Novel cardioprotective effects of TYB-3823 on ischemic damage in the working hearts of rats: comparison with lidocaine.
The cardioprotective effects of a new antiarrhythmic drug, TYB-3823 [1-(2,6-dimethylphenyl)-dimethylaminoguanidine hydrochloride] were examined in the working hearts of rats and compared with those of lidocaine. Before ischemia, TYB-3823 at 5 x 10(-5) M produced a slight negative inotropic effect, resulting in a decrease in aortic flow and cardiac output. However, at lower concentrations (10(-6) and 10(-5) M), the drug had no significant effect on the functional cardiac parameters before ischemia. Lidocaine at such concentrations also had no effect. Global ischemia for 15 min decreased cardiac function rapidly which only recovered partially, with a delay, after reperfusion in the control hearts. Treatment with TYB-3823 accelerated the time course of recovery during reperfusion markedly, significantly improving functional cardiac parameters. However, lidocaine had little effect on recovery of function. Reperfusion-induced arrhythmia was equipotently inhibited by TYB-3823 and lidocaine. Leakage of cytosolic enzymes (lactate dehydrogenase, creatine phosphokinase and alpha-hydroxybutylic dehydrogenase) during reperfusion was inhibited more effectively by TYB-3823 than lidocaine. Light microscopic and electron microscopic examinations revealed that treatment with TYB-3823 protected against the histological damage induced by ischemia, such as hyaline degeneration of myocardium, absence of cross-striation and swelling of mitochondria. These results suggest that, unlike lidocaine, TYB-3823 causes a novel cardioprotective effect through unknown mechanisms in addition to its antiarrhythmic action.
Ohmura
T
T
Department of Pharmacology, Fukui Medical School, Japan.
Muramatsu
I
I
Kigoshi
S
S
Noguchi
H
H
Muraoka
R
R
Komoriya
Y
Y
Hayashi
H
H
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003402:Creatine Kinase / Q000378:metabolism; D006146:Guanidines / Q000627:therapeutic use*; D006884:Hydroxybutyrate Dehydrogenase / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008012:Lidocaine / Q000627:therapeutic use*; D008297:Male; D015425:Myocardial Reperfusion; D051381:Rats; D011919:Rats, Inbred Strains
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; C059816:restacorin; D008012:Lidocaine; D007770:L-Lactate Dehydrogenase; D006884:Hydroxybutyrate Dehydrogenase; D003402:Creatine Kinase