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)

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

Right ventricular dysfunction is a common clinical event after heart transplantation. The major cause is the failure of right ventricle (RV) to adapt to the pulmonary hypertension (PH) secondary to chronic heart failure. Nevertheless, this dysfunction is usually transient owing to the reversibility of PH, the nature of which is mainly passive. Therefore, it is particularly important to perform a preoperative hemodynamic study to identify those cases in which PH is a permanent component, a situation that excessively increases the risk of postoperative RV failure. Once this occurs, the treatment is complex. The available therapeutic measures include the use of vasodilators such as prostaglandin E1 and nitric oxide.
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PMID:[Special anesthesia care in heart transplantation. The management of right ventricular failure]. 877 18

The mechanism responsible for the regulation of cardiac function by endogenous nitric oxide (NO) remains unclear. In this investigation, O2 consumption by freshly isolated myocardial muscle segments from the left ventricular free wall of canine hearts was quantified by a Clark-type O2 electrode at 37 degrees C. S-nitroso-N-acetylpenicillamine (SNAP, 9 +/- 3% to 50 +/- 8%), bradykinin (BK, 14 +/- 3% to 30 +/- 5%), or carbachol (CCh, 15 +/- 4% to 29 +/- 4%) significantly attenuated tissue O2 consumption at doses of 10(-7) to 10(-4) mol/L (mean +/- SE, P < .05). The effects of BK and CCh, but not SNAP, were blocked by 10(-4) mol/L NG-nitro-L-arginine, consistent with both BK and CCh stimulating NO biosynthesis and with SNAP decomposing to release NO, respectively. Similar doses of 8-Br-cGMP caused a respiratory inhibition, but to a lesser extent (9 +/- 2% to 14 +/- 6%). A mitochondrial uncoupler, 2,4-dinitrophenol (at 1 mmol/L), blocked the effects of 8-Br-cGMP, but not those of SNAP, BK, or CCh, suggesting that the major site of action of NO is on mitochondrial electron transport. Myocardial muscle from dogs with pacing-induced heart failure had a basal O2 consumption rate of 251 +/- 21 nmol.min-1.g-1, which was 54% higher than the rate seen in muscle from normal healthy canine hearts. The inhibitory effects of BK and CCh on O2 consumption were not observed in failing cardiac tissue, but SNAP showed an unaltered inhibitory effect. Therefore, our results indicate that NO released from microvascular endothelium by BK, stimulation of muscarinic receptors, and perhaps flow velocity may play an important physiological role in the control of cardiac mitochondrial respiration, and the loss of this regulatory function may contribute to the development of heart failure.
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PMID:Role of endothelium-derived nitric oxide in the modulation of canine myocardial mitochondrial respiration in vitro. Implications for the development of heart failure. 878 71

A number of reflexes participate in the control of coronary vascular resistance through activation of the sympathetic or parasympathetic nervous system. Classically, activation of vagal efferent fibers to the heart results in vasodilation due to the release of acetylcholine and activation of muscarinic receptors. Recently, we have found that activation of a number of reflexes in conscious dogs, the Bezold-Jarisch reflex and the carotid chemoreflex in particular, results in cholinergic coronary vasodilation which is blocked by an inhibitor of nitric oxide synthesis, nitro-L-arginine. After the development of pacing-induced heart failure, the cholinergic dilation subsequent to activation of the Bezold-Jarisch or carotid chemoreflex is essentially abolished, since coronary blood vessels no longer produce nitric oxide. In contrast, after brief exercise training, there is a potentiation of Bezold-Jarisch reflex-induced coronary vasodilation since exercise upregulates nitric oxide production by coronary blood vessels. Since the Bezold-Jarisch reflex may be important as a compensatory mechanism during acute myocardial infarction, and the carotid chemoreflex is the acute mechanisms responsible for ameliorating systemic hypoxemia, the role of nitric oxide in reflex cholinergic coronary vasodilation may be essential in the compensatory vascular adjustments evoked by these and other reflexes.
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PMID:Neural regulation of coronary vascular resistance: role of nitric oxide in reflex cholinergic coronary vasodilation in normal and pathophysiologic states. 880 85

