UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
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In heart failure, neurohumoral factors are important determinants of left-ventricular function, not only by direct mechanisms on the myocardium, but also by indirect effects through modulation of pre- and afterload. In experimental models of heart failure, as well as in patients with cardiac dysfunction, it has been demonstrated in the early phase of the disease that the sympathetic activity and the secretion of atrial natriuretic peptide are stimulated. This is associated with an increased synthesis of vasodilator prostaglandins in the kidney, predominately prostaglandin E2. Prostaglandin E2 plays an important role by its vasodilator and natriuretic properties in preserving renal blood flow, natriuresis and diuresis. The stimulation of the secretion of atrial natriuretic peptide in relatively moderate heart failure leads to a suppression of the activation of the renin-angiotensin-aldosterone system. In more severe heart failure vasoconstrictor, sodium and water-retaining mechanisms like the renin-angiotensin-aldosterone system are activated with the consequence of an increase of systemic vascular resistance, a reduction of renal blood flow, and an increased fluid retention. The inhibition of cyclooxygenase, leading to a blockade of the synthesis of prostaglandins, leads in early heart failure to a dramatic change in renal blood flow with an increase of renal vascular resistance and a decrease of renal perfusion which causes renal functional impairment.
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PMID:[Renin, aldosterone and prostaglandins in heart failure]. 179 34

Conditions like heart failure that augment the activity of neurohumoral mechanisms i.e. the renin-angiotensin systems, sympathetic nerve activity and vasopressin secretion are commonly associated with a decreased effective blood volume and a reduced renal perfusion. This leads to an increased dependence of renal hemodynamics on endogenous renal prostaglandin synthesis as a vasodilator and natriuretic counter-regulating system. We investigated the role of prostaglandins in renal functional control in an experimental setting of congestive heart failure by chronic inhibition of cyclooxygenase by indomethacin. In chronic moderate heart failure plasma levels of prostaglandin E2 and prostacyclin were unchanged whereas the urinary excretion of prostaglandin E2 was significantly increased, indicating an augmented synthesis within the kidney (Figures 1 to 3). After inhibition of prostaglandin synthesis we observed a profound increase of renal vascular resistance associated with a reduction of effective renal plasma flow and renal blood flow. This was mainly due to a constriction of the vas afferens of the glomerulum. This led to an impairment of renal function indicated by an increase of serum creatinine and blood urea nitrogen associated with a reduction of urinary flow and fluid retention (Figures 4 and 5). We also studied in a randomized, double-blind, placebo-controlled, parallel-group trial in 40 patients with congestive heart failure effects of acetylsalicylic acid (500 mg t.i.d.) on renal functional parameters. In patients with normal sodium intake acetylsalicylic acid reduced urinary prostaglandin E2 concentration by 37% which led to a reduction of daily urinary sodium excretion by 29% in comparison to placebo (Figure 6). These results clearly show the importance of vasodilator prostaglandins in the regulation of kidney function in heart failure where inhibition of cyclooxygenase results in profound deterioration of renal perfusion and kidney function and retention of fluid and sodium.
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PMID:[Role of prostaglandins in regulation of kidney function in heart failure]. 206 53

Changes of neurohumoral factors including vasodilatory prostaglandins (PGs) were investigated in an experimental model of moderate low-cardiac-output status induced by rapid right ventricular pacing (240 beats/min). After 7 days of pacing, we studied the response of renal, hormonal, and hemodynamic parameters to cyclooxygenase inhibition by indomethacin and the effects of the renin system by converting-enzyme blockade in addition to the inhibition of PG synthesis. Lowering cardiac output increased plasma levels of norepinephrine and atrial natriuretic peptide. Plasma renin concentration was suppressed, despite a fall in cardiac output and blood pressure and a stimulation of sympathetic nerve activity. Urinary excretion of PGE2 was increased (P less than 0.04); plasma levels of PGE2 and 6-keto-PGF1 alpha were unchanged as measured in blood from the renal vein, pulmonary artery, and aorta. During low cardiac output, we found a significant decrease of glomerular filtration rate, whereas renal blood flow and renal and peripheral vascular resistances were unchanged. Administration of indomethacin decreased plasma and urinary PGs significantly, markedly reduced renal blood flow, and increased renal vascular resistance without affecting peripheral vascular resistance. The additional blockade of the renin-angiotensin system by captopril showed mainly a vasodilator effect on peripheral arterial resistance vessels, resulting in an increase of cardiac output. Our results suggest that, in moderate low-cardiac-output status, renal blood flow is maintained by renal vasodilator PGs, which counterbalance vasoconstrictor mechanisms like the activated sympathetic nerve activity. We indirectly showed the importance of angiotensin II in preserving glomerular filtration rate, which declines when renin secretion is suppressed, as it may be the case in moderate heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Circulatory and renal control by prostaglandins and renin in low cardiac output in dogs. 252 99

