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)

Blockade of the angiotensin II (ANG II) type 1 receptor (AT(1)) has been shown to restore baroreflex sensitivity in rats and rabbits with experimental chronic heart failure (CHF). Because the modulation of baroreflex function in response to ANG II is mediated in part by AT(1) receptors located in the area postrema, we hypothesized that lesions of the area postrema would prevent the enhancement in baroreflex function in response to AT(1)-receptor blockade in rabbits with pacing-induced CHF. Experiments were carried out on 24 male New Zealand White rabbits that were divided into sham (n = 12) and lesioned (n = 12) groups further divided into normal and CHF subgroups (n = 6 each). All rabbits were identically instrumented to measure cardiac external dimensions, central venous pressure, arterial pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA). After 3-4 wk of pacing, baroreflex sensitivity (infusions of phenylephrine and nitroprusside) was evaluated before and after intravenous administration of the AT(1)-receptor antagonist L-158,809. Maximum baroreflex sensitivity in nonpaced rabbits was 5.4 +/- 0.7 beats. min(-1). mmHg(-1) and 5.2 +/- 0.5% of maximum/mmHg for HR and RSNA curves, respectively, and was not altered by L-158,809 in either intact or lesioned rabbits. In contrast, L-158,809 enhanced baroreflex sensitivity in intact rabbits with CHF (HR from 1.6 +/- 0.3 to 4.1 +/- 0.7 beats. min(-1). mmHg(-1), P < 0.001; RSNA from 2.3 +/- 0.2 to 4.9 +/- 0.4% of maximum/mmHg, P < 0.001). However, in CHF rabbits with area postrema lesions, L-158,809 failed to enhance baroreflex sensitivity. Interestingly, area postrema lesions did not normalize the baroreflex in CHF rabbits. From these data we conclude that the area postrema mediates the normalization of baroreflex sensitivity after AT(1) blockade in rabbits with CHF but does not modify resting baroreflex function.
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PMID:ANG II and baroreflex function in rabbits with CHF and lesions of the area postrema. 1040 14

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.
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PMID:Interactions between angiotensin II and nitric oxide during exercise in normal and heart failure rats. 1044 15

The purpose of this study was to elucidate the role of circulating ANG II in mediating changes in systemic and renal hemodynamics, salt and water balance, and neurohormonal activation during the early progression of heart failure. This objective was achieved by subjecting six dogs to 14 days of rapid ventricular pacing (240 beats/min) while fixing plasma ANG II concentration (by infusion of captopril + ANG II) either at approximately normal (days 1-8, 13-14) or at high physiological (days 9-12) levels. Salt and water retention occurred during the initial days of pacing before sodium and fluid balance was achieved by day 8. At this time, cardiac output and mean arterial pressure were reduced to approximately 55 and 75% of control, respectively; compared with cardiac output, reductions in renal blood flow were less pronounced. Although plasma ANG II concentration was maintained at approximately normal levels, there were sustained elevations in total peripheral resistance (to approximately 135% of control), filtration fraction (to approximately 118% of control), and plasma norepinephrine concentration (to 2-3 times control). During the subsequent high rate of ANG II infusion on days 9-12, there were no additional sustained long-term changes in either systemic or renal hemodynamics other than a further rise in right atrial pressure. However, high plasma levels of ANG II induced sustained antinatriuretic, sympathoexcitatory, and dipsogenic responses. Because these same long-term changes occur in association with activation of the renin-angiotensin system during the natural evolution of this disease, these results suggest that increased plasma levels of ANG II play a critical role in the spontaneous transition from compensated to decompensated heart failure.
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PMID:Influence of angiotensin on the early progression of heart failure. 1064 24

Angiotensin II (ANG II), the effector hormone of the renin-angiotensin system (RAS), has been implicated in the pathophysiology and progression of heart failure. Therefore, the measurement of ANG II has become important to characterize the role of this neurohormone in heart failure. However, because ANG II has been difficult to measure, other components of the RAS have been measured to characterize ANG II production. The RAS components (e.g., renin, angiotensin I-converting enzyme [ACE], angiotensin II) have been measured with a variety of techniques. In this review, RAS physiology and the techniques used to measure the RAS components are discussed. In addition, the advantages and disadvantages of the RAS measurement methods are described.
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PMID:Measurement of the renin-angiotensin system in heart failure. 1123 16

