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In carbonate‐forming environments, authigenic minerals can cement surface sediments into centimeter‐sized intraclasts that are later reworked into "flat‐pebble" or "edgewise" conglomerates. Flat‐pebble conglomerates comprise only a small portion of facies in modern marine environments but are common in ancient strata, implying that seafloor cements were more widespread in the past. Flat‐pebble conglomerates nearly disappeared after the Ordovician radiation, yet it is unclear if this decline was due to changing seawater chemistry or if increased infaunalization and bioturbation simply worked to break down nascent clasts. We discovered a process analog that produces flat‐pebble conglomerates around the Great Salt Lake, Utah, USA, and studied these facies using field observations, wave models, satellite imagery, petrography, and microanalytic chemical data. Clasts were sourced from wave‐rippled grainstone that cemented in situ in offshore environments. Lake floor cements formed under aragonite saturation states that are lower than modern marine settings, suggesting that physical processes are at least as important as chemical ones. Results from our wave models showed that coarse sediments near the field site experience quiescent periods of up to 6 months between suspension events, allowing isopachous cements to form. Using a simple mathematical framework, we show that the main difference between Great Salt Lake and modern, low‐energy marine settings is that the latter has enough bioturbating organisms to break up clasts. Observations from Great Salt Lake demonstrate how geologic trends in flat‐pebble abundance could largely reflect changes in total infaunal biomass and ecology without requiring regional‐to‐global changes in seawater chemistry. Plain Language Summary: Calcium carbonate is a common sedimentary mineral that precipitates quickly under Earth surface conditions. If carbonate sediments are at rest for long periods of time, they may solidify via cementation into flat, pebble‐sized clasts. Geologic trends show that flat pebbles are anticorrelated with burrows, suggesting they may tell us about animal evolution and ecology. However, it was unknown if animals disrupt clasts through chemical means, leading to slower rates of mineral growth, or if they physically push sediments apart, breaking up nascent cements. We studied flat pebbles forming in Great Salt Lake, Utah, where the water is too salty for burrowing animals. The composition of lake water should lead to slower growth rates for carbonate minerals, yet clasts still form. We conclude that pebbles form during quiescent intervals with little physical energy to move grains, either from waves or from burrowing organisms. As a result, ancient flat pebbles are probably not unique markers for seawater chemistry. Key Points: Sediment cohesion within carbonate environments depends on both physical and chemical energy near the sediment‐water interfaceIf sediment transport is infrequent, burrowing animals provide a significant source of physical energySubstrate cohesion may record physical changes related to the number and behavior of animals rather than geochemical conditions [ABSTRACT FROM AUTHOR]

Background and Purpose: Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca²⁺ current (I(Ca)), slow delayed rectifier K⁺ current (I(Ks)) and fast delayed rectifier K⁺ current (I(Kr)) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations.Experimental Approach: Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques.Key Results: In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the I(Kr) blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the I(Ks) blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the I(Ca) blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating I(Ca) followed by a rise in I(Ks) , both currents increased with increasing the cycle length.Conclusions and Implications: The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of I(Ks) - but not I(Kr) - may be responsible for the observed shortening of action potentials. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca2+ current ( ICa), slow delayed rectifier K+ current ( IKs) and fast delayed rectifier K+ current ( IKr) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations. EXPERIMENTAL APPROACH Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques. KEY RESULTS In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the IKr blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the IKs blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the ICa blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating ICa followed by a rise in IKs, both currents increased with increasing the cycle length. CONCLUSIONS AND IMPLICATIONS The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of IKs- but not IKr- may be responsible for the observed shortening of action potentials. [ABSTRACT FROM AUTHOR]

