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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the differential rate and extent of down regulation and recovery of rat myocardial beta adrenoceptor subtypes during and after short term (up to 72 h) subcutaneous isoprenaline infusions (40 micrograms/kg per h) in vivo using osmotic minipumps. Maximum density (Bmax) of the receptors in ventricular membranes was assessed by radioligand binding, saturation analysis using 125I-pindolol. Groups of animals were sacrificed following various agonist infusion times and then during recovery after removal of minipumps following initial infusion of isoprenaline for 72 h. During agonist infusion, beta 2 adrenoceptors down regulated significantly more rapidly and to a greater extent than the beta 1 subtype (maximum change from control 66% beta 2, 34% beta 1 P less than 0.05). In the recovery phase of the experiments following initial maximum down regulation, beta 2 adrenoceptor density also returned to control values more rapidly (by 24 h) than the beta 1 subtype (greater than 72 h). These results are qualitatively different to those reported in other tissues from this species using selective and non selective catecholamine agonists and in human myocardium in end stage heart failure following chronic sympathetic nervous stimulation. This may be due to differences in tissue cellular composition, the nature/selectivity of the agonist or the length of time of agonist exposure.
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PMID:Differential rates of down regulation and recovery of rat myocardial beta-adrenoceptor subtypes in vivo. 217 48

The syndrome of heart failure results from inappropriate sodium and water retention by the kidneys which results, at least in part, from changes in renal haemodynamics. Renal blood flow at rest in heart failure is reduced in proportion to the reduction in cardiac output and falls dramatically during exercise as the cardiac output is redistributed to the exercising muscles. Both these phenomena are associated with a rise in plasma noradrenaline concentration. Afferent arteriolar tone is partly controlled by alpha-adrenoceptor stimulation while stimulation of beta 2-receptors will stimulate renal release of renin; through the elaboration of angiotensin II, profound effects on extra- and intra-renal vascular tone can occur. Although alpha-adrenoceptor stimulation can result in coronary vasoconstriction and a fall in coronary blood flow in patients with heart failure due to underlying atheromatous coronary heart disease, increased myocardial oxygen demand as the result of beta 1 (and cardiac beta 2) simulation may be more relevant. The control of limb blood flow is of great importance symptomatically. The systemic vasoconstriction that typifies the severe heart failure state has been a target for many vasodilatory interventions including alpha 1-receptor blockade and beta 2-receptor stimulation. Unfortunately, there is little evidence that such treatment leads to any specific increase in muscle blood flow either at rest or during exercise. In severe heart failure, sympathetic activity is increased at rest leading to vasoconstriction in several vascular beds, while in milder heart failure, excessive sympathetic stimulation is evident only during exercise. In either circumstance, however, it is evident that certain advantages may accrue from modulation of this excessive sympathetic activity.
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PMID:Sympathetic activity and regional blood flow in heart failure. 218 37

Corwin is a new, long-acting beta 1-adrenergic partial agonist for oral and intravenous (i.v.) use. The effects of corwin were compared with those of dobutamine in acute ischemic left ventricular failure in dogs. Failure was produced by embolization of the left main coronary artery with 50 micron plastic microspheres. This induced severe depression in left ventricular function, as evidenced by a marked increase in left ventricular end-diastolic pressure, reduction in left ventricular dP/dtmax, and cardiac output. After 45 min was allowed for stabilization, the 27 dogs were randomly assigned to three groups: control (n = 9), dobutamine-treated (5-10 micrograms/kg/min i.v., n = 9), and corwin-treated (0.025-0.10 mg/kg i.v., n = 9). The doses of dobutamine and corwin were adjusted to give an increase in left ventricular dP/dtmax of 50%. Both drugs similarly increased cardiac output (p less than 0.01), lowered left ventricular end-diastolic pressure (p less than 0.01) and total peripheral vascular resistance (p less than 0.01), but did not affect the heart rate. Only dobutamine increased the mean arterial pressure (p less than 0.01). Both drugs also increased the arterial concentrations and myocardial uptake of fatty acids (p less than 0.05) but caused only a small and nonsignificant increase in myocardial oxygen consumption. Our findings indicate that the hemodynamic and metabolic profiles of corwin and dobutamine are similar, and both drugs should be of special value in the treatment of congestive heart failure. Since corwin can be given orally and has a longer duration of action, it is potentially useful in the long-term treatment of heart failure.
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PMID:Comparative effects of dobutamine and corwin, a beta 1-adrenergic partial agonist, in experimental left ventricular failure. 241 Jul 22