Using spontaneously hypertensive and aortic banded rats, we have shown that expression of myocardial osteopontin, an extracellular matrix protein, coincides with the development of heart failure and is inhibited by captopril, suggesting a role for angiotensin II (ANG II). This study tested whether ANG II induces osteopontin expression in adult rat ventricular myocytes and cardiac microvascular endothelial cells (CMEC), and if so, whether induction is mediated via activation of mitogen-activated protein kinases (p42/44 MAPK) and involves reactive oxygen species (ROS). ANG II (1 microM, 16 h) increased osteopontin expression (fold increase 3.3+/-0.34, n = 12, P < 0.01) in CMEC as measured by northern analysis, but not in ARVM. ANG II stimulated osteopontin expression in CMEC in a time- (within 4 h) and concentration-dependent manner, which was prevented by the AT1 receptor antagonist, losartan. ANG II elicited robust phosphorylation of p42/44 MAPK as measured using phospho-specific antibodies, and increased superoxide production as measured by cytochrome c reduction and lucigenin chemiluminescence assays. These effects were blocked by diphenylene iodonium (DPI), an inhibitor of the flavoprotein component of NAD(P)H oxidase. PD98059, an inhibitor of p42/44 MAPK pathway, and DPI each inhibited ANG II-stimulated osteopontin expression. Northern blot analysis showed basal expression of p22phox, a critical component of NADH/NADPH oxidase system, which was increased 40-60% by exposure to ANG II. These results suggest that p42/44 MAPK is a critical component of the ROS-sensitive signaling pathways activated by ANG II in CMEC and plays a key role in the regulation of osteopontin gene expression. Published 2001 Wiley-Liss, Inc.
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PMID:Regulation of angiotensin II-stimulated osteopontin expression in cardiac microvascular endothelial cells: role of p42/44 mitogen-activated protein kinase and reactive oxygen species. 1138 29

To examine if the neuroendocrine link between volume sensing and renal function is preserved in compensated chronic heart failure [HF, ejection fraction 0.29 +/- 0.03 (mean +/- SE)] we tested the hypothesis that intravascular and central blood volume expansion by 3 h of water immersion (WI) elicits a natriuresis. In HF, WI suppressed ANG II and aldosterone (Aldo) concentrations, increased the release of atrial natriuretic peptide (ANP), and elicited a natriuresis (P < 0.05 for all) compared with seated control. Compared with control subjects (n = 9), ANG II, Aldo, and ANP concentrations were increased (P < 0.05) in HF, whereas absolute and fractional sodium excretion rates were attenuated [47 +/- 16 vs. 88 +/- 15 micromol/min and 0.42 +/- 0.18 vs. 0.68 +/- 0.12% (mean +/- SE), respectively, both P < 0.05]. When ANG II and Aldo concentrations were further suppressed (P < 0.05) during WI in HF (by sustained angiotensin-converting enzyme inhibitor therapy, n = 9) absolute and fractional sodium excretion increased (P < 0.05) to the level of control subjects (108 +/- 34 micromol/min and 0.70 +/- 0.23%, respectively). Renal free water clearance increased during WI in control subjects but not in HF, albeit plasma vasopressin concentrations were similar in the two groups. In conclusion, the neuroendocrine link between volume sensing and renal sodium excretion is preserved in compensated HF. The natriuresis of WI is, however, modulated by the prevailing ANG II and Aldo concentrations. In contrast, renal free water clearance is attenuated in response to volume expansion in compensated HF despite normalized plasma AVP concentrations.
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PMID:Neuroendocrine and renal effects of intravascular volume expansion in compensated heart failure. 1144 48

We studied the gradual onset of pressure overload (PO) induced by a mildly constricting aortic band in 8-wk-old puppies (n = 8) that increased to 98 +/- 11 mmHg at 9 mo. Left ventricular (LV) weight/body weight was increased in PO versus sham-operated littermate controls [8.11 +/- 0.60 (SE) vs. 4.46 +/- 0.38 g/kg, P < 0.001]. LV end-diastolic diameter, diastolic pressure, and fractional shortening did not differ in PO versus control dogs. There were no inducible arrhythmias in response to an aggressive electrophysiological stimulation protocol in PO dogs. Furthermore, isolated cardiomyocyte function did not differ between control and PO dogs. LV angiotensin II (ANG II) levels were increased (68 +/- 12 vs. 20 +/- 5 pg/g, P < 0.01) as steady-state ANG II type 1 (AT(1)) receptor mRNA was decreased 40% and endothelial nitric oxide synthase mRNA levels were increased 2.5-fold in PO versus control dogs (P < 0.05). Total ANG II receptor binding sites of freshly prepared cardiac membranes demonstrated no difference in the dissociation constant, but there was a 60% decrease in maximum binding (B(max)) in PO versus control dogs (P < 0.01). LV ANG II levels correlated negatively with AT(1) receptor mRNA levels (r = -0.75, P < 0.01) and total AT(1) receptor B(max) (r = -0.77, P < 0.02). These results suggest that LV ANG II negatively regulates AT(1) receptor expression and that this is an adaptive response to chronic PO before the onset of myocardial failure in the young dog.
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PMID:Downregulation of ANG II receptor is associated with compensated pressure-overload hypertrophy in the young dog. 1178 26

