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Atrial fibrillation (AF) is the most common arrhythmia seen in general practice. Muscarinic ACh receptors (M2R, M3R) are involved in vagally induced AF. M2R and M3R activate the heterotrimeric G proteins, [G.sub.i] and [G.sub.q], respectively, by promoting GTP binding, and these in turn activate distinct [K.sup.+] channels. Signaling is terminated by GTP hydrolysis, a process accelerated by regulator of G protein signaling (RGS) proteins. RGS2 is selective for [G.sub.q] and thus may regulate atrial M3R signaling. We hypothesized that knockout of RGS2 ([RGS2.sup.-/-] ) would render the atria more susceptible to electrically induced AF. One-month-old male [RGS2.sup.-/-] and C57BL/6 wild-type (WT) mice were instrumented for intracardiac electrophysiology. Atrial effective refractory periods (AERPs) were also determined in the absence and presence of carbachol, atropine, and/or the selective M3R antagonist darifenacin. Susceptibility to electrically induced AF used burst pacing and programmed electrical stimulation with one extrastimulus. Real-time RT-PCR measured atrial and ventricular content of RGS2, RGS4, M2R, M3R, and M4R mRNA. AERP was lower in [RGS2.sup.-/-] compared with WT mice in both the high right atrium (HRA) (30 [+ or -] 1 vs. 34 [+ or -] 1 ms, P < 0.05) and mid right atrium (MRA) (21 [+ or -] 1 vs. 24 [+ or -] 1 ms, P < 0.05). Darifenacin eliminated this difference (HRA: 37 [+ or -] 2 vs. 39 [+ or -] 2 ms, and MRA: 30 [+ or -] 2 vs. 30 [+ or -] 1, P > 0.4). [RGS2.sup.-/-] were more susceptible than WT mice to atrial tachycardia/fibrillation (AT/F) induction (11/22 vs. 1/25, respectively, P < 0.05). Muscarinic receptor expression did not differ between strains, whereas M2R expression was 70-fold higher than M3R (P < 0.01). These results suggest that RGS2 is an important cholinergic regulator in the atrium and that [RGS2.sup.-/-] mice have enhanced susceptibility to AT/F via enhanced M3 muscarinic receptor activity. autonomic; atrial fibrillation; electrophysiology; murine doi: 10.1152/ajpheart.00779.2009

We sought to determine whether ingestion of a between-meal supplement containing 30 g of carbohydrate and 15 g of essential amino acids (CAA) altered the metabolic response to a nutritionally mixed meal in healthy, recreationally active male volunteers. A control group (CON; n = 6, 38 [+ or -] 8 yr, 86 [+ or -] 10 kg, 179 [+ or -] 3 cm) received a liquid mixed meal [protein, 23.4 [+ or -] 1.0 g (essential amino acids, 14.7 [+ or -] 0.7 g); carbohydrate, 126.6 [+ or -] 4.0 g; fat, 30.3 [+ or -] 2.8 g] every 5 h (0830, 1330, 1830). The experimental group (SUP; n = 7, 36 [+ or -] 10 yr, 87 [+ or -] 12 kg, 180 [+ or -] 3 cm) consumed the same meals but, in addition, were given CAA supplements (1100, 1600, 2100). Net phenylalanine balance (NB) and fractional synthetic rate (FSR) were calculated during a 16-h primed constant infusion of L-[ring-[sup.2]Hs]phenylalanine. Ingestion of a combination of CAA supplements and meals resulted in a greater mixed muscle FSR than ingestion of the meals alone (SUP, 0.099 [+ or -] 0.008; CON, 0.076 [+ or -] 0.005%/h; P < 0.05). Both groups experienced an improvement in NB after the morning (SUP, -2.2 [+ or -] 3.3; CON, -1.5 [+ or -] 3.5 nmol x [min.sup.-1] x 100 ml leg [volume.sup.-1]) and evening meals (SUP, -9.7 [+ or -] 4.3; CON, -6.7 [+ or -] 4.1 nmol x [min.sup.-1] x 100 ml leg [volume.sup.-1]). NB after CAA ingestion was significantly greater than after the meals, with values of 40.2 [+ or -] 8.5 nmol x [min.sup.-1] 100 ml leg [volume.sup.-1]. These data indicate that CAA supplementation produces a greater anabolic effect than ingestion of intact protein but does not interfere with the normal metabolic response to a meal. protein metabolism; diet; supplement; skeletal muscle