We evaluated the amount of beta 1- and beta 2-adrenoceptors in human right and left atrium as well as in right and left ventricular wall obtained from heart transplant recipients who suffered from end-stage congestive cardiomyopathy. The total number of myocardial beta-adrenoceptors was assessed with the nonsubtype selective beta-adrenoceptor radioligand (-)[125I]iodocyanopindolol (ICYP); concomitantly, the number of beta 1-adrenoceptors was determined with the selective beta 1-adrenoceptor radioligand (-)[3H]bisoprolol. The number of beta 2-adrenoceptors was calculated by subtracting (-)[3H]bisoprolol binding sites from ICYP binding sites. With this technique, a beta 1/beta 2-ratio of approximately 65/35% for both atria and of approximately 75/25% for both ventricles was found. Identical results were obtained when the beta 1/beta 2-ratio was calculated indirectly by nonlinear regression analysis of competition curves of the selective beta 1-adrenoceptor antagonist bisoprolol and the selective beta 2-adrenoceptor antagonist ICI 118,551 with ICYP binding. In addition, on atria and on ventricles, adenylate cyclase was activated by norepinephrine (presumably by beta 1- and beta 2-adrenoceptor stimulation) and by procaterol (by beta 2-adrenoceptor stimulation). It is concluded that in the human heart functional beta 1- and beta 2-adrenoceptors coexist on both atria and both ventricles. In end-stage congestive cardiomyopathy, there appears to be a selective down-regulation of cardiac beta 1-adrenoceptors, whereas beta 2-adrenoceptors are obviously not affected. This may explain the beneficial effects of beta 2-adrenoceptor agonists in severe heart failure.
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PMID:Regional distribution of beta-adrenoceptors in the human heart: coexistence of functional beta 1- and beta 2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. 243 52

A prospective randomised trial compared the immediate haemodynamic effects of intravenous diuretic (frusemide), venodilator (isosorbide dinitrate), arteriolar dilator (hydralazine), and positive inotropic stimulation (prenalterol) as first-line therapy for acute left ventricular (LV) failure following myocardial infarction. Forty-eight patients with transmural myocardial infarction and a pulmonary artery occluded pressure (PAOP) of greater than 20 mm Hg were studied within 18 h of admission to a coronary care unit. Both frusemide (-4 mm Hg; p less than 0.01) and isosorbide dinitrate (-6 mm Hg; p less than 0.01) reduced LV filling pressure without change in cardiac index and heart rate. Although both hydralazine and prenalterol increased cardiac index (p less than 0.01), the reduction in LV filling pressure (-2 mm Hg; p less than 0.05) was less than with frusemide and isosorbide dinitrate, and was associated with an increased heart rate (+8 and +13 beats min-1; p less than 0.01). These data suggest that in acute heart failure following myocardial infarction the four treatment modalities could be ranked in descending order of potential benefit as follows: venodilatation (isosorbide dinitrate)--decrease of LV pressure/work; diuretic therapy (frusemide)--decrease of LV pressure/work offset by a transient pressor effect; arteriolar dilatation (hydralazine)--decrease of LV pressure/work and of PAOP, but offset by tachycardia; and positive inotropic therapy (beta 1-agonist prenalterol)--tachycardia and augmented LV afterload. Combination of the former and latter agents, because of their differing modes of action, should offer haemodynamic advantages over monotherapy and deserves further evaluation.
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PMID:First-line treatment of left ventricular failure complicating acute myocardial infarction: a randomised evaluation of immediate effects of diuretic, venodilator, arteriodilator, and positive inotropic drugs on left ventricular function. 244 Nov 52

The results of the present study show that the reduction of the total number of beta adrenoceptors affected the beta 1-adrenoceptor subpopulation, whereas the beta 2 adrenoceptors were not detectably altered in the failing heart. Dopexamine had a 9.8-fold greater affinity to beta 2 adrenoceptors than to beta 1 adrenoceptors. In nonfailing myocardium, dopexamine increased force of contraction concentration-dependently. However, dopexamine alone had no effect in papillary muscle strips from moderately (NYHA II-III) and severely (NYHA IV) failing myocardium. However, in the presence of milrinone, it concentration-dependently increased force of contraction. Under this condition, the effectiveness was slightly less pronounced in NYHA IV than in NYHA II-III. Dopexamine concentration-dependently stimulated adenylate cyclase activity. Experiments with the beta 1-selective antagonist CGP 207.12 A and the beta 2-selective antagonist ICI 118.551 showed that both stimulation of adenylate cyclase and the increase of force of contraction are mediated by beta 2 adrenoceptors. It is concluded that although the number of beta 2 adrenoceptors is preserved in the failing myocardium, dopexamine alone does not increase force of contraction. However, the positive inotropic effect of dopexamine, which is observed in the presence of milrinone and the stimulation of adenylate cyclase activity by dopexamine are mediated by beta 2 adrenoceptors. Therefore, beta 2 adrenoceptors exist in the human myocardium, are coupled to adenylate cyclase, and are capable of increasing force of contraction. These results provide evidence for an impaired coupling of beta 2 adrenoceptors to mechanisms beyond receptor occupation in terminal heart failure.
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PMID:Reduced effects of dopexamine on force of contraction in the failing human heart despite preserved beta 2-adrenoceptor subpopulation. 247 68

