Background-Inhibition of L-type Ca 2ϩ current contributes to negative inotropy of ␤ 3 adrenergic receptor (␤ 3 AR) activation, but effects on other determinants of excitation-contraction coupling are not known. Of these, the Na ϩ -K ϩ pump is of particular interest because of adverse effects attributed to high cardiac myocyte Na ϩ levels and upregulation of the ␤ 3 AR in heart failure. Methods and Results-We voltage clamped rabbit ventricular myocytes and identified electrogenic Na ϩ -K ϩ pump current (I p ) as the shift in holding current induced by ouabain. The synthetic ␤ 3 AR agonists BRL37344 and CL316,243 and the natural agonist norepinephrine increased I p . Pump stimulation was insensitive to the ␤ 1 /␤ 2 AR antagonist nadolol and the protein kinase A inhibitor H-89 but sensitive to the ␤ 3 AR antagonist L-748,337. Blockade of nitric oxide synthase abolished pump stimulation and an increase in fluorescence of myocytes loaded with a nitric oxide-sensitive dye. Exposure of myocytes to ␤ 3 AR agonists decreased ␤ 1 Na ϩ -K ϩ pump subunit glutathionylation, an oxidative modification that causes pump inhibition. The in vivo relevance of this was indicated by an increase in myocardial ␤ 1 pump subunit glutathionylation with elimination of ␤ 3 AR-mediated signaling in ␤ 3 AR Ϫ/Ϫ mice. The in vivo effect of BRL37344 on contractility of the nonfailing and failing heart in sheep was consistent with a beneficial effect of Na ϩ -K ϩ pump stimulation in heart failure. Conclusions-The ␤ 3 AR mediates decreased ␤ 1 subunit glutathionylation and Na ϩ -K ϩ pump stimulation in the heart. Upregulation of the receptor in heart failure may be a beneficial mechanism that facilitates the export of excess Na ϩ . (Circulation. 2010;122:2699-2708.)Key Words: heart failure Ⅲ molecular biology Ⅲ myocardium Ⅲ nitric oxide synthase Ⅲ receptors, adrenergic T he ␤ 3 adrenergic receptor (␤ 3 AR) differs from ␤ 1 /␤ 2 ARs in its molecular structure, genetic coding, 1,2 and affinities for adrenergic ligands. 3 Cellular responses to receptor activation also differ. In cardiac tissue, ␤ 3 AR activation decreases contractility, contrasting with the increase mediated by the ␤ 1 AR. 4 Consistent with this, ␤ 3 AR activation is associated with a decrease in the amplitude of the cytosolic Ca 2ϩ transient that initiates contraction. 5-7 Inhibition of sarcolemmal L-type Ca 2ϩ current 5,7 that triggers release of sarcoplasmic reticulum Ca 2ϩ is likely to contribute to this. However, effects of ␤ 3 AR activation on other proteins that are important for excitation-contraction coupling remain to be determined. 7 The membrane Na ϩ -K ϩ pump is of particular interest because it maintains the transmembrane electrochemical gradient for Na ϩ that provides the electrochemical energy for the Na ϩ -Ca 2ϩ exchanger, quantitatively the most important determinant of total cell Ca 2ϩ and hence sarcoplasmic reticulum Ca 2ϩ that is triggered for release during systole. A modest increase in the intracellular Na ϩ concentration, and hence cell Ca 2ϩ , increases con...

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Apoptosis of cardiomyocytes in chronic HF is associated with increased wall stress, which may be responsible for the activation of a Fas/FasL and caspase-8 interaction in the region of intercalated discs.

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Summary and conclusionsFifty-three pregnant women with moderately severe hypertension were randomly allocated to treatment with methyldopa or oxprenolol. There were no significant differences between the groups in age, height, weight, parity, or To examine the effects of antihypertensive treatment more closely and to evaluate alternative forms of treatment we conducted a randomised comparison of methyldopa and a non-selective beta-adrenoceptor-blocking drug, oxprenolol.

Acute myocardial infarction (AMI) is one of the leading causes of mortality and morbidity worldwide. There has been an extensive search for cardioprotective therapies to reduce myocardial ischemia-reperfusion (I/R) injury. Remote ischemic preconditioning (RIPC) is a phenomenon that relies on the body's endogenous protective modalities against I/R injury. In RIPC, non-lethal brief I/R of one organ or tissue confers protection against subsequent lethal I/R injury in an organ remote to the briefly ischemic organ or tissue. Initially it was believed to be limited to direct myocardial protection, however it soon became apparent that RIPC applied to other organs such as kidney, liver, intestine, skeletal muscle can reduce myocardial infarct size. Intriguing discoveries have been made in extending the concept of RIPC to other organs than the heart. Over the years, the underlying mechanisms of RIPC have been widely sought and discussed. The involvement of blood-borne factors as mediators of RIPC has been suggested by a number of research groups. The main purpose of this review article is to summarize the possible circulating mediators of RIPC, and recent studies to establish the clinical efficacy of these mediators in cardioprotection from lethal I/R injury.

Left ventricular (LV) remodeling is a process whereby structural alterations attempt to compensate altered hemodynamic load. In the chronic setting this process becomes maladaptive, self-sustaining and is associated with worsened survival. The extracellular matrix (ECM) of the heart, once believed an inert scaffold for cardiomyocytes, is now known to play an important role in LV remodeling. The enzyme system primarily responsible for ECM turnover is the matrix metalloproteinases (MMPs), and these enzymes are robustly altered in cardiovascular pathologies, including myocardial infarction (MI) and ischemic heart failure. A cause-and-effect relationship has been established between MMPs and LV remodeling post MI, as MMP inhibition prevents LV dilation and preserves cardiac function in animal models of infarction. In spite of this, initial clinical experience with MMP inhibition post MI has been disappointing. This review examines the structural and functional roles of the myocardial ECM, the evidence for MMP involvement in LV remodeling, and recent investigations into MMPs as prognostic markers and therapeutic targets.