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)

The adaptive changes that accompany hypertension and involve the kidney, heart, and vessels, namely, muscle hypertrophy/hyperplasia, endothelial dysfunction and extracellular matrix increase can, in fact, be maladaptive and eventually lead to end-organ disease, such as renal failure, heart failure, and coronary disease. However, these changes vary markedly between individuals with similar levels of hypertension. Nitric oxide (NO), an endogenous vasodilator and inhibitor of vascular smooth muscle and mesangial cell growth, is synthesized in the endothelium by a constitutive NO synthase (NOS). NO antagonizes the effects of angiotensin II on vascular tone and growth and also down-regulates the synthesis of angiotensin converting enzyme (ACE) and angiotensin II type 1 (AT-1) receptors. In hypertension, the physiologic response to the increased shear stress and cyclic strain is to upregulate NOS activity in endothelial cells. Upregulation of vascular NOS activity is a homeostatic adaptation to the increased hemodynamic workload that may help in preventing end-organ damage. Indeed, hypertension-prone salt-sensitive rats manifest a decrease (instead of an increase) in vascular NOS activity when hypertensive; these rats develop severe vascular hypertrophy, left ventricular hypertrophy, and renal injury. Studies in hypertensive humans suggest that, independent of the effects of salt on blood pressure, salt sensitivity may be a marker for susceptibility to the development of endothelial dysfunction as well as cardiovascular and renal injury. We hypothesize that in hypertension, recognition of markers of cardiovascular susceptibility to injury and the understanding of the pathophysiological mechanisms involved may open new opportunities for therapeutic intervention. In this context, only those antihypertensive agents that lower blood pressure and concomitantly restore the homeostatic balance of vasoactive agents such as angiotensin II and NO within the vessel wall would be effective in preventing or arresting end-organ disease.
 ...
PMID:Angiotensin II, nitric oxide, and end-organ damage in hypertension. 983 77

Patients with chronic heart failure (CHF) are hemodynamically characterized by increased vasoconstriction and a reduced vasodilator response to exercise. In addition to various compensatory neurohumoral mechanisms, there is evidence that the endothelium plays an important role in the abnormal vasodilator response. This evidence comes from studies investigating the microvascular response to regional, intra-arterial administration of the endothelium-dependent vasodilator acetylcholine, which found that the vasodilator response and therefore the bioavailability of nitric oxide (NO) was impaired in the microcirculation of the leg, forearm, and myocardium of patients with CHF. The mechanisms underlying this abnormal response are not entirely clear but may reflect a muscarinic receptor abnormality. Because conduit artery vasodilatation during hyperemic blood flow is also impaired and because this response is not dependent on muscarinic receptor activation, this possibility appears to be unlikely. However, impaired smooth muscle responsiveness to NO stimulation, impaired L-arginine availability or utilization, endothelial release of vasoconstricting prostanoids, increased NO degradation and reduced NO synthase activity have all been implicated in this impaired response. In addition, the vasoconstrictor activity of endothelin (ET)-1 appears to play an important role in the regulation of tone in CHF, although the importance of different ET receptors is not yet clear.
 ...
PMID:Endothelial control of vascular tone in chronic heart failure. 988 51

We performed experiments to test the hypothesis that experimental heart failure (HF) is associated with altered nitric oxide (NO)-dependent influences on the renal microvasculature, including diminished modulation of constrictor responses to ANG II. Eight to ten weeks after inducing HF in rats by coronary artery ligation, we administered enalaprilat to suppress ANG II synthesis and studied renal arteriolar function using the in vitro blood-perfused juxtamedullary nephron technique. In kidneys from sham-operated rats, NO synthase inhibition [100 microM Nomega-nitro-L-arginine (L-NNA)] reduced afferent arteriolar diameter by 4.1 +/- 0.6 microm and enhanced ANG II responsiveness (10 nM ANG II decreased afferent diameter by 10.1 +/- 1.4 micrometer before and 12.8 +/- 1.6 micrometer during L-NNA treatment; P < 0.05). In kidneys from HF rats, L-NNA did not alter afferent arteriolar baseline diameter or ANG II responsiveness (10 nM ANG II decreased diameter by 12.5 +/- 1.5 micrometer before and 12.5 +/- 2.3 micrometer during L-NNA). The effects of L-NNA on efferent arteriolar function were also abated in HF rats. In renal cortex of HF rats, NO synthase activity was decreased by 63% and superoxide dismutase activity was diminished by 39% relative to tissue from sham-operated rats. Urinary nitrate/nitrite excretion was also reduced in HF rats. Thus both diminished synthesis and augmented degradation are likely to contribute to a decreased renal microvascular impact of endogenous NO during chronic HF, the consequences of which include loss of NO-dependent modulation of ANG II-induced vasoconstriction.
 ...
PMID:Suppressed impact of nitric oxide on renal arteriolar function in rats with chronic heart failure. 988 83