Vascular responses to many physiological stresses are abnormal in heart failure. Increased peripheral resistance and a reduction in the vasodilator response to exercise and ischemia are examples of this abnormal vascular control. Such abnormal vascular control in heart failure is a result of interplay between neural, hormonal, and local vascular factors. This study was designed to test the hypothesis that a specific local mechanism, endothelium-dependent relaxation to acetylcholine (ACh), is depressed in experimental heart failure. Experiments were performed on 11 purebred beagles. Experimental heart failure was induced by rapid ventricular pacing for approximately 30 days. Femoral artery diameter was measured by sonomicrometry, and dose-response relationships to ACh, norepinephrine (NE), and nitroglycerin (NTG) were done before and after inhibition of cyclooxygenase by indomethacin. Heart failure resulted in a significant depression of ACh relaxation at all concentrations. In dogs with heart failure, indomethacin enhanced the dilation response to low concentrations of ACh. Constriction to NE and dilation to NTG were unchanged by heart failure. These data demonstrate that in the canine femoral artery endothelium-dependent dilation to ACh is depressed in experimental heart failure. Depression of endothelium-dependent vasodilation represents one local mechanism for abnormal control of the vasculature in congestive heart failure.
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PMID:Heart failure depresses endothelium-dependent responses in canine femoral artery. 270 66

Ten patients in heart failure of various etiologies underwent a placebo-controlled study to determine the effect of indomethacin (150 mg daily by mouth) on urine volume, sodium chloride excretion, glomerular filtration rate, renal prostaglandins, as well as plasma renin and aldosterone concentrations before and after administration of 40 mg frusemide by mouth. None had hyponatremia and plasma renin levels were within normal limits, but prostaglandin synthesis inhibition by indomethacin significantly reduced urine volume (-50%), sodium excretion (-70%) and glomerular filtration rate (-50%), as well as the urinary excretion of prostaglandin E2 (-80%) and 6-keto-prostaglandin F1 alpha (-70%). Frusemide-induced diuresis was halved by indomethacin. The suppression of renal prostaglandin excretion induced by inhibition of cyclooxygenase was not much influenced by frusemide. Plasma renin and aldosterone concentrations after indomethacin administration were not significantly raised by frusemide. The results indicate that renal prostaglandin synthesis is of great importance in the pathophysiology and treatment of mild to moderate heart failure.
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PMID:[Indomethacin and furosemide in patients with cardiac insufficiency. Kidney function, the renin-angiotensin system and renal prostaglandins]. 331 42

Cyclooxygenase inhibitors may affect the hemodynamic status of patients with heart failure adversely and may also block the vasodilatory effects of angiotensin-converting enzyme (ACE) inhibitors in such patients. Relatively low doses of the cyclooxygenase inhibitor acetylsalicylic acid (ASA) are now used routinely in ischemic heart disease, the most important cause of heart failure. Therefore, we investigated the hemodynamic interaction between ASA and captopril in heart failure. In a randomized, cross-over study, 13 patients with congestive heart failure (CHF) who were already receiving maintenance treatment with an ACE inhibitor received a single dose of 25 mg captopril combined with 236 mg ASA or placebo. Peripheral blood flow was studied noninvasively by venous occlusion plethysmography of the calves. Liver blood flow was estimated from indocyanine green (ICG) clearance. Administration of captopril alone significantly decreased blood pressure (BP), and ICG clearance. Calf blood flow remained unchanged. However, after arterial occlusion, hyperemic calf blood flow persisted for longer. Captopril alone did not significantly change the plasma levels of the vasodilating prostaglandins PGI2 and PGE2 or the vasoconstricting thromboxane A2 (TXA2). In contrast, captopril combined with ASA reduced the plasma levels of these vasoactive substances, with significant decreases in PGE2 and TXA2 as compared with captopril alone, yet the hemodynamic alterations after captopril plus ASA were similar to those observed after captopril alone. A single antithrombotic dose of ASA (236 mg) in 13 patients with CHF [New York Heart Association (NYHA) class II-IV] undergoing chronic treatment with ACE inhibitors had no discernible effect on hemodynamic status.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of acetylsalicylic acid on peripheral hemodynamics in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. 751 53