Aim The aim of this work was to study antagonistic interactions between the effects of various types of Ca2+ channel blockers and isoproterenol on the amplitude of L-type Ca2+ current in canine ventricular cells. Methods Whole-cell version of the patch clamp technique was used to study the effect of isoproterenol on Ca2+ current in the absence and presence of Ca2+ channel-blocking agents, including nifedipine, nisoldipine, diltiazem, verapamil, Co Cl2 and Mn Cl2. Results Five micromolar Nifedipine, 1 μ M nisoldipine, 10 μ M diltiazem, 5 μ M verapamil, 3 m M Co Cl2 and 5 m M Mn Cl2 evoked uniformly a 90-95% blockade of Ca2+ current in the absence of isoproterenol. Isoproterenol (100 n M) alone increased the amplitude of Ca2+ current from 6.8 ± 1.3 to 23.7 ± 2.2 pA/ pF in a reversible manner. Isoproterenol caused a marked enhancement of Ca2+ current even in the presence of nifedipine, nisoldipine, diltiazem and verapamil, but not in the presence of Co Cl2 or Mn Cl2. Conclusion The results indicate that the action of isoproterenol is different in the presence of organic and inorganic Ca2+ channel blockers. Co Cl2 and Mn Cl2 were able to fully prevent the effect of isoproterenol on Ca2+ current, while the organic Ca2+ channel blockers failed to do so. This has to be born in mind when the effects of organic Ca2+ channel blockers are evaluated either experimentally or clinically under conditions of increased sympathetic tone. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The transient receptor potential vanilloid 1 (TRPV1) plays a role in the activation of sensory neurons by various painful stimuli and is a therapeutic target. However, functional TRPV1 that affect microvascular diameter are also expressed in peripheral arteries and we attempted to characterize this receptor. EXPERIMENTAL APPROACH Sensory TRPV1 activation was measured in rats by use of an eye wiping assay. Arteriolar TRPV1-mediated smooth muscle specific responses (arteriolar diameter, changes in intracellular Ca2+) were determined in isolated, pressurized skeletal muscle arterioles obtained from the rat and wild-type or TRPV1−/− mice and in canine isolated smooth muscle cells. The vascular pharmacology of the TRPV1 agonists (potency, efficacy, kinetics of action and receptor desensitization) was determined in rat isolated skeletal muscle arteries. KEY RESULTS Capsaicin evoked a constrictor response in isolated arteries similar to that mediated by noradrenaline, this was absent in arteries from TRPV1 knockout mice and competitively inhibited by TRPV1 antagonist AMG9810. Capsaicin increased intracellular Ca2+ in the arteriolar wall and in isolated smooth muscle cells. The TRPV1 agonists evoked similar vascular constrictions (MSK-195 and JYL-79) or were without effect (resiniferatoxin and JYL-273), although all increased the number of responses (sensory activation) in the eye wiping assay. Maximal doses of all agonists induced complete desensitization (tachyphylaxis) of arteriolar TRPV1 (with the exception of capsaicin). Responses to the partial agonist JYL-1511 suggested 10% TRPV1 activation is sufficient to evoke vascular tachyphylaxis without sensory activation. CONCLUSIONS AND IMPLICATIONS Arteriolar TRPV1 have different pharmacological properties from those located on sensory neurons in the rat. [ABSTRACT FROM AUTHOR]

Background and Purpose: In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration-dependent effects of rosiglitazone on action potential morphology and the underlying ion currents were studied in dog hearts.Experimental Approach: Standard microelectrode techniques, conventional whole cell patch clamp and action potential voltage clamp techniques were applied in enzymatically dispersed ventricular cells from dog hearts.Key Results: At concentrations ≥10 µM rosiglitazone decreased the amplitude of phase-1 repolarization, reduced the maximum velocity of depolarization and caused depression of the plateau potential. These effects developed rapidly and were readily reversible upon washout. Rosiglitazone suppressed several transmembrane ion currents, concentration-dependently, under conventional voltage clamp conditions and altered their kinetic properties. The EC(50) value for this inhibition was 25.2 ± 2.7 µM for the transient outward K(+) current (I(to)), 72.3 ± 9.3 µM for the rapid delayed rectifier K(+) current (I(Kr)) and 82.5 ± 9.4 µM for the L-type Ca(2+) current (I(Ca) ) with Hill coefficients close to unity. The inward rectifier K(+) current (I(K1)) was not affected by rosiglitazone up to concentrations of 100 µM. Suppression of I(to), I(Kr), and I(Ca) was confirmed also under action potential voltage clamp conditions.Conclusions and Implications: Alterations in the densities and kinetic properties of ion currents may carry serious pro-arrhythmic risk in case of overdose with rosiglitazone, especially in patients having multiple cardiovascular risk factors, like elderly diabetic patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: While the slow delayed rectifier K(+) current (I(Ks)) is known to be enhanced by the stimulation of β-adrenoceptors in several mammalian species, phosphorylation-dependent regulation of the rapid delayed rectifier K(+) current (I(Kr)) is controversial.Experimental Approach: In the present study, therefore, the effect of isoprenaline (ISO), activators and inhibitors of the protein kinase A (PKA) pathway on I(Kr) and I(Ks) was studied in canine ventricular myocytes using the whole cell patch clamp technique.Key Results: I (Kr) was significantly increased (by 30-50%) following superfusion with ISO, forskolin or intracellular application of PKA activator cAMP analogues (cAMP, 8-Br-cAMP, 6-Bnz-cAMP). Inhibition of PKA by Rp-8-Br-cAMP had no effect on baseline I(Kr). The stimulating effect of ISO on I(Kr) was completely inhibited by selective β₁-adrenoceptor antagonists (metoprolol and CGP-20712A), by the PKA inhibitor Rp-8-Br-cAMP and by the PKA activator cAMP analogues, but not by the EPAC activator 8-pCPT-2'-O-Me-cAMP. In comparison, I(Ks) was increased threefold by the activation of PKA (by ISO or 8-Br-cAMP), and strongly reduced by the PKA inhibitor Rp-8-Br-cAMP. The ISO-induced enhancement of I(Ks) was decreased by Rp-8-Br-cAMP and completely inhibited by 8-Br-cAMP.Conclusions and Implications: The results indicate that the stimulation of β₁-adrenoceptors increases I(Kr), similar to I(Ks), via the activation of PKA in canine ventricular cells. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to give a parametric description of the most important K+ currents flowing during canine ventricular action potential. Methods: Inward rectifier K+ current (IK1), rapid delayed rectifier K+ current ( IKr), and transient outward K+ current ( Ito) were dissected under action potential clamp conditions using BaCl2, E-4031, and 4-aminopyridine, respectively. Results: The maximum amplitude of Ito was 3.0 ± 0.23 pA/pF and its integral was 29.7 ± 2.5 fC/pF. The current peaked 4.4 ± 0.7 ms after the action potential upstroke and rapidly decayed to zero with a time constant of 7.4 ± 0.6 ms. IKr gradually increased during the plateau, peaked 7 ms before the time of maximum rate of repolarization ( V ) at −54.2 ± 1.7 mV, had peak amplitude of 0.62 ± 0.08 pA/pF, and integral of 57.6 ± 6.7 fC/pF. IK1 began to rise from −22.4 ± 0.8 mV, peaked 1 ms after the time of V at −58.3 ± 0.6 mV, had peak amplitude of 1.8 ± 0.1 pA/pF, and integral of 61.6 ± 6.2 fC/pF. Good correlation was observed between peak IK1 and V ( r = 0.93) but none between IKr and V . Neither IK1 nor IKr was frequency-dependent between 0.2 and 1.66 Hz. Congruently, IKr failed to accumulate in canine myocytes at fast driving rates. Conclusion: Terminal repolarization is dominated by IK1, but action potential duration is influenced by several ion currents simultaneously. As Ito was not active during the plateau, and neither IK1 nor IKr was frequency-dependent, other currents must be responsible for the frequency dependence of action potential duration at normal and slow heart rates in canine ventricular cells. [ABSTRACT FROM AUTHOR]

