How flow changes polymer depletion in a slit.

A theoretical model is developed for predicting dynamic polymer depletion under the influence of fluid flow. The results are established by combining the two-fluid model and the self-consistent field theory. We consider a uniform fluid flow across a slit containing a solution with polymer chains. The two parallel and infinitely long walls are permeable to solvent only and the polymers do not adsorb to these walls. For a weak flow and a narrow slit, an analytic expression is derived to describe the steady-state polymer concentration profiles in a Θ-solvent. In both Θ- and good-solvents, we compute the time evolution of the concentration profiles for various flow rates characterized by the Peclet number. The model reveals the interplay of depletion, solvent condition, slit width, and the relative strength of the fluid flow.

Compaction of ordered dithered images with arithmetic coding.

Ordered dither is considered to be a simple and effective method among all halftoning techniques. In this paper, compaction of ordered dithered images using arithmetic coding is studied. A preprocessor referred to as pixel interleaving (i.e., grouping pixels with similar dithering thresholds) is employed in such a way that dithered images can be efficiently coded with the JBIG1 code and high compressibility can be achieved. Experimental results reveal that the four-pixel interleaving achieves the best compression performance.

ACE inhibition improves cardiac NE uptake and attenuates sympathetic nerve terminal abnormalities in heart failure.

Cardiac sympathetic nerve terminal dysfunction plays an important role in the downregulation of myocardial beta-adrenoceptors in heart failure. To determine whether chronic angiotensin-converting enzyme (ACE) inhibition improved cardiac sympathetic nerve terminal function and hence increased myocardial beta-adrenergic responsiveness, we administered ACE inhibitors to dogs with chronic right-sided heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. The RHF animals exhibited fluid retention, elevated right heart filling pressures, blunted inotropic response to isoproterenol, and reduced beta-adrenoceptor density. These changes were accompanied by decreases in right ventricular norepinephrine (NE) uptake and neuronal NE histofluorescence and tyrosine hydroxylase immunoreactive profiles. ACE inhibitors had no effect on the production of heart failure but greatly reduced the attenuation of cardiac NE uptake, neuronal NE histofluorescence, and tyrosine hydroxylase immunoreactive profiles. ACE inhibition also improved the inotropic response to isoproterenol and restored myocardial beta-adrenoceptor density. The changes probably are caused by reduction of cardiac NE release by ACE inhibition and may contribute to the beneficial effects of ACE inhibitor therapy in patients with chronic heart failure.

Elevated myocardial interstitial norepinephrine concentration contributes to the regulation of Na+,K(+)-ATPase in heart failure.

Myocardial Na+,K(+)-ATPase is reduced in congestive heart failure. To study the regulation of Na+,K(+)-ATPase in congestive heart failure, we performed Western and Northern blot analyses of ventricular myocardium of dogs with pacing-induced congestive heart failure and chronic norepinephrine infusion, using isoform-specific antibodies and cDNA probes. Congestive heart failure and norepinephrine infusion caused similar increases in myocardial interstitial norepinephrine concentration and reductions of myocardial Na+,K(+)-ATPase alpha 3-subunit protein, but differed in their effects on myocardial Na+,K(+)-ATPase alpha 3-subunit gene expression. Chronic norepinephrine infusion produced no changes in the steady-state mRNA level for the alpha 3-subunit of Na+,K(+)-ATPase, suggesting that the changes in Na+,K(+)-ATPase protein were induced via a post-transcriptional mechanism. In contrast, down-regulation of the Na+,K(+)-ATPase alpha 3-subunit in the failing heart was accompanied by a decreased alpha 3-subunit mRNA level, indicating the presence of a transcriptional event. The alpha 1-subunit protein content and mRNA level were not affected by either norepinephrine infusion or rapid ventricular pacing. We conclude that, while elevated myocardial interstitial norepinephrine levels may contribute substantially to the down-regulation of the Na+,K(+)-ATPase alpha 3-subunit in the failing myocardium, additional regulatory factors are responsible for the decreased myocardial alpha 3-subunit mRNA expression in congestive heart failure.

