TIME-COURSE OF A NEW ULTRASHORT-ACTING BETA-ADRENOCEPTOR-BLOCKING DRUG, ONO-1101 - COMPARISON WITH THOSE OF ESMOLOL AND PROPRANOLOL BY USING THE CANINE ISOLATED, BLOOD-PERFUSED HEART PREPARATIONS

Time courses of beta-adrenoceptor-blocking actions of ONO-1101, a new cardioselective beta-blocker, were compared with those of esmolol and propranolol by using the isolated, blood-perfused sinoatrial node (SAN ) and papillary muscle (PM) preparations of dogs. ONO-1101 per se give n intraarterially (i.a.) in each nutrient artery did not affect basal sinoatrial rates (SARs; 99 +/- 2 beats/min, n = 7) in the SAN and deve loped tension (DT; 3.2 +/- 0.7 g, n = 7) of the PM preparations. Norep inephrine (NE) injected i.a. into the each artery induced increases in SAR (42 +/- 6 beats/min at 0.051 +/- 0.014 mu g) and PMDT (2.9 +/- 0. 4 g at 0.048 +/- 0.011 mu g). The i.a. injections of NE were repeated every 3 min after i.v. bolus injections of ONO-1101 into the support d og. NE-induced increases in SAR and PMDT were maximally inhibited 3 to 6 min after the i.v. injections of ONO-1101. Maximal percent age inhi bitions by ONO-1101 of NE-induced increases in SAR were 54 +/- 6, 78 /- 3, and 96 +/- 2% at 0.01, 0.1, and 1 mg/kg of the drug, respectivel y. Similarly, maximal percentage inhibitions by ONO-1101 of NE-induced increases in PMDT were 50 +/- 12, 93 +/- 2, and 100% +/- 0, respectiv ely. The inhibition was quickly recovered; times required for 50% reco very (RT1/2) were 12 +/- 3, 17 +/- 3, and 32 +/- 10 min in the SAN pre paration, and 13 +/- 3, 16 +/- 2, and 39 +/- 11 min in the PM preparat ions, after i.v. injections of 0.01, 0.1, and 1 mg/kg of ONO-1101, res pectively. In comparison, maximal percentage inhibitions by esmolol of NE-induced increases in SAR were 45 +/- 5, 79 +/- 6, and 96 +/- 2%, a nd those in PMDT were 34 +/- 4, 75 +/- 5, and 97 +/- 1%, whereas the R T1/2 values were 11 +/- 2, 15 +/- 4, and 40 +/- 12 min in the SAN prep aration, and 10 +/- 2, 16 +/- 7, and 27 +/- 6 min in the PM preparatio ns, after i.v. injections of 0.01, 0.1, and 1 mg/kg of esmolol, respec tively. In contrast, the maximal percentage inhibitions by an i.v. bol us injection of 0.1 mg/kg of propranolol of NE-induced increases in SA R and PMDT were 77 +/- 18% and 87 +/- 13% (n = 4). respectively. The m aximal inhibitions were obtained 6-15 min after injections of proprano lol and then slowly recovered only by 21% in the SAN and 8% in the PM preparations, even after 60 min. These results clearly demonstrate tha t ONO-1101 is an ultrashort-acting beta-blocker, but the recovery time is dose dependent, and that the beta-blocking action of ONO-1101 is a lmost similar to or slightly more potent (or both) than esmolol.