The endothelium is a major regulator of vascular tone, releasing vasoactive substances such as endothelium-derived nitric oxide (EDRF), endothelium-derived hyperpolarizing factor(s), cycloxygenase metabolites, endothelin and other endothelium-derived contracting factors (EDCF). In a number of cardiovascular pathologies, such as hypertension or heart failure, the balance in the endothelial production of vasodilating and vasoconstricting mediators is altered. The resulting apparent decrease in endothelium-dependent relaxations is termed 'endothelial dysfunction'. In hypertensive patients and in animal models of hypertension, endothelium-dependent relaxations are impaired. However, this endothelial dysfunction presents different characteristics depending on the model studied. In Dahl-salt-sensitive rats, the decrease in endothelium-dependent relaxations is associated with impaired constitutive nitric oxide synthase activity. The presence of an endogenous nitric oxide synthase inhibitor and a decreased response of vascular smooth muscle to the mediator may contribute also to the dysfunction observed in this model. In other animal models of hypertension (such as spontaneous hypertension). the contribution of the L-arginine nitric oxide pathway to endothelium-dependent responses appears normal or impaired despite reports of increased nitric oxide synthase activity or expression. In large arteries from SHR, endothelium-dependent relaxations are impaired mainly because of the concomitant augmented release of endoperoxides activating thromboxane-endoperoxide receptors. Superoxide anions may also play a role in some models, but only in the early phase of the disease: whether or not these species contribute to further development of endothelial dysfunction or to increases in blood pressure remains to be examined. The endothelial dysfunction observed in hypertension is likely to be a consequence of high blood pressure. but it could facilitate the maintenance of elevated peripheral resistance at a later stage in the disease and favour the occurrence of complications, such as atherosclerosis.
 ...
PMID:Secondary endothelial dysfunction: hypertension and heart failure. 1007 14

1. Among the diverse functions of endothelins (ET), their role in the remodelling of blood vessels remains poorly examined. In the present review, we summarize findings obtained in our laboratory and present four independent lines of evidence to support this novel function. We also demonstrate that the motogenic and angiogenic effects of ET are mediated via the ETB receptor and that the functional endothelial nitric oxide synthase (NOS) is requisite for this action. 2. We demonstrated that ET stimulates transmigration of endothelial cells in a modified Boyden chamber and accelerates endothelial wound healing acting via ETB receptors. 3. In genetically engineered Chinese hamster ovary cells expressing either ETB receptor or endothelial NOS or both, application of ET results in accelerated cell migration only when the receptor and the enzyme are coexpressed. Application of antisense oligonucleotides producing a specific knockdown of the endothelial NOS results in the loss of ET ability to stimulate endothelial cell migration in response to ET. 4. Finally, using a novel model of in vivo angiogenesis, we were able to demonstrate that ET enhances formation of new vessels, but this effect requires functional endothelial NOS. 5. The described phenomenon of NO production, serving as a prerequisite for endothelial cell locomotion in response to activation of ETB receptor may explain a host of pathophysiological observations on inadequate angiogenesis despite enhanced generation of ET-1. 6. Based on the contribution of endothelial cell migration to angiogenesis, these data may implicate insufficient NO production in pathological states (e.g. atherosclerosis, heart failure and hypertension) in the inappropriate response to angiogenic stimuli.
 ...
PMID:Co-operation between endothelin and nitric oxide in promoting endothelial cell migration and angiogenesis. 1008 26