Isoform-specific regulation of myocardial Na,K-ATPase alpha-subunit in congestive heart failure. Role of norepinephrine.

BACKGROUND: Myocardial ouabain-binding sites and Na,K-ATPase activity are reduced in congestive heart failure (CHF), but the mechanisms by which CHF reduces the Na,K-ATPase remain unknown. We proposed to investigate whether the changes are accompanied by isoform-specific reductions of the Na,K-ATPase alpha-subunit proteins in CHF and whether similar changes could be produced by exogenous norepinephrine administration. METHODS AND RESULTS: CHF was induced in dogs by rapid ventricular pacing at a rate of 225 beats per minute for 8 weeks (protocol 1). A second group of dogs were paced at 100 beats per minute and served as controls. In protocol 2, norepinephrine was infused in normal dogs using a subcutaneous osmotic minipump for 8 weeks. The control dogs received normal saline through the pump. Animals were studied after 8 weeks of pacing or norepinephrine infusion. After the baseline hemodynamics and interstitial norepinephrine concentration had been obtained, the hearts were removed for measuring [3H]ouabain-binding sites and Na,K-ATPase alpha-subunit proteins using isoform-specific monoclonal antibodies. RESULTS: Myocardial [3H]ouabain-binding sites were reduced in dogs with CHF and chronic norepinephrine infusion. The Western blot analysis showed that adult canine hearts possess both alpha 1 and alpha 3 isoforms of the Na,K-ATPase alpha-subunit but not the alpha 2 isoform protein. CHF and NE infusion had no effect on the Na,K-ATPase alpha 1-subunit protein but did reduce the alpha 3 isoform protein significantly. In addition, there was a significant inverse correlation between the amount of myocardial alpha 3 isoform protein and interstitial norepinephrine content in the dogs. In contrast, the specific activity of the sarcolemmal marker 5'-nucleotidase did not differ among the groups of animals. CONCLUSIONS: The reduction of myocardial Na,K-ATPase in CHF is limited to the alpha 3 isoform. Furthermore, because similar changes in myocardial ouabain-binding sites and Na,K-ATPase alpha 3 isoform were produced by chronic norepinephrine infusion, the decrease in the Na,K-ATPase in CHF is most likely mediated via excess sympathetic stimulation.

Reductions of myocardial Na-K-ATPase activity and ouabain binding sites in heart failure: prevention by nadolol.

To study the changes in myocardial digitalis binding sites in heart failure, we measured myocardial ouabain binding sites, Na-K-adenosinetriphosphatase (ATPase) activity, and ventricular muscle mechanical responses to acetylstrophanthidin in dogs with right-heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. Sham-operated dogs were studied as the control. RHF produced a significant decrease in ouabain binding sites in the right and left ventricular myocardium, which was accompanied by a proportional decrease in Na-K-ATPase activity. However, RHF and sham-operated dogs did not differ in systemic hemodynamic or right ventricular trabeculate muscle isometric contractile responses to acetylstrophanthidin. To determine whether chronic beta-adrenergic stimulation contributed to the development of Na-K-ATPase downregulation, we administered nadolol (40 mg/day) to a separate group of dogs during an early stage of RHF development. Nadolol effectively prevented the reduction of myocardial ouabain binding sites that occurred in RHF. Thus we conclude that myocardial ouabain binding sites and Na-K-ATPase activity are reduced in dogs with experimental heart failure and that these changes probably occur as a result of the attendant heightened sympathetic activity.

Both cell surface and internalized beta-adrenoceptors are reduced in the failing myocardium.

To study myocardial beta-adrenoceptor internalization in heart failure, we measured beta-adrenoceptor density in the particulate, light vesicle and supernatant fractions of ventricular tissue of dogs with experimental right ventricular failure and sham-operated dogs. Tissue was fractionated by centrifugation, and beta-adrenoceptors were measured by [125I]iodocyanopindolol binding. Compared to sham-operated controls, beta-adrenoceptors were reduced in all fractions of right ventricular tissue from heart failure animals. Thus, the decreased surface (particulate fraction) receptors observed cannot be explained by internalization alone, and must be associated with altered receptor synthesis or degradation.

Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation.

The reduction of myocardial beta-adrenoceptor density in congestive heart failure has been thought to be caused by agonist-induced homologous desensitization. However, recent evidence suggests that excessive adrenergic stimulation may not produce myocardial beta-receptor downregulation unless there is an additional defect in the local norepinephrine (NE) uptake mechanism. To investigate the association between beta-adrenoceptor regulation and NE uptake activity, we carried out studies in 30 dogs with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary artery constriction and 23 sham-operated control dogs. We determined NE uptake activity by measuring accumulation of [3H]NE in tissue slices, NE uptake-1 carrier density by [3H]mazindol binding and beta-adrenoceptor density by [3H]dihydroalprenolol binding. Compared with sham-operated dogs, RHF dogs showed a 26% decrease in beta-adrenoceptor density, a 51% reduction in NE uptake activity, and a 57% decrease in NE uptake-1 carrier density in their right ventricles. In addition, right ventricle beta-receptor density correlated significantly with NE uptake activity and NE uptake-1 carrier density. In contrast, neither NE uptake activity nor beta-receptor density in the left ventricle and renal cortex was affected by RHF. Thus, the failing myocardium is associated with an organ- and chamber-specific subnormal neuronal NE uptake. This chamber-specific loss of NE uptake-1 carrier could effectively reduce local NE clearance, and represent a local factor that predisposes the failing ventricle to beta-adrenoceptor downregulation.

Alterations in cardiac beta-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs.

The effects of congestive heart failure on the physiological and biochemical functions of the cardiac beta-adrenoceptor-coupled adenylate cyclase system were studied in dogs with right heart failure produced by progressive pulmonary artery constriction and tricuspid avulsion. The cardiac inotropic response to dobutamine was attenuated in congestive heart failure, as determined by the right and left ventricular dP/dt responses. Adrenergic beta-receptor density, measured by [3H]dihydroalprenolol binding, was reduced in membrane fractions of the failing right ventricle, but not in the left ventricle. The functional activity of the adenylate cyclase system was studied in vitro by measuring the net cyclic AMP production following additions of isoproterenol, 5'-guanylylimidodiphosphate (Gpp(NH)p), forskolin, or manganese chloride, which act either directly on the beta-adrenergic receptors or on one of the post-receptor components of the adenylate cyclase system. Congestive heart failure reduced the net production of cyclic AMP by isoproterenol, Gpp(NH)p, and forskolin in both the right and left ventricles, but did not alter the effect of manganese chloride. Thus, beta-receptor down-regulation is chamber-specific, occurring only in the hemodynamically stressed right ventricle. In contrast, the post-receptor defect of the adenylate cyclase system occurred in both ventricles of the heart failure dogs. This decreased activation of adenylate cyclase by beta-agonists may be responsible, at least in part, for the diminished cardiac inotropic response to catecholamines in congestive heart failure.

Age-related reduction of beta-adrenoceptor sensitivity in rat heart occurs by multiple mechanisms.

Myocardial responsiveness to catecholamines was evaluated by measuring isoproterenol-stimulated adenylate cyclase activities in myocardial particulate fractions from Fischer 344 rats of 3, 12, and 24 months of age. Dose-response curves of isoproterenol revealed a progressive increase in the activation constant (Kact) with advancing age. In addition, the maximal velocity (Vmax) for 12- and 24-month-old groups was about 20-25% lower than for the 3-month-old group. Analysis of receptor-binding data and nonreceptor-mediated enzyme activities suggests that the age-related decrease in Vmax for isoproterenol may result from a loss of myocardial beta-receptors, whereas the increase in Kact is probably due to a deficit in the postreceptor components of the receptor-cyclase complex.