Angiotensin converting enzyme inhibitors (ACEIs) are a cornerstone of treatment of hypertension and heart failure yet their mechanism of action is still debated. This study was designed to test whether the ACEI captopril increases skin microvascular blood flow by a bradykinin-dependent mechanism. Local changes in microvascular blood flow were measured in the skin of rabbits and of human volunteers using a laser Doppler flow probe. Captopril injected intradermally increased skin blood flow over the dose range of 10(-12)-10(-8) mol site in rabbits and humans. In both species the response was abolished by coinjecting either a nitric oxide synthase (NOS) inhibitor or a cyclooxygenase inhibitor. Intradermal bradykinin also increased rabbit skin microvascular blood flow; at 10(-11) mol site it increased mean +/- SE basal blood flow by 88 +/- 12%. The responses to bradykinin or captopril were abolished by coinjecting a bradykinin antagonist, a specific bradykinin B2 receptor antagonist, or inhibitors of NOS or cyclooxygenase. Injecting a specific angiotensin II receptor antagonist at a dose that antagonized the constrictor effects of exogenous angiotensin II did not cause a significant increase in rabbit skin blood flow. This suggests that endogenous angiotensin II does not influence microvascular blood flow in this model. The results indicate that captopril increases skin microvascular blood flow in rabbits and humans secondary to an increase in endogenous tissue bradykinin; this stimulates B2 receptors with subsequent release of prostaglandins and nitric oxide. ACEIs may increase microvascular perfusion by a bradykinin-dependent mechanism.
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PMID:Captopril increases skin microvascular blood flow secondary to bradykinin, nitric oxide, and prostaglandins. 789 12

We hypothesized that in cardiac muscles, angiotensin II partially inhibits the contractile response to beta-agonists. We studied the contractile response of isolated rat left ventricular papillary muscles to isoproterenol and the effect of angiotensin II on this response. We also investigated whether the effect of angiotensin II is mediated by bradykinin, prostaglandins, nitric oxide, and/or cGMP. Contractility of isolated papillary muscles was recorded with a force transducer, and rest tension, maximal developed tension (DT), maximal rate of rise in developed tension [T(+)], and maximal velocity of relaxation [T(-)] were measured (1) under basal conditions, (2) after pretreatment with various drugs, and (3) after cumulative doses of isoproterenol. Pretreatment groups included (1) vehicle (controls); (2) angiotensin II; (3) angiotensin II and N(omega)-nitro-L-arginine, an inhibitor of nitric oxide release; (4) L-arginine, the substrate for nitric oxide synthase; (5) L-arginine and N(omega)-nitro-L-arginine; (6) 8-bromo-cGMP, analogous to the second messenger of nitric oxide; (7) angiotensin II and icatibant (Hoe 140), a bradykinin B2 antagonist; and (8) angiotensin II and indomethacin, a cyclooxygenase inhibitor. There were no differences in contractile parameters before and after any of the pretreatments. Isoproterenol increased DT, T(+), and T(-), and these effects were attenuated by angiotensin II, L-arginine, and 8-bromo-cGMP. The effects of angiotensin II and L-arginine were blocked by inhibition of nitric oxide release with N(omega)-nitro-L-arginine. Neither the bradykinin B2 antagonist nor the cyclooxygenase inhibitor altered the effects of angiotensin II. We concluded that angiotensin II partially inhibits the contractile response of cardiac papillary muscles to isoproterenol This effect is likely mediated by nitric oxide release, perhaps acting via cGMP. Kinins and prostaglandins do not appear to participate in the inhibitory effect of angiotensin II. Attenuation of the contractile effect of isoproterenol by angiotensin II may help explain why cardiac function improves in heart failure after blockade of the renin-angiotensin system.
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PMID:Myocardial contractility is modulated by angiotensin II via nitric oxide. 861 28