An enhanced peripheral chemoreflex has been documented in patients with chronic heart failure (CHF). This study aimed to examine the characteristics of carotid body (CB) chemoreceptors in response to isocapnic hypoxia in a rabbit model of pacing-induced CHF and to evaluate the possible role that nitric oxide (NO) plays in the altered characteristics. The chemosensitive characteristics of the CB were evaluated by recording single-unit activity from the carotid sinus nerve in both an intact and a vascularly isolated preparation. It was found that the baseline discharge under normoxia (intact preparation: arterial PO2 90-95 Torr; isolated preparation: PO2 100-110 Torr) and the chemosensitivity in response to graded hypoxia (PO2 40-70 Torr) were enhanced in CHF vs. sham rabbits. These alterations were independent of the CB preparations (intact vs. isolated). NO synthase inhibition by Nomega-nitro-L-arginine increased the baseline discharge and the chemosensitivity in the intact preparation, whereas L-arginine (10(-5) M) inhibited the baseline discharge and the chemosensitivity in the isolated preparation in sham but not in CHF rabbits. S-nitroso-N-acetylpenicillamine, an NO donor, inhibited the baseline discharge and the chemosensitivity in both CB preparations in CHF rabbits but only in the isolated preparation in sham rabbits. The amount of NO produced in vitro by the CB under normoxia was less in CHF rabbits than in sham rabbits (P < 0.05). NO synthase-positive varicosities of nerve fibers within the CB were less in CHF rabbits than in sham rabbits (P < 0.05). These data indicate that an enhanced input from CB occurs in the rabbit model of pacing-induced CHF and that an impairment of NO production may contribute to this alteration.
 ...
PMID:Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide. 1019 13

Endothelial-derived nitric oxide (NO) is an important mediator of vascular function. Clinical studies indicate that HMG-CoA reductase inhibitors (statins) improve endothelial function and reduce the incidence of stroke and myocardial infarction. Treatment of human endothelial cells with statins increased the expression of endothelial NO synthase (eNOS) protein and mRNA expression. Statins increased eNOS mRNA half-life but did not change eNOS gene transcription. Inhibition of mevalonate synthesis by statins not only blocks the formation of cholesterol but also of isoprenoids. The upregulation of eNOS expression by statins was independent of cholesterol but mediated via the inhibition of the isoprenoid geranylgeraniol, whereas farnesiol had no effect on eNOS. Immunoblot analyses, (35S)-GTP gamma S-binding assays and transfection studies revealed that statins upregulate eNOS expression by blocking the geranylgeranylation of the GTPase Rho which is necessary for its membrane-associated activity. Studies with mice showed, that statin treatment upregulates eNOS expression and function independent of serum cholesterol levels. Prophylactic treatment with statins augmented cerebral blood flow and reduced cerebral infarcts in normocholesterolemic mice. These effects of statins were completely absent in eNOS-deficient mice indicating that enhanced eNOS activity by statins is the predominant mechanism by which these agents protect against cerebral injury. Our results suggest that statins provide a novel prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia. Upregulation of eNOS by inhibiting Rho may provide a new pharmacologic target for the treatment of arteriosclerosis, pulmonary hypertension, and heart failure.
 ...
PMID:[Regulation of endothelial NO production by Rho GTPase]. 1037 57

Heme oxygenase (HO)-1 is a stress protein (HSP 32) and, together with HO-2, catalyses oxidation of the heme molecule to generate carbon monoxide, a gas with vasodilatory properties, and bilirubin, an antioxidant. Right-sided heart failure (RHF) resulted in a two-fold increase in the HO-1 transcript (;1.8 kb) in the right ventricle (RV) of RHF dogs compared to that of controls. In contrast, the left ventricle showed no increase in HO-1 mRNA in RHF. The change in HO was unique to HO-1, because neither the HO-2 transcripts (;1.3 and 1.9 kb) nor the HSP 70 mRNA was altered in either ventricle. This increase in HO-1 mRNA in RV was accompanied by a two-fold increase in immunoreactive HO-1 protein, as judged by Western blot analysis, as well as by a significant increase in cGMP levels. There was, however, no significant increase in RV total nitric oxide synthase activity in RHF. Furthermore, since norepinephrine infusion also increased HO-1 transcript and protein levels, the HO-1 system probably was induced in RHF by the increased interstitial norepinephrine levels known to occur in failing myocardium. This differential regulation and induction of HO-1 gene in the failing ventricle might be one of the defense mechanisms by which the heart attempts to protect from stress caused by congestive heart failure.
 ...
PMID:Chamber-specific regulation of heme oxygenase-1 (heat shock protein 32) in right-sided congestive heart failure. 1042 55