1 Blockers of the rapid component of the delayed rectifier potassium current (I[SUBKr]) prolong cardiac action potential duration (APD) and effective refractory period (ERP) in a reverse rate-dependent manner. Since activation of β-adrenoceptors attenuates prolongation of APD evoked by I[SUBKr] blockers, rate-dependent neuronal noradrenaline liberation in the myocardium may contribute to the reverse rate-dependent nature of the effects of I[SUBKr] blockers. In order to test this hypothesis, we studied the effects of dofetilide, a pure I[SUBKr] blocker, on ERP after activation or blockade of β-adrenoceptors and after catecholamine depletion in guinea-pig left atrial myoardium placed at 3, 2 and 1 Hz, in vitro. 2 Dofetilide (100 nM) lengthened ERP in a reverse rate-dependent manner in the left atrial myocardium of guinea-pigs. Strong activation of β-adrenoceptors using 10 nM isoproterenol abolished the dofetilide-induced lengthening of ERP at all pacing rates. 3 Blockade of the β-adrenoceptors with metoprolol (1 μM), atenolol (3 μM), atenolol (3 μM) or propranolol (300 nM) increased the dofetilide-evoked prolongation of ERP at 3 and 2 Hz, but not at 1 Hz. As a consequence, metoprolol attenuated while propranolol and atenolol fully eliminated the reverse rate-dependent nature of the dofetilide-induced ERP lengthening. In catecholamine-depleted atrial preparations of the guinea-pig (24 h pretreatment with 5 mg kg[SUP-1] reserpine i.p.), the effect of dofetilide on ERP was not frequency dependent, and propranolol did not alter the effects of dofetilide. 4 In contrast to results obtained in guinea-pig atrial preparations, propranolol failed to change the reverse rate-dependent effect of dofetilide on ERP in the right ventricular papillary muscles of rabbits and guinea-pigs. [ABSTRACT FROM AUTHOR]

An abstract of the article "Can the Electrophysiological Actions of Antipsychoptic Risperidone Explain Its Cardiac Side Effects?" by V. Kecskemeti and colleagues is presented.