All elements of the renin-angiotensin system (RAS) are present in the forebrain, particularly in circumventricular organs surrounding the third cerebral ventricle. We tested the hypothesis that forebrain angiotensin-converting enzyme (ACE) has a tonic excitatory influence on sympathetic drive. Neurally intact and sinoaortic-denervated pentobarbital-anesthetized rats were treated with forebrain-directed intracarotid artery (ICA) versus intravenous injections of angiotensin I (ANG I) and of the ACE inhibitor captopril. In intact rats, ICA ANG I elicited a rise in arterial pressure and a concomitant reduction in renal sympathetic nerve activity (RSNA; ICA captopril elicited the opposite responses). In barodenervated rats, ICA ANG I increased and ICA captopril decreased arterial pressure and RSNA in parallel; intravenous ANG I had no effect on RSNA. The findings suggest that the intrinsic forebrain RAS has a tonic excitatory influence on sympathetic drive that is overshadowed in normal rats by baroreflex mechanisms, but may assume a more prominent role in pathophysiological states (e.g., heart failure) in which baroreflex mechanisms are impaired and RAS activity is augmented.
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PMID:Forebrain renin-angiotensin system has a tonic excitatory influence on renal sympathetic nerve activity. 1183 83

The purpose of this study was to determine if the cardiac sympathetic afferent reflex (CSAR) was augmented in rats with coronary ligation-induced chronic heart failure (CHF), and if central angiotensin II (ANG II) was involved in this enhancement. Under alpha-chloralose and urethane anesthesia, mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded in sino-aortic denervated and cervical vagotomized rats. An intracerebroventricular cannula was implanted. The CSAR was examined by epicardial application of bradykinin (BK, 0.04 and 0.4 microg in 2.0 microl) or capsaicin (0.04 and 0.4 microg in 2.0 microl) to the anterior and posterior wall of the left ventricle. The CSAR evoked by BK or capsaicin was augmented in rats with CHF. In sham rats, there was no significant difference of the CSAR induced by BK or capsaicin between anterior and posterior epicardial application. However, in rats with CHF, the CSAR induced by BK (0.04 microg) to anterior epicardial application was blunted compared with posterior application. Intracerebroventricular injection of losartan (500 nmol) normalized the enhanced CSAR in rats with CHF, but had no significant effects on the CSAR in sham rats. However, intravenous application of the same dose of losartan only decreased the baseline MAP, but did not alter baseline RSNA or the CSAR in sham or CHF rats. Pre-treatment with epicardial application of lidocaine to the anterior wall abolished the CSAR evoked by application of BK or capsaicin but had no effects on the CSAR evoked by epicardial application of BK or capsaicin to the posterior wall. These results suggest that the CSAR induced by epicardial application of BK and capsaicin is enhanced in the rats with CHF, and the enhanced CSAR is mediated by central AT(1) receptors.
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PMID:Central AT1 receptors are involved in the enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure. 1211 Oct 42

Heart failure and hypertension are associated with increases in angiotensin II (ANG II) activity. One brain area where ANG II effects may be particularly important in these situations is the nucleus of the solitary tract (NTS). Located in the dorsomedial medulla, the NTS is the termination site of baroreceptor afferents and is essential for mediating the baroreflex. In hypertensive animals the baroreflex is impaired; this may be reversed by antagonizing ANG II AT1 receptors in the NTS. Recently, we showed that the baroreflex depressant action of ANG II in the NTS is mediated by activation of endothelial nitric oxide synthase (eNOS) and enhanced release of GABA. Using conventional pharmacological tools and a range of adenoviral-mediated expression of dominant negative proteins, we have determined the intracellular pathway(s) in the NTS by which ANG II activates eNOS. Our data indicate that ANG II acting in the NTS depresses the baroreflex via a Gq protein-mediated activation of phospholipase C, which through 1,4,5-inositol triphosphate causes release of calcium from the IP3-sensitive intracellular stores and calcium-calmodulin formation. In contrast, multiple site disruption of a pathway leading to eNOS activation via the serine/threonine kinase Akt was ineffective
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PMID:Genetic and pharmacological dissection of pathways involved in the angiotensin II-mediated depression of baroreflex function. 1237 82


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