Interaction between anesthetics and the sodium-hydrogen exchange inhibitor HOE 642 (cariporide) in ischemic and reperfused rat hearts.
BACKGROUND
Sodium (Na+)-hydrogen (H+) exchange (NHE) inhibitors are effective cardioprotective agents. The potent NHE inhibitor HOE 642 (cariporide) is being evaluated clinically in high-risk patients, including those having coronary artery bypass. Volatile anesthetics are also cardioprotective, most likely via different mechanisms. The potential interaction between anesthetics and HOE 642 was investigated.


METHODS
Electrically paced isolated rat hearts were perfused at constant flow. Left ventricular developed pressure and end-diastolic pressure were monitored as determinants of function. Hearts were subjected to 60 min each of total ischemia followed by reperfusion. Isoflurane (0.93 minimum alveolar concentration [MAC]), sevoflurane (1.03 MAC), or sufentanil (1.2 nM) was added 15 min before ischemia and throughout reperfusion, either alone or in combination with HOE 642 (5 microM). The effect of HOE 642 alone was also studied. At the end of reperfusion, hearts were freeze-clamped for subsequent determination of tissue metabolites.


RESULTS
In control hearts, left ventricular developed pressure recovered to 40% of preischemia values, whereas left ventricular end-diastolic pressure increased by 650% after reperfusion. Sevoflurane, isoflurane, or HOE 642 alone significantly enhanced left ventricular developed pressure recovery to more than 90%, although recovery with HOE 642 was more rapid and accompanied by significantly reduced left ventricular end-diastolic pressure. HOE 642 plus volatile anesthetics produced additive effects, with left ventricular developed pressure recovering by more that 100%, although left ventricular end-diastolic pressure was not further reduced. Sufentanil had no effect in terms of developed pressure, but protection with HOE 642 was maintained. HOE 642 with or without volatile anesthetics also preserved adenosine triphosphate levels.


CONCLUSIONS
Isoflurane, sevoflurane, and HOE 642 enhance ventricular recovery, but the effect of HOE 642 is also associated with reduced contracture and adenosine triphosphate preservation. A combination of the NHE inhibitor and either volatile agent confers additive and superior protection, which could be relevant for the establishment of ideal cardioprotective strategies during surgery.
Mathur
S
S
Department of Pharmacology, University of Western Ontario, London, Canada.
Karmazyn
M
M
D018685:Anesthetics, Inhalation / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D004987:Ethers / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D008738:Methyl Ethers; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D017409:Sufentanil / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D004987:Ethers; D006146:Guanidines; D008738:Methyl Ethers; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D000077149:Sevoflurane; C093373:cariporide; D017409:Sufentanil; D007530:Isoflurane