Present study was performed to compare the dynamics of human L-type calcium current ( ICa,L) flowing during rectangular voltage pulses, voltage ramps, and action potentials (APs) recorded from epicardiac and endocardiac canine ventricular cells. ICa,L was recorded in single myocytes isolated from undiseased human hearts using the whole cell voltage clamp technique. The decay of ICa,L was monotonic when using rectangular pulses or endocardial APs as voltage commands, whereas the current became double-peaked (displaying a second rise and fall) during epicardial (EPI) APs or voltage ramps used to mimic EPI APs. These ICa,L profiles were associated with single-hooked and double-hooked phase-plane trajectories, respectively. No sustained current was observed during the AP commands. Kinetics of deactivation and recovery from inactivation of human ICa,L were determined using twin-pulse voltage protocols and voltage ramps, and the results were similar to those obtained previously in canine cells under identical experimental conditions. ICa,L can inactivate partially before and deactivate during the phase-1 repolarization of the epicardiac AP, and reopening of these channels seems to be associated with formation of the dome. [ABSTRACT FROM AUTHOR]

Abstract Aim: The aim of this study was to compare the action potential configuration, contractility, intracellular Ca2+ and H+ concentrations in mammalian cardiac tissues bathed with Krebs and Tyrode solutions at 37 °C. Results: In Langendorff-perfused guinea-pig hearts, loaded with the fluorescent Ca2+ -indicator Fura-2, or H+ -sensitive dye carboxy-SNARF, shifts from Krebs to Tyrode solution caused intra-cellular acidification, increased diastolic pressure and [Ca2+ ]i , decreased systolic pressure and [Ca2+ ]i , leading to a reduction in the amplitude of [Ca2+ ]i transients and pulse pressure. Contractility was also depressed in canine ventricular trabeculae when transferred from Krebs to Tyrode solution. Shifts from Krebs to Tyrode solution increased the duration of action potentials in multicellular cardiac preparations excised from canine and rabbit hearts but not in isolated cardiomyocytes. All these changes in action potential morphology, contractility, [Ca2+ ]i and [H+ ]i were readily reversible by addition of 26 mmol L-1 bicarbonate to Tyrode solution. Effects of dofetilide and CsCl, both blockers of the delayed rectifier K current, on action potential duration were compared in Krebs and Tyrode solutions. Dofetilide lengthened rabbit ventricular action potentials in a significantly greater extent in Tyrode than in Krebs solution. Exposure of canine Purkinje fibres to CsCl evoked early after depolarizations within 40 min in all preparations incubated with Tyrode solution, but not in those bathed with Krebs solution. Conclusion: It is concluded that the marked differences in action potential morphology, [Ca2+ ]i , [H+ ]i and contractility observed between preparations bathed with Krebs and Tyrode solutions are more likely attributable to differences in the intracellular buffering capacities of the two media. [ABSTRACT FROM AUTHOR]

Background: The small GTPase Rad is a negative regulator of voltage-dependent L-type calcium channel current (ICaL); however, the effects of Rad ablation on cardiomyocyte function are unknown. The objective of this study is to test the hypothesis that Rad-depletion causes positive inotropic effects without inducing cardiac hypertrophy., Methods and Results: Ventricular myocytes from adult Rad(-/-) mice were isolated and evaluated by patch-clamp recordings for I(Ca,L) and action potentials, Ca(2+) transients, and sarcomere shortening. Maximum I(CaL) is elevated in Rad(-/-) (maximal conductance 0.35 ± 0.04 picoSiemens/picoFarad (pS/pF) wild-type; 0.61 ± 0.14 pS/pF Rad(-/-)), decay kinetics are faster, and I(Ca,L) activates at lower voltages (activation midpoint -7.2 ± 0.6 wild-type; -11.7 ± 0.9 Rad(-/-)) mimicking effects of β-adrenergic receptor stimulation. Diastolic and twitch calcium are elevated in Rad(-/-) (F340/380: 1.03 diastolic and 0.35 twitch for wild-type; 1.47 diastolic and 0.736 twitch for Rad(-/-)) and sarcomere shortening is enhanced (4.31% wild-type; 14.13% Rad(-/-)) at lower pacing frequencies. Consequentially, frequency-dependence of Ca(2+) transients is less in Rad(-/-), and the frequency dependence of relaxation is also blunted. In isolated working hearts, similar results were obtained; chiefly, +dP/dt was elevated at baseline and developed pressure was relatively nonresponsive to acute β-adrenergic receptor stimulation. In single cells, at subphysiological frequencies, nonstimulated calmodulin-dependent protein kinase-sensitive calcium release is observed. Remarkably, Rad(-/-) hearts did not show hypertrophic growth despite elevated levels of diastolic calcium., Conclusions: This study demonstrates that the depletion of Rad GTPase is equivalent to sympathomimetic β-adrenergic receptor, without stimulating cardiac hypertrophy. Thus, targeting Rad GTPase is a novel potential therapeutic target for Ca(2+)-homeostasis-driven positive inotropic support of the heart.