Contribution of shrinkage of extracellular space to extracellular K+ accumulation in myocardial ischaemia of the rabbit.

1. The contribution of the concentrating effect due to shrinkage of the extracellular space (ECS) to cellular K+ efflux on extracellular potassium ([K+]o) accumulation in response to ischaemia was investigated in an isolated, blood‐perfused rabbit papillary muscle preparation with a confined extracellular space. 2. The ECS was quantified using either of two extracellular markers, choline or tetramethyl ammonium (TMA), each with specific ion‐selective electrodes, as well as by measurement of extracellular resistance (ro). [K+]o and [Na+]o were also measured simultaneously using K(+)‐ and Na(+)‐selective electrodes. 3. During ischaemia, [K+]o increased 3‐fold from 4.2 +/‐ 0.1 to 12.6 +/‐ 1.0 mM at 10 min (n = 10) analogous to changes in the ischaemic heart in vivo. The ECS decreased to 83.9 +/‐ 3.2% of control measured using 1 mM choline extracellularly (n = 9, P < 0.01) or to 85.7 +/‐ 0.7% of control using 1 mM TMA (n = 6, P < 0.01). Nearly identical decreases in ro (84.1 +/‐ 2.4%, n = 15, P < 0.01) occurred simultaneously. 4. The small decrease in the ECS contributed only 0.8‐0.9 mM to the total increase in [K+]o of 8.4 mM and had a minor effect on transmembrane K+ flux. No significant differences between the relative changes in [choline] and [Na+]o were observed. This excluded a major transmembrane Na+ movement during early ischaemia. 5. Bumetanide (10 mM), an inhibitor of K(+)‐Cl‐ cotransport, a process which is involved in cell volume regulation consequent to osmotic cell swelling, significantly attenuated the increase in [K+]o after 6 min of ischaemia (8.3 +/‐ 0.6 mM, n = 5 vs. 10.3 +/‐ 0.4 mM in the control group, n = 6, P < 0.05), whereas N‐ethylmaleimide (1 mM), a stimulator of this cotransporter, augmented [K+]o accumulation (12.0 +/‐ 0.6 mM at 6 min, P < 0.05). 6. We conclude that during early myocardial ischaemia, a major component of [K+]o accumulation is not caused by diminution of ECS per se, but rather by increased net K+ efflux due in part to K(+)‐Cl cotransport secondary to myocyte volume regulation.