The impaired inotropic responsiveness of myocardial tissue to catecholamines in congestive heart failure has been ascribed to downregulation of beta-adrenergic receptors. It has been reported recently that resistance to catecholamines is related to a defect in the guanine nucleotide binding protein that couples the beta-adrenergic receptor to adenylate cyclase. Studies of beta-adrenergic receptors were carried out using three different experimental protocols: (a) the interactions of the atypical agonists pindolol and celiprolol with beta-adrenergic receptors from C6 glioma cells (40% beta 1, 60% beta 2) were compared with those of the full agonist isoproterenol; (b) the ability of pindolol, celiprolol, and isoproterenol to induce downregulation and sequestration of beta-adrenergic receptors in wild-type S49 lymphoma cells was compared with the responses observed with a mutant line of S49 cells (cyc-, which lack Gs activity); and (c) the differential response of patients with heart failure and age-matched control subjects to exercise-induced changes in the density of beta-adrenergic receptors and isoproterenol-stimulated adenylate cyclase activity on circulating lymphocytes was investigated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of downregulation of beta-adrenergic receptors: perspective on the role of beta-adrenergic receptors in congestive heart failure. 247 5

The sympathetic nervous system is markedly activated in most patients with congestive heart failure, but it is not clear whether such activity is clinically beneficial (and should be enhanced) or detrimental (and should be blocked). Some insights into this question can be gained by reviewing the results of clinical trials with beta-adrenergic agonists and antagonists. Long-term treatment with agents that stimulate the beta-receptor (prenalterol and pirbuterol) has not proved to be useful in the treatment of chronic heart failure; moreover, prolonged treatment with beta-agonists (dobutamine and pirbuterol) may adversely affect survival. Most of the studies with beta-agonists, however, have employed agents that interact nonselectively and with a high degree of intrinsic activity with both beta 1-and beta 2-receptors. It is possible that the problems that have been encountered with the use of beta-agonists could be minimized by agents that are more selective and have less intrinsic activity. Yet, such agents may actually function as beta-adrenergic antagonists (rather than agonists) in states of heightened sympathetic activity. Indeed, sustained therapy with drugs that attenuate the effects of the sympathetic nervous system (by blocking tyrosine hydroxylase or beta-adrenergic receptors) may produce hemodynamic and clinical improvement and may reduce long-term mortality in chronic heart failure. Although beta-adrenergic blockade carries important risks, these might be minimized by the use of drugs that spare myocardial and vascular beta 2-receptors or possess some intrinsic agonist activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Is activation of the sympathetic nervous system beneficial or detrimental to the patient with chronic heart failure? Lessons learned from clinical trials with beta-adrenergic agonists and antagonists. 247 8

The pharmacokinetics of xamoterol, a beta 1-adrenoceptor partial agonist, have been studied in patients with liver disease and a group of age- and sex-matched normal controls. No significant differences were observed after the oral administration of xamoterol 200 mg. The low bioavailability of xamoterol was confirmed (6.1% in patients, 6.9% in controls). After i.v. xamoterol 0.2 mg kg-1, no significant differences between the groups were observed. A small increase in the terminal plasma elimination half-life (t1/2) was observed in patients when compared with controls (15.3 +/- 6.4 vs 8.4 +/- 2.8 h, mean +/- s.d., P = 0.08). Renal clearance accounted for about 50% of total clearance in patients and about 30% in controls. It is suggested that in patients with heart failure, hepatic dysfunction would probably not influence xamoterol disposition.
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PMID:The pharmacokinetics of xamoterol in liver disease. 253 23

Quantitative autoradiography was used to determine the location and density of beta 1- and beta 2-adrenoceptors in the right atrium (RA), left ventricular free wall (LVFW), right ventricular free wall (RVFW), interventricular septum (IVS), right atrium from an area near the atrioventricular node (RAAV) and cardiac nerves (N) taken from a patient with end-stage cardiac failure. The densities of beta-adrenoceptors detected by the non-selective beta-adrenoceptor antagonist radioligand (-)-[125I] cyanopindolol (50pM) were 4.93 (N), 10.6 (RVFW), 12.2 (RA), 12.4 (IVS), 15.8 (LVFW) and 18.7 fmol (mg protein)-1 (RAAV). The proportion of beta 2-adrenoceptors ranged from 19.5% (RAAV) to 95% (N). RA taken from patients with ischaemic heart disease had a higher density of beta-adrenoceptors (29.3 fmol (mg protein)-1). The results suggest that both beta 1- and beta 2-adrenoceptors are down-regulated in patients with end-stage cardiac failure. Positive inotropic responses were established to (-)-isoprenaline, RO363 (beta 1-selective), procaterol (beta 2-selective) and dopexamine in the absence or presence of the antagonist CGP 20712A (beta 1-selective) or ICI 118,551 (beta 2-selective) in electrically driven human right atrial appendage strips. RO363 and procaterol were nearly full agonists in this preparation and produced their responses through activation of beta 1- or beta 2-adrenoceptors, while dopexamine was a partial agonist which produced its inotropic responses through activation of both receptor subtypes. These studies demonstrate the presence and location of beta 1- and beta 2-adrenoceptors in the human heart.
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PMID:Coexistence and localization of beta 1- and beta 2-adrenoceptors in the human heart. 255 7


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