Our hypothesis is that regulation of the lung vessel tone and microvascular permeability may be disrupted in chronic heart failure (CHF) and angiotensin converting enzyme (ACE) inhibition may contribute to their readjustment. This hypothesis is based on the fact that KII-ACE, the same enzyme that converts angiotensin I and inactivates bradykinin, is highly concentrated in the luminal surface of the lung vessels and its blockade in CHF may reduce their exposure to an excess of angiotensin II and augment the action of prostaglandins and nitric oxide (NO) deriving from local kinin hyperconcentration. We probed whether ACE-inhibitors influence the pulmonary function; this is peculiar of CHF; they act as KII- or ACE-blockers. Aspirin was utilized as a prostaglandin synthesis inhibitor. We investigated 16 CHF patients and 16 age- and sex-matched normal volunteers or mild untreated hypertensives. All were non-smokers, not taking ACE-inhibitors, aspirin or other cyclooxygenase inhibitors. Pulmonary function tests, exercise testing with respiratory gases and echocardiography were performed in the run-in and repeated at the end of placebo, enalapril (10 mg t.i.d.), enalapril plus aspirin (325 mg/day) and aspirin given in random order and double-blind fashion for 15 days each. Enalapril, as compared to placebo, caused an increase in mean voluntary ventilation (MVV) and alveolar-capillary diffusing capacity for carbon monoxide (DLCO) in CHF, that were counteracted by the addition of aspirin. Aspirin alone was not effective. Enalapril and aspirin were ineffective on the pulmonary function of controls. As to the functional capacity, enalapril increased exercise tolerance time, oxygen consumption (VO2p), minute ventilation (VEp) tidal volume (VTp) and reduced the ratio of volume of dead space gas (VDp) to VTp (VD/VTp), at peak exercise in CHF patients. These effects all were inhibited by the combination of aspirin and were not observed in controls. In CHF VO2p changes from placebo correlated with those in DLCO (r = 0.80, p < 0.0001) and not with those in ejection fraction. This correlation was abolished by aspirin and was not seen in controls. Variations in VD/VTp in CHF patients while on enalapril were related to those in DLCO (r = -0.69, p = 0.003). In CHF the ventilatory equivalent for carbon dioxide production per minute at 1 liter was diminished with enalapril and not in combination with aspirin. Derangements related to CHF are the substrate for benefits of ACE-inhibition on pulmonary function and exercise capacity. Pulmonary diffusion limitation is an important mediator of exercise impairment and its improvement with enalapril goes in parallel with VD/VT, MVV, VT, VE to VCO2 relationship and not with ejection fraction. These patterns reflect changes occurring within the lung that are not related to left ventricular function. The counteracting influence of aspirin on these affects bespeaks a substantial participation of prostaglandins that might readjust capillary permeability and lung interstitial fluid content or alveolar capillary membrane diffusing capacity.
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PMID:[Acetylsalicylic acid antagonism vs ACE inhibitor in congestive heart failure as shown by a diminished respiratory and exercise capacity]. 876 15

It is well accepted that sympathetic tone is elevated in chronic heart failure (HF) and that the cardiac sympathetic afferent reflex is a sympathoexcitatory reflex. There have been no studies designed to examine the role of this reflex in control of sympathetic outflow in the HF state. In this study we tested the hypothesis that cardiac sympathetic afferent reflexes are enhanced in HF and are, therefore, capable of contributing to the increase in sympathetic outflow in this disease state. Ventricular pacing was carried out in 14 dogs until signs of HF were evident. Fourteen sham dogs served as controls. At the time of the acute experiment the dogs were anesthetized with alpha-chloralose. The hemodynamic [arterial pressure and heart rate (HR)] and renal sympathetic nerve activity (RSNA) responses to left ventricular epicardial application of two doses of bradykinin (BK) and capsaicin (Cap) were determined in the sinoaortic-denervated and vagotomized state. The MAP, RSNA, and HR responses to BK were greater in the HF group compared with the sham group. The RSNA response to BK (50 micrograms) in the HF group was significantly increased (34.0 +/- 5.9 vs. 11.5 +/- 4.2%, P < 0.05). The MAP, RSNA, and HR responses to Cap in the HF group were similar to the responses to BK. The RSNA response to Cap in the HF group was significantly increased (29.8 +/- 11.3 vs. 13.8 +/- 2.3% for 10 micrograms, P < 0.05 and 46.5 +/- 10.7 vs. 18.7 +/- 3.1% for 100 micrograms, P < 0.05). The cyclooxygenase blocker indomethacin (5 mg/kg i.v.) attenuated the reflex responses to BK in the HF group. These data suggest that the enhanced cardiac sympathetic afferent reflex to epicardial BK in HF appears to be mediated by altered levels of prostaglandin synthesis. Blockade of cardiac sympathetic afferents with topical lidocaine reduced baseline of RSNA significantly more in the HF state than in the normal state (-24.2 +/- 3.6 vs. -4.3 +/- 4.5%, P < 0.05). We conclude from these data that the cardiac sympathetic afferent reflex is sensitized in the HF state and speculate that this enhanced cardiac sympathetic afferent reflex may contribute to the sustained higher sympathetic tone in chronic HF.
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PMID:Cardiac sympathetic afferent reflex in dogs with congestive heart failure. 885

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