Effects of moderate hypothermia on sarcolemmal Na(+)/H(+) exchanger activity and its inhibition by cariporide in cardiac ventricular myocytes.
1. 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 degrees 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. 2. As the index of NHE activity, trans-sarcolemmal acid efflux rate (J(H)) was determined by microepifluorescence in single cells (n = 8 to 11 per group), during recovery from intracellular acidosis in bicarbonate-free conditions. 3. Initially, myocytes were subjected to two consecutive acid pulses; these both occurred at 37 degrees C in the normothermic control group but the second pulse was at 25 degrees C in the moderate hypothermia group. J(H) values obtained after the first pulse were superimposed in both groups, indicating comparable cell populations. However, after the second pulse, J(H) values in the moderate hypothermia group were approximately 50% of those in the normothermic control group over the pH(i) range 6.80 - 7.10. 4. Similar results were obtained in cells subjected to a single acid pulse at 37 or 25 degrees C, with J(H) values in the latter group measuring approximately 60% of those in the former over the pH(i) range 6.80-7.10. 5. Cariporide (0.01, 0.03, 0.1, 0.3, 1.0 or 3.0 microM), present during recovery from a single acid pulse, reduced J(H) in a concentration-dependent manner, with IC(50) values of 150 and 130 nM at 37 and 25 degrees C, respectively. 6. 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.
Hoshino
K
K
Centre for Cardiovascular Biology and Medicine, King's College London, London SE1 7EH, UK.
Avkiran
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002138:Calibration; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000592:standards; D006146:Guanidines / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006863:Hydrogen-Ion Concentration; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D013696:Temperature
D000889:Anti-Arrhythmia Agents; D005452:Fluoresceins; D006146:Guanidines; D013450:Sulfones; C093373:cariporide; D000254:Sodium-Potassium-Exchanging ATPase