Hoe 694, a new Na+/H+ exchange inhibitor and its effects in cardiac ischaemia.
1. The benzoylguanidine derivative Hoe 694 ((3-methylsulphonyl-4- piperidino-benzoyl) guanidine methanesulphonate) was characterized as an inhibitor of Na+/H+ exchange in rabbit erythrocytes, rat platelets and bovine endothelial cells. The potency of the compound was slightly lower or comparable to ethylisopropyl amiloride (EIPA). 2. To investigate a possible cardioprotective role of the Na+/H+ exchange inhibitor Hoe 694, rat isolated working hearts were subjected to ischaemia and reperfusion. In these experiments all untreated hearts suffered ventricular fibrillation on reperfusion. Addition of 10(-7) M Hoe 694 to the perfusate almost abolished reperfusion arrhythmias in the rat isolated working hearts. 3. Hoe 694 reduced the release of lactate dehydrogenase (LDH) and creatine kinase (CK), which are indicators of cellular damage during ischaemia, into the venous effluent of the hearts by 60% and 54%, respectively. 4. The tissue content of glycogen at the end of the experiments was increased by 60% and the high energy phosphates ATP and creatine phosphate were increased by 240% and 270% respectively in the treated hearts as compared to control hearts. 5. Antiischaemic effects of the Na+/H+ exchange inhibitor, Hoe 694, were investigated in a second experiment in anaesthetized rats undergoing coronary artery ligation. In these animals, pretreatment with Hoe 694 caused a dose-dependent reduction of ventricular premature beats and ventricular tachycardia as well as a complete suppression of ventricular fibrillation down to doses of 0.1 mg kg-1, i.v. Blood pressure and heart rate remained unchanged. 6. We conclude that the new Na+/H+ exchange inhibitor, Hoe 694, shows cardioprotective and antiarrhythmic effects in ischaemia and reperfusion in rat isolated hearts and in anaesthetized rats. In view of the role which Na+/H+ exchange seems to play in the pathophysiology of cardiac ischaemia these effects could probably be attributed to Na+/H+ exchange inhibition.
Scholz
W
W
Hoechst AG, Frankfurt/M, Germany.
Albus
U
U
Lang
H J
HJ
Linz
W
W
Martorana
P A
PA
Englert
H C
HC
Schölkens
B A
BA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002417:Cattle; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007474:Ion Exchange; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D010725:Phosphocreatine / Q000378:metabolism; D011188:Potassium / Q000097:blood / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012964:Sodium / Q000097:blood / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use
D006146:Guanidines; D013450:Sulfones; D010725:Phosphocreatine; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D000584:Amiloride; D000255:Adenosine Triphosphate; D006003:Glycogen; D012964:Sodium; D011188:Potassium; C039614:ethylisopropylamiloride