We recently demonstrated that muscle protein synthesis was stimulated to a similar extent in young and elderly subjects during a 3-h amino acid infusion. We sought to determine if a more practical bolus oral ingestion would also produce a similar response in young (34 [+ or -] 4 yr) and elderly (67 [+ or -] 2 yr) individuals. Arteriovenous blood samples and muscle biopsies were obtained during a primed (2.0 [micro]mol/kg) constant infusion (0.05 [micro]mol x [kg.sup.-1] x [min.sup.-1]) of L-[ring-[sup.2][H.sub.5]]phenylalanine. Muscle protein kinetics and mixed muscle fractional synthetic rate (FSR) were calculated before and after the bolus ingestion of 15 g of essential amino acids (EAA) in young (n = 6) and elderly (n = 7) subjects. After EAA ingestion, the rate of increase in femoral artery phenylalanine concentration was slower in elderly subjects but remained elevated for a longer period. EAA ingestion increased FSR in both age groups by ~0.04%/h (P < 0.05), However, muscle intracellular (IC) phenylalannie concentration remained significantly higher in elderly subjects at the completion of the study (young: 115.6 [+ or -] 5.4 nmol/ml; elderly: 150.2 [+ or -] 19.4 nmol/ml). Correction for the free phenylalanine retained in the muscle IC pool resulted in similar net phenylalanine uptake values in the young and elderly. EAA ingestion increased plasma insulin levels in young (6.1 [+ or -] 1.2 to 21.3 [+ or -] 3.1 [micro]IU/ml) but not in elderly subjects (3.0 [+ or -] 0.6 to 4.3 [+ or -] 0.4 [micro]IU/ml). Despite differences in the time course of plasma phenylalanine kinetics and a greater residual IC phenylalanine concentration, amino acid supplementation acutely stimulated muscle protein synthesis in both young and elderly individuals. aging; supplementation; nutrition; sarcopenia

Debilitating injury is accompanied by hypercortisolemia, muscle wasting, and disruption of the normal anabolic response to food. We sought to determine whether acute hypercortisolemia alters muscle protein metabolism following ingestion of a potent anabolic stimulus: essential amino acids (EAA). A 27-h infusion (80 [micro]*[kg.sup.-1]*[h.sup.-1]) of hydrocortisone sodium succinate mimicked cortisol (C) levels accompanying severe injury (>30 [micro]g/dl), (C + AA; n = 6). The control group (AA) received intravenous saline (n = 6). Femoral arteriovenous blood samples and muscle biopsies were obtained during a primed (2.0 [micro]mol/kg) constant infusion (0.05 [micro]mol*[kg.sup.-1]*[min.sup.-1]) of L-[ring-[sup.2][H.sub.5]] phenylalanine before and alter ingestion of 15 g of EAA. Hypercortisolemia [36.5 [+ or -] 2.1 (C + AA) vs. 9.0 [+ or -] 1.0 [micro]g/dl (AA)] increased postabsorptive arterial, venous, and muscle intracellular phenylalanine concentrations. Hypercortisolemia also increased postabsorptive and post-EAA insulin concentrations. Net protein balance was blunted (40% lower) following EAA ingestion but remained positive for a greater period of time (60 vs. 180 min) in the C + AA group. Thus, although differences in protein metabolism were evident, EAA ingestion improved muscle protein anabolism during acute hypercortisolemia and may help minimize muscle loss following debilitating injury. cortisol; stress; metabolism; injury; stable isotopes

Research was conducted to test whether ATP-energized Ca2+ uptake activity of cardiac sarcoplasmic reticulum (SR) isolated from rats with defibrillaton shocks is depressed compared with controls. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was utilized to determine the protein composition of cardiac SR isolated from control and shocked rats. Results indicated that the shock-induced depression in Ca2+ uptake activity was voltage dependent but was not accompanied by alterations in the Ca2+-ATPase content of the SR.

Discusses the decrease in arrhythmogenic effects of catecholamines in heart failure induced by rapid pacing in dogs. Minimal dose of exogenous norepinephrine; Inducement of ventricular tachycardia; Action potential duration.

