Effects of moderate hypothermia on sarcolemmal Na+/H+ exchanger activity and its inhibition by cariporide in cardiac ventricular myocytes

Authors


Centre for Cardiovascular Biology and Medicine, King's College London, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK; E-mail: metin.avkiran@kcl.ac.uk

Abstract

  • Specific inhibitors of the sarcolemmal Na+/H+ exchanger (NHE) such as cariporide are being evaluated for cardioprotective therapy during cardiac surgery. We determined the effects of moderate hypothermia (25°C), as occurs during cardiac surgery, on (1) sarcolemmal NHE activity and (2) the NHE-inhibitory potency of cariporide, in isolated adult rat ventricular myocytes.

  • As the index of NHE activity, trans-sarcolemmal acid efflux rate (JH) was determined by microepifluorescence in single cells (n=8 to 11 per group), during recovery from intracellular acidosis in bicarbonate-free conditions.

  • Initially, myocytes were subjected to two consecutive acid pulses; these both occurred at 37°C in the normothermic control group but the second pulse was at 25°C in the moderate hypothermia group. JH values obtained after the first pulse were superimposed in both groups, indicating comparable cell populations. However, after the second pulse, JH values in the moderate hypothermia group were approximately 50% of those in the normothermic control group over the pHi range 6.80 – 7.10.

  • Similar results were obtained in cells subjected to a single acid pulse at 37 or 25°C, with JH values in the latter group measuring approximately 60% of those in the former over the pHi range 6.80 – 7.10.

  • Cariporide (0.01, 0.03, 0.1, 0.3, 1.0 or 3.0 μM), present during recovery from a single acid pulse, reduced JH in a concentration-dependent manner, with IC50 values of 150 and 130 nM at 37 and 25°C, respectively.

  • We conclude that moderate hypothermia produces (1) a significant, but partial, inhibition of sarcolemmal NHE activity, and (2) no significant effect on the NHE-inhibitory potency of cariporide.

British Journal of Pharmacology (2001) 134, 1587–1595; doi:10.1038/sj.bjp.0704405

Ancillary