SUMMARY1. The effect on intracellular pH (pH1) and intracellular Na+ activity (aNk) of exposure to hyperosmolar solutions was investigated in guinea-pig ventricular muscle using ion-sensitive microelectrodes.2. Exposure of tissue to solution made hyperosmolar by the addition of 100 mmsucrose produced an intracellular alkalinization of 0-10 pH units and hyperpolarization of the membrane potential.3. When extracellular Na+ was reduced to 15 mm by substitution of NaCl with choline chloride, exposure to hyperosmolar solutions caused a decrease in pHi.Identical experiments using LiCl as the sodium substitute resulted in an increase in pHi of a magnitude similar to that seen at physiological Na+ levels.4! In the presence of 50 gzM-5-(N,N-dimethyl)amiloride (DMA), an inhibitor of Na+-H+ exchange, pHi decreased upon exposure to hyperosmolar solution. 5. The recovery of pHi from an intracellular acidosis (induced by brief exposure to NH4C1) was enhanced in hyperosmolar solution when compared to recovery in isosmolar solution. This enhancement was observed even when aNa was markedly elevated (> 25 mM) by inhibition of the Na+-K+ pump. 6. There was an increase in aka during exposure to hyperosmolar solutions. When the Na+-K+ pump was inhibited with dihydro-ouabain a component of this increase in aka was sensitive to DMA.7. We conclude that exposure of cardiac tissue to hyperosmolar solutions results in an intracellular alkalosis due to activation of the sarcolemmal Na+-H+ exchanger.Such changes should be considered when exposure to hyperosmolar solutions is used in the study of excitation-contraction coupling and cardiac muscle mechanics.

The effect on intracellular pH (pHi) of exposure to solutions of progressively increasing osmolarity from 418 to 620 mosM and to hyposmolar solutions (240 mosM) was examined in guinea pig ventricular muscle using ion-selective microelectrodes. Exposure of tissue to 418 mosM Tyrode solution (100 mM sucrose added) produced an intracellular alkalosis of approximately 0.1 U, whereas exposure to 620 mosM solution (300 mM sucrose added) caused an intracellular acidosis of approximately 0.1 U. The maximal rate of recovery of pHi from acidosis induced by an NH4Cl prepulse increased progressively as extracellular osmolarity was raised from 310 to 620 mosM. This suggests that the acidosis observed at steady state in 620 mosM solution is not due to inhibition of the Na(+)-H+ exchanger. In the presence of 10 microM ryanodine, exposure to 620 mosM solution produced a sustained intracellular alkalosis. We suggest that the decrease in pHi during exposure to 620 mosM solution is due, at least in part, to the acidifying influence of Ca2+ release from the sarcoplasmic reticulum. This decrease in pHi is expected to contribute to the negative inotrop reported in studies of cardiac contractility in markedly hyperosmolar solutions. There was no change in pHi when tissue was exposed to hyposmolar solution. However, the maximal rate of recovery of pHi from acidosis was slower in hyposmolar than in isosmolar solution, despite a concomitant decrease in the intracellular buffer capacity. This suggests that osmotic cell swelling results in inhibition of the sarcolemmal Na(+)-H+ exchanger.

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1. Standard microelectrode techniques were used to record intracellular action potentials from guinea-pig ventricular myocardium superfused with either control physiological saline (pH 7.5; pO2 500 mmHg; [K+] 5.6 mmol/L) or 'simulated ischaemic' solution (pH 6.4; pO2 90 mmHg; [K+] 11.2 mmol/L). 2. The effects on action potential parameters of therapeutic concentrations of lignocaine, amiodarone and encainide were studied under both conditions. 3. Simulated ischaemia, in the absence of drugs, produced marked reductions in resting potential (-86.6 +/- 2.3 to -64.7 +/- 3.5 mV), maximum rate of depolarization (Vmax; 263 +/- 66 to 106 +/- 36 V/s) and action potential duration (164 +/- 24 to 97 +/- 26 ms). No drug produced any additional effect on resting potential. 4. All three drugs produced enhanced depression of Vmax in ischaemia compared to control conditions (class I effect). This was much more marked for lignocaine and amiodarone (inactivated channel blockers) than for encainide (open channel blocker). 5. In addition the prolongation of action potential duration seen with acute exposure to amiodarone (174 +/- 12 to 192 +/- 17 ms; class III effect) was abolished under simulated ischaemic conditions. 6. It is concluded that lignocaine and amiodarone exert greater selectivity for ischaemic tissue than does encainide and that amiodarone may function primarily as a class I agent under ischaemic conditions.

The inhibitory effect of amiodarone on Na(+)-K(+) pump current is thyroid-dependent, whereas the effects on heart rate and QT(c) are at least partially mediated by thyroid-independent mechanisms. In contrast to its parent compound, dronedarone has no significant effects on the activity of the Na(+)-K(+) pump.