No abstract

Intracellular pH (pHi) is an important modulator of cardiac function. The spatial regulation of pH within the cytoplasm depends, in part, on intracellular H+ (Hi+) mobility. The apparent diffusion coefficient for Hi+, DHapp, was estimated in single ventricular myocytes isolated from the rat, guinea pig, and rabbit. DHapp was derived by best-fitting predictions of a two-dimensional model of H+ diffusion to the local rise of intracellular [H+], recorded confocally (ratiometric seminaphthorhodafluor fluorescence) downstream from an acid-filled, whole cell patch pipette. Under CO2/HCO3--free conditions, DHapp was similar in all three species (mean values: 8-12.5 x 10-7 cm2/s) and was over 200-fold lower than that for H+ in water. In guinea pig myocytes, DHapp was increased 2.5-fold in the presence of CO2/HCO3- buffer, in agreement with previous observations in rabbit myocytes. Hi+ mobility is therefore low in cardiac cells, a feature that may predispose them to the generation of pHi gradients in response to sarcolemmal acid/base transport or local cytoplasmic acid production. Low Hi+ mobility most likely results from H+ shuttling among cytoplasmic mobile and fixed buffers. This hypothesis was explored by comparing the pHi dependence of intrinsic, intracellular buffering capacity, measured for all three species, and subdividing buffering into mobile and fixed fractions. The proportion of buffer that is mobile will be the main determinant of DHapp. At a given pHi, this proportion appeared to be similar in all three species, consistent with a common value for DHapp. Over the pHi range of 6.0-8.0, the proportion is expected to change, predicting that DHapp may display some pHi sensitivity.

The Na + -HCO 3 − cotransporter (NBC) is an important sarcolemmal acid extruder in cardiac muscle. The characteristics of NBC expressed functionally in heart are controversial, with reports suggesting electroneutral (NBCn; 1HCO 3 − : 1Na + ; coupling coefficient N = 1) or electrogenic forms of the transporter (NBCe; equivalent to 2HCO 3 − : 1Na + ; N = 2). We have used voltage-clamp and epifluorescence techniques to compare NBC activity in isolated ventricular myocytes from rabbit, rat and guinea pig. Depolarization (by voltage clamp or hyperkalaemia) reversibly increased steady-state pH i while hyperpolarization decreased it, effects seen only in CO 2 /HCO 3 − -buffered solutions, and blocked by S0859 (cardiac NBC inhibitor). Species differences in amplitude of these pH i changes were rat > guinea pig ≈ rabbit. Tonic depolarization (−140 mV to −0 mV) accelerated NBC-mediated pH i recovery from an intracellular acid load. At 0 mV, NBC-mediated outward current at resting pH i was +0.52 ± 0.05 pA pF −1 (rat, n = 5), +0.26 ± 0.05 pA pF −1 (guinea pig, n = 5) and +0.10 ± 0.03 pA pF −1 (rabbit, n = 9), with reversal potentials near −100 mV, consistent with N = 2. The above results indicate a functionally active voltage-sensitive NBCe in these species. Voltage-clamp hyperpolarization negative to the reversal potential for NBCe failed, however, to terminate or reverse NBC-mediated pH i -recovery from an acid load although it was slowed significantly, suggesting electroneutral NBC may also be operational. NBC-mediated pH i recovery was associated with a rise of [Na + ] i at a rate ∼25% of that mediated via NHE, and consistent with an apparent NBC stoichiometry between N = 1 and N = 2. In conclusion, NBCe in the ventricular myocyte displays considerable functional variation among the three species tested (greatest in rat, least in rabbit) and may coexist with some NBCn activity.

This article investigates major effects of misspecification in stationary linear time series models when we fit a pth-order autoregressive model. The true model can be an autoregressive moving average model. We derive the formulas of bias and mean squared error (MSE) of the least squares estimator and the hth period ahead prediction MSE in the time domain. Contrary to previous studies, the process in estimation is not necessarily independent of the process in prediction, and the distribution of process is not necessarily Gaussian. We examine the effects of this dependence and nonnormality on prediction in misspecified models.

In the heart, intracellular Na(+) concentration (Na(+) (i)) is a controller of intracellular Ca(2+) signaling, and hence of key aspects of cell contractility and rhythm. Na(+) (i) will be influenced by variation in Na(+) influx. In the present work, we consider one source of Na(+) influx, sarcolemmal acid extrusion. Acid extrusion is accomplished by sarcolemmal H(+) and HCO(3) (-) transporters that import Na(+) ions while exporting H(+) or importing HCO(3) (-). The capacity of this system to import Na(+) is enormous, up to four times the maximum capacity of the Na(+)-K(+) ATPase to extrude Na(+) ions from the cell. In this review we consider the role of Na(+)-H(+) exchange (NHE) and Na(+)-HCO(3) (-)co-transport (NBC) in mediating Na(+) influx into cardiac myocytes. We consider, in particular, the role of NBC, as so little is known about Na(+) influx through this transporter. We show that both proteins mediate significant Na(+) influx and that although, in the ventricular myocyte, NBC-mediated Na(+) influx is less than through NHE, the proportions may be altered under a variety of conditions, including exposure to catecholamines, membrane depolarization, and interference with activity of the enzyme, carbonic anhydrase.