Expression of innate immune response proteins, including IL-1beta, TNF, and the cytokine-inducible isoform of nitric oxide synthase (iNOS), have been documented in the hearts of humans and experimental animals with heart failure regardless of etiology, although the proximal events leading to their expression are unknown. Noting that expression of a human homologue of Drosophila Toll, a proximal innate immunity transmembrane signaling protein in the fly, now termed human Toll-like receptor 4 (hTLR4), appeared to be relatively high in the heart, we examined TLR4 mRNA and protein abundance in isolated cellular constituents of cardiac muscle and in normal and abnormal murine, rat, and human myocardium. TLR4 expression levels in cardiac myocytes and in coronary microvascular endothelial cells could be enhanced by either LPS or IL-1beta, an effect inhibited by the oxygen radical scavenger PDTC. Transfection of a constitutively active TLR4 construct, CD4/hTLR4, resulted in activation of a nuclear factor-kappaB reporter construct, but not of an AP-1 or an iNOS reporter construct, in cardiac myocytes. In normal murine, rat, and human myocardium, TLR4 expression was diffuse, and presumably cytoplasmic, in cardiac myocytes. However, in remodeling murine myocardium remote from sites of ischemic injury and in heart tissue from patients with idiopathic dilated cardiomyopathy, focal areas of intense TLR4 staining were observed in juxtaposed regions of 2 or more adjacent myocytes; this staining was not observed in control myocardium. Increased expression and signaling by TLR4, and perhaps other Toll homologues, may contribute to the activation of innate immunity in injured myocardium.
 ...
PMID:Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. 1043 Jun 8

We hypothesized that nitric oxide (NO) opposes ANG II-induced increases in arterial pressure and reductions in renal, splanchnic, and skeletal muscle vascular conductance during dynamic exercise in normal and heart failure rats. Regional blood flow and vascular conductance were measured during treadmill running before (unblocked exercise) and after 1) ANG II AT(1)-receptor blockade (losartan, 20 mg/kg ia), 2) NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME); 10 mg/kg ia], or 3) ANG II AT(1)-receptor blockade + NOS inhibition (combined blockade). Renal conductance during unblocked exercise (4.79 +/- 0.31 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased after ANG II AT(1)-receptor blockade (6.53 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.12 +/- 0.20 ml x 100 g(-1) x min(-1) x mmHg(-1)) and combined inhibition (3.96 +/- 0.57 ml x 100 g(-1) x min(-1) x mmHg(-1); all P < 0.05 vs. unblocked). In heart failure rats, renal conductance during unblocked exercise (5.50 +/- 0.66 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased by ANG II AT(1)-receptor blockade (8.48 +/- 0.83 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.68 +/- 0.22 ml x 100 g(-1) x min(-1) x mmHg(-1); both P < 0.05 vs. unblocked), but it was unaltered during combined inhibition (4.65 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)). Because our findings during combined blockade could be predicted from the independent actions of NO and ANG II, no interaction was apparent between these two substances in control or heart failure animals. In skeletal muscle, L-NAME-induced reductions in conductance, compared with unblocked exercise (P < 0.05), were abolished during combined inhibition in heart failure but not in control rats. These observations suggest that ANG II causes vasoconstriction in skeletal muscle that is masked by NO-evoked dilation in animals with heart failure. Because reductions in vascular conductance between unblocked exercise and combined inhibition were less than would be predicted from the independent actions of NO and ANG II, an interaction exists between these two substances in heart failure rats. L-NAME-induced increases in arterial pressure during treadmill running were attenuated (P < 0.05) similarly in both groups by combined inhibition. These findings indicate that NO opposes ANG II-induced increases in arterial pressure and in renal and skeletal muscle resistance during dynamic exercise.
 ...
PMID:Interactions between angiotensin II and nitric oxide during exercise in normal and heart failure rats. 1044 15


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