Myocarditis is thought to be caused by various viruses, and accumulating evidence links viral myocarditis with the eventual development of dilated cardiomyopathy. Recently the importance of hepatitis C virus infection was noted in patients with dilated cardiomyopathy. Cytokines are increasingly recognized as an important factor in the pathogenesis and pathophysiology of myocarditis and cardiomyopathy. Elevated circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. A number of recent studies showed that cytokines generated by activated immune cells cause an increase in NO (nitric oxide) via induction of NO synthase. Increased generation of NO may induce negative inotropism and myocardial damage. This review discusses the etiology and pathogenesis of myocarditis and cardiomyopathy from this point of view.
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PMID:Cytokines in myocarditis and cardiomyopathies. 883 73

Because controversies surround the increased negative inotropic effects of calcium antagonists in heart failure, other mechanisms may explain their lack of efficacy in this condition. We hypothesized that altered coronary sensitivity through endothelial dysfunctions may be involved. Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left ventricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyopathic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem concentration-response curves for both coronary dilation and its negative inotropic effects were charted under control conditions and in the presence of the specific nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Diltiazem concentration-response curves for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 microM, respectively). In contrast, the coronary dilator effects of diltiazem were impaired in failing hearts (EC50 for diltiazem-induced coronary dilation increased from 90 nM in normal hearts to 1.1 microM in failing hearts, p < 0.01). The involvement of endothelial dysfunctions in the observed coronary "desensitization" to diltiazem in heart failure was evaluated through the NO-synthase and cyclooxygenase pathways. Diltiazem concentration-response curves from failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart failure. These findings suggest that coronary "desensitization" to diltiazem occurs through parallel production and/or release of a vasoconstricting factor or factors originating from the cyclooxygenase pathway. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These findings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better understanding of factors modulating the effects of calcium antagonists in heart failure.
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PMID:Impaired coronary sensitivity to diltiazem in experimental heart failure: involvement of the cyclooxygenase but not the nitric oxide-synthase pathway. 885 78

Nitric oxide may act at autonomic sites in the brain to regulate sympathetic outflow. Our goal was to determine whether gene expression of the neuronal isoform of nitric oxide synthase (nNOS) is altered in discrete autonomic brain regions of rats in the chronic phase of heart failure compared to sham-operated control rats. Experiments were performed in rats 4 to 5 weeks after left coronary artery ligation. Histological data indicated that there was a 39% outer and a 45% inner infarct of the left ventricular myocardium in the heart failure group. The myocardium in sham-operated rats showed no observable damage. Total RNA was purified from microdissected brain tissue blocks containing hypothalamus, dorsal pons, dorsal medulla, rostral ventrolateral medulla, and caudal ventrolateral medulla. Changes in nNOS mRNA were semiquantified in each region using reverse transcription-polymerase chain reactions in which known concentrations of deletion mutant of the gene were coamplified as an internal standard. Compared with controls, significant decreases in nNOS mRNA levels were found in hypothalamus (19%), dorsal pons (43%) and dorsal medulla (34%) of rats with heart failure. There were no statistically significant differences in nNOS mRNA levels in rostral or caudal ventrolateral medulla between the control and heart failure groups. Concomitant with the changes nNOS gene expression in central sites, the plasma concentration of norepinephrine was significantly elevated in rats with heart failure compared to sham-operated control rats. Our results show that heart failure is associated with decreases in nNOS gene expression in at least three regions of the brain and with increased sympathetic outflow to the periphery. The decreased NO production that is likely associated with the decreases in nNOS gene expression may lead to the increased sympathetic drive seen in chronic heart failure.
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PMID:Decreased gene expression of neuronal nitric oxide synthase in hypothalamus and brainstem of rats in heart failure. 889 16

Nitric oxide (NO), the free radical that accounts for the biological activity of endothelium-derived relaxing factor, is synthesized from L-arginine by NO synthase (NOS). There is evidence that NO availability is reduced in the peripheral vasculature of patients with congestive heart failure (CHF). The aim of this study was to investigate the expression of NOS in the descending aorta and in the skeletal muscles of rats subjected to heart failure. The alkaloid, monocrotaline, was used to induce pulmonary hypertension and cardiac failure in rats. The expression of both the constitutive (ecNOS) and the inducible (iNOS) isoforms of the enzyme was assessed by Western blot analysis. In CHF animals, the ecNOS location in the aorta is altered: the endothelial protein expression is substantially reduced (from 0.083 +/- 0.012 to 0.003 +/- 0.004 OD/microgram total proteins, P < 0.001) whereas the expression of ecNOS in the smooth muscle is increased (from 0.024 +/- 0.004 to 0.059 +/- 0.009 OD/ microgram total proteins, P < 0.01). The total aortic ecNOS is diminished in CHF respect to control animals (0.062 +/- 0.009 v 0.107 +/- 0.013 OD/microgram total proteins, P < 0.01). On the contrary, no difference in ecNOS protein expression was observed in the extensor digitorum longus and soleus muscles. Furthermore, iNOS was not detected in any of the tissues considered. In conclusion, experimental CHF causes a re-setting of the ecNOS protein expression in the descending aorta but not in skeletal muscles. The reduced abundance of ecNOS in the aortic endothelium is consistent with the impairment of the vasodilating function reported in patients with CHF.
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PMID:Aorta and skeletal muscle NO synthase expression in experimental heart failure. 893 77