Obstructive sleep apnea, which involves chronic intermittent hypoxia (CIH), is a major risk factor for developing atrial fibrillation (AF). Whether or not CIH alone alters cardiac mechanisms to support AF is unknown. This study investigated the effects of CIH on atrial electrophysiology and arrhythmia vulnerability and evaluated the role of autonomics in CIH promotion of AF. Adult male Sprague-Dawley rats were exposed to 8 h/day of CIH or normoxia for 7 days. After exposure, rats were anesthetized for intracardiac electrophysiological experiments. Atrial effective refractory periods (AERPs) and AF inducibility were determined using programmed electrical stimulation and burst pacing in the absence and presence of autonomic receptor agonists and antagonists. Western blot analysis measured atrial protein expression of muscarinic M2, M3, and β 1 -adrenergic receptors. Compared with normoxia-exposed control rats, CIH-exposed rats had enhanced AF vulnerability using both programmed electrical stimulation and burst pacing, accompanied by greater AERP responses to carbachol and propranolol, lesser responses to isoproterenol, and higher atrial M2 receptor protein levels. Enhanced atrial vulnerability was accentuated by carbachol and abolished by atropine, indicating that the AF-promoting effects of CIH depended principally on parasympathetic activation. Enhancement of atrial vulnerability and AERP shortening with cholinergic agonists in CIH-exposed rats is consistent with sensitivity to parasympathetic activation. Higher responses to adrenergic receptor blockade in CIH-exposed rats is consistent with sympathetic potentiation. These findings implicate CIH as an important mediator of enhanced AF susceptibility in obstructive sleep apnea and provide novel insights into the underlying mechanisms. NEW & NOTEWORTHY Our study demonstrates, for the first time, that chronic intermittent hypoxia alone enhances vulnerability to atrial arrhythmia induction, which depends principally on parasympathetic activation. Enhanced atrial vulnerability was accompanied by heightened electrophysiological responses of the atrial myocardium to carbachol and isoproterenol, dampened responses to propranolol, and increased atrial M2 receptor protein levels.

Skeletal muscle atrophy during bed rest is attributed, at least in part, to slower basal muscle protein synthesis (MPS). Essential amino acids (EAA) stimulate mammalian target of rapamycin (mTORC1) signaling, amino acid transporter expression, and MPS and are necessary for muscle mass maintenance, but there are no data on the effect of inactivity on this anabolic mechanism. We hypothesized that bed rest decreases muscle mass in older adults by blunting the EAA stimulation of MPS through reduced mTORC1 signaling and amino acid transporter expression in older adults. Six healthy older adults (67 ± 2 yr) participated in a 7-day bed rest study. We used stable isotope tracers, Western blotting, and real-time qPCR to determine the effect of bed rest on MPS, muscle mTORC1 signaling, and amino acid transporter expression and content in the postabsorptive state and after acute EAA ingestion. Bed rest decreased leg lean mass by ∼4% (P < 0.05) and increased postabsorptive mTOR protein (P < 0.05) levels while postabsorptive MPS was unchanged (P > 0.05). Before bed rest acute EAA ingestion increased MPS, mTOR (Ser(2448)), S6 kinase 1 (Thr(389), Thr(421)/Ser(424)), and ribosomal protein S6 (Ser(240/244)) phosphorylation, activating transcription factor 4, L-type amino acid transporter 1 and sodium-coupled amino acid transporter 2 protein content (P < 0.05). However, bed rest blunted the EAA-induced increase in MPS, mTORC1 signaling, and amino acid transporter protein content. We conclude that bed rest in older adults significantly attenuated the EAA-induced increase in MPS with a mechanism involving reduced mTORC1 signaling and amino acid transporter protein content. Together, our data suggest that a blunted EAA stimulation of MPS may contribute to muscle loss with inactivity in older persons.

Atrial fibrillation (AF), the most common cardiac arrhythmia seen in general practice, can be promoted by conduction slowing. Cardiac impulse conduction depends on gap junction channels, which are composed of connexins (Cxs). While atrial Cx40 and Cx43 are equally expressed, AF studies have primarily focused on Cx40 reductions. The G60S Cx43 mutant (Cx43(G60S/+)) mouse model of Oculodentodigital dysplasia has a 60% reduction in Cx43 in the atria. Cx43(G60S/+) mice were compared with Cx40-deficient (Cx40(-/-)) mice to determine the role of Cxs in atrial tachycardia/fibrillation (AT/F). Intracardiac electrophysiological studies were done in 6-mo-old male C57BL/6 Cx43(G60S/+) mutant, littermate (Cx43(+/+)), Cx40(-/-), and C57BL/6 wild-type (WT) mice. AT/F induction used an extra stimulus during sinus rhythm, programmed electrical stimulation, or burst pacing (1-ms pulses, 50-Hz, 400-ms train) in the absence and presence of carbachol (CCh). Atrial effective refractory periods did not differ between strains. Cx43(G60S/+) mice were more susceptible to induction of sustained AT/F (duration >2 min, 9 of 12; maximum >35 min) compared with Cx43(+/+) mice (3 of 11; χ(2) = 5.24; P = 0.02). CCh enhanced sustained AT/F susceptibility in WT (from 1 of 12 without, to 7 of 10 with CCh; χ(2) = 8.98; P < 0.01) but not in Cx40(-/-) mice (1 of 13 without vs. 2 of 9 with CCh; χ(2) = 0.95; P = NS). The pattern of epicardial recordings during AT/F in Cx43(G60S/+) mice was left preceding right, with left atrial fractionated activation patterns consistent with clinical observations of AF. In conclusions, while Cx43(G60S/+) mice had severe AT/F, Cx40(-/-) mice were resistant to CCh-induced AT/F.