), suggesting that the rise in plasma NOx during heart failure is due to decreased renal function not increased NO production.
 ...
PMID:Mechanisms of nitrate accumulation in plasma during pacing-induced heart failure in conscious dogs. 944 9

Since the classical studies by Furchgott and Zawadski (Nature, 1980, 286, 373-376), the vascular endothelium is known to play a fundamental role in the regulation of haemostasis and vasomotor activity. This is primarily due to its strategic interface position between the circulating blood and smooth muscle cells of the media. Due to the presence of specific receptors to mediators released during platelet aggregation (thrombin, ATP, serotonin, PAF, etc.), and the presence of mechanoreceptors sensitive to shearing forces generated by blood flow along the vessel wall, the endothelium is able to release, at the two poles of the cell, vasodilator and antiaggregant substances called "endothelium derived relaxing factors" (EDRFs), the best known for which are nitric oxide (NO) ans prostacyclin (PGl2). In the absence of endothelium (angioplasty), or in the case of endothelium dysfunction related to cardiovascular diseases such as hypertension, heart failure, atherosclerosis or diabetes, EDRF synthesis is absent or defective and its oxidative catabolism in increased (particularity by superoxide anion), resulting in varying degrees of disorders of haemostasis (thrombosis) and/or arterial and venous vasomotor activity. The only known effective treatment to palliate these dysfunctions is exogenous NO, supplied in the form of nitrate (nitroglycerin, isosorbide dinitrate, 5-mononitrate) or "NO donors" (Sin1, nitroprussate). The advantage of these substances is that their vasodilator effects (and, in some cases, their antiaggregant effects) are strictly endothelium-independent and they remain effective regardless of the causes and severity of endothelial dysfunction.
 ...
PMID:[Nitrates and coronary vascular endothelium dysfunction]. 945 72

Hypertension is accompanied by architectural changes in the kidney, heart, and vessels that are often maladaptive and can eventually contribute to end-organ disease such as renal failure, heart failure, and coronary disease. Nitric oxide, an endogenous vasodilator and antithrombotic agent synthesized in the endothelium by a constitutive nitric oxide synthase, inhibits growth-related responses to injury in vascular cells. Specifically, in the presence of hypertension, nitric oxide may work in the kidney by inhibiting both mesangial cell hypertrophy and hyperplasia as well as synthesis of extracellular matrix and in the heart and systemic vessels by modulating smooth muscle cell hypertrophy and hyperplasia. The effects of nitric oxide are antagonistic of the effects of angiotensin II. Shear stress and cyclic strain, physical forces known to operate in hypertension, are accompanied by increases in endothelial nitric oxide synthase expression, nitric oxide synthase protein, and nitric oxide synthase activity in endothelial cells. Experimental studies using genetic models of hypertension show a variation in hypertension-modulated vascular nitric oxide synthase activity in different strains of rats. These studies suggest that upregulation of vascular nitric oxide synthase activity is a homeostatic adaptation to increased hemodynamic workload in hypertension and that this may help prevent end-organ damage. If these findings apply to humans, differences in end-organ disease seen in patients with similar degrees of hypertension may be due in part to genetic differences in vascular nitric oxide synthase activity in response to hypertension.
 ...
PMID:Nitric oxide in hypertension: relationship with renal injury and left ventricular hypertrophy. 945 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>