Coordinated release of relaxing and contracting factors from the endothelium modulates arterial distensibility. Recently, a similar release of the same and other factors from the coronary endothelium was shown to modulate myocardial performance in humans. This paracrine modulation of left ventricular (LV) performance by substances released from the coronary endothelium mainly affects diastolic LV function. This was evident from the reduction in end-systolic LV pressure, the earlier onset of LV relaxation and the increased LV diastolic distensibility observed in normal subjects during bi-coronary infusion of substance P. In experimental preparations, substance P elicited similar effects on diastolic LV function, which were attributed to a paracrine myocardial action of nitric oxide (NO) because they were absent after addition of hemoglobin. In normal subjects, the myocardial effects of NO were investigated during bi-coronary infusion of the NO-donor sodium nitroprusside and resembled the effects observed during bi-coronary infusion of substance P. This paracrine control of diastolic LV function by the coronary endothelium is influenced by substrate availability and by many neurohumoral substances, whose plasma levels are raised in heart failure. In transplant recipients, bi-coronary co-infusion of substance P and of L-arginine, the substrate for NO production, potentiated the fall in LV filling pressures. Pretreatment with intravenous dobutamine augmented the drop in LV end-systolic pressures observed during bi-coronary infusion of substance P. In isolated papillary muscles, a higher baseline myocardial c-GMP level, as induced by atrial natriuretic peptide, potentiates the negative inotropic and relaxation hastening effects of NO. In isolated ejecting guinea-pig hearts, an endothelin receptor antagonist improved diastolic LV function and this improvement implies paracrine myocardial action on diastolic LV function not only of NO but also of endothelin. Coronary endothelial control of myocardial function affects LV performance both acutely and chronically. An acute increase in heart rate augments release of NO because of coronary reactive hyperemia, lowers LV filling pressures thereby promoting subendocardial perfusion, and hastens LV relaxation thereby prolonging the diastolic time interval for coronary perfusion. Chronic changes in coronary endothelial function could also influence diastolic LV performance. Enhanced coronary endothelial NO release, as occurs during chronic exercise or pacing, could explain increased LV diastolic distensibility observed in athlete's heart and in tachycardia cardiomyopathy. Reduced endothelial NO release, as occurs with aging or after transplantation, could contribute to reduced LV diastolic distensibility in the elderly or in allograft recipients.
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PMID:Paracrine coronary endothelial modulation of diastolic left ventricular function in man: implications for diastolic heart failure. 895 74

We studied the role of endothelium in control of forearm blood flow during reactive and exercise hyperemia in patients with heart failure as well as in normal subjects. First, endothelium-dependent forearm vasodilation in response to acetylcholine (ACh), substance P, and endothelium-independent forearm vasodilation in response to sodium nitroprusside (SNP) were examined in patients with heart failure and in normal subjects. Endothelium-dependent forearm vasodilation in response to ACh but not to substance P was impaired in patients with heart failure. Endothelium-independent forearm vasodilation to SNP was also preserved in patients with heart failure. Second, the role of nitric oxide (NO) in reactive hyperemia and exercise hyperemia was examined in normal subjects using NG-monomethyl-L-arginine (L-NMMA), a blocker of NO synthesis. Results suggest that NO plays a minimal role in peak reactive hyperemia and exercise hyperemia in normal human forearm vessels. Finally, we determined if L-arginine, a precursor of NO, improves impaired endothelium-dependent vasodilation due to ACh and reactive and exercise hyperemia in patients with heart failure. L-Arginine augmented impaired ACh-induced vasodilation as well as reactive and exercise hyperemia in patients with heart failure. Our results suggest that defective endothelial function may contribute to abnormal control of forearm blood flow in patients with heart failure.
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PMID:Role of endothelium in control of forearm blood flow in patients with heart